Clincosm LogoSign in Get a demo

A Study MLN2480 in Combination With MLN0128 or Alisertib, or Paclitaxel, or Cetuximab, or Irinotecan in Adult Participants With Advanced Nonhematologic Malignancies

Sponsor
Millennium Pharmaceuticals, Inc. (Industry)
Overall Status
Completed
CT.gov ID
NCT02327169
Collaborator
(none)
81
Enrollment
14
Locations
6
Arms
41.6
Actual Duration (Months)
5.8
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The primary purpose of this study is to determine the safety profile and the maximum tolerated doses (MTDs)/ potential recommended phase 2 doses (RP2Ds) of the combination treatments of MLN2480 + MLN0128, MLN2480 + alisertib, MLN2480 + paclitaxel, MLN2480 + cetuximab, and MLN2480 + irinotecan in participants with advanced nonhematologic malignancies.

Condition or Disease Intervention/Treatment Phase
Phase 1

Detailed Description

The drug being tested in this study is called MLN2480 (TAK-580). MLN2480 was tested to evaluate side effects and determine the maximum tolerated dose (MTD) and recommended dose for future studies when administered in combination with five other medications. This study was to assess the safety of MLN2480 as well as how it is processed by the body in participants with solid nonhematologic malignancies who have failed standard therapies.

The study was to be conducted in two phases, the dose escalation phase and the dose expansion phase. A total of 71 participants were enrolled in the escalation phase. Participants in this phase were assigned to one of the five treatment groups:

  • MLN2480 + MLN0128

  • MLN2480 + Alisertib

  • MLN2480 + Paclitaxel

  • MLN2480 + Cetuximab

  • MLN2480 + Irinotecan

Once the MTD for each combination treatment arm was established in the escalation phase, one or more of the combination treatments will be selected for the expansion phase. A total of 10 participants were enrolled in the expansion phase.

This multi-centre trial was be conducted worldwide. The overall time to participate in this study is approximately 14 months. Participants made multiple visits to the clinic including an end of study visit 30 days after last dose of study drug for a follow-up assessment.

Study Design

Study Type:
Interventional
Actual Enrollment :
81 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Multiarm, Open-label, Phase 1b Study of MLN2480 (an Oral A-, B-, and CRAF Inhibitor) in Combination With MLN0128 (an Oral mTORC 1/2 Inhibitor), or Alisertib (an Oral Aurora A Kinase Inhibitor), or Paclitaxel, or Cetuximab, or Irinotecan, in Adult Patients With Advanced Nonhematologic Malignancies
Actual Study Start Date :
Jan 14, 2015
Actual Primary Completion Date :
Jul 2, 2018
Actual Study Completion Date :
Jul 2, 2018

Arms and Interventions

Arm Intervention/Treatment
Experimental: MLN2480 + MLN0128

Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles.

Drug: MLN2480
MLN2480 tablets.
Other Names:
  • TAK-580

    • Drug: MLN0128
    MLN0128 capsules.
    Experimental: MLN2480 + Alisertib

    Dose Escalation Phase: MLN2480 100-200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30-40 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.

    Drug: MLN2480
    MLN2480 tablets.
    Other Names:
  • TAK-580

    • Drug: Alisertib
    Alisertib tablets.
    Experimental: MLN2480 + Paclitaxel

    Dose Escalation Phase: MLN2480 100-200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 milligram per square meter (mg/m^2), intravenous (IV) infusion, once weekly (QW) for 3 weeks in each 28-day cycle for up to 12 cycles or MLN2480 400-600 mg tablets, orally, QW on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care.

    Drug: MLN2480
    MLN2480 tablets.
    Other Names:
  • TAK-580

    • Drug: Paclitaxel
    Paclitaxel IV infusion.
    Experimental: MLN2480 + Cetuximab

    Dose Escalation Phase: MLN2480 400-600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and cetuximab administered intravenously at a loading dose of 400 mg/m^2 (cycle 1 Day 1), then at 250 mg/m^2 QW on Days 8, 15, and 22 of cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose was based on the standard of care.

    Drug: MLN2480
    MLN2480 tablets.
    Other Names:
  • TAK-580

    • Drug: Cetuximab
    Cetuximab IV infusion.
    Experimental: ML2480 + Irinotecan

    Dose Escalation Phase: MLN2480 400-600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and irinotecan 180 mg/m^2, IV infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose was based on the standard of care.

    Drug: MLN2480
    MLN2480 tablets.
    Other Names:
  • TAK-580

    • Drug: Irinotecan
    Irinotecan IV infusion.
    Experimental: MLN2480 600 mg + Paclitaxel 80 mg (Dose Expansion Phase)

    Dose Expansion Phase: MLN2480 600 mg, tablets, orally, once per week on Days 2, 9, 16 and 23 of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg, capsules, orally, once on 1, 8, and 15 of a 28-day cycle for up to 12 cycles.

    Drug: MLN2480
    MLN2480 tablets.
    Other Names:
  • TAK-580

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [From Day 1, Cycle 1 through 30 days after the last dose of study drug (up to 13 months)]

      An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with this treatment. An SAE means any untoward medical occurrence that at any dose results in death, is life-threatening, requires in patient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or is a medically important event.

    2. Number of Participants With Dose-Limiting Toxicities (DLTs) [From Day 1, Cycle 1 through 30 days after the last dose in Cycle 1 (up to 8 weeks)]

      DLT was defined using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 and included: any drug-related hematologic toxicity ≥Grade 4 with the exception of Grade 4 neutropenia <7 days duration; Grade 3 or 4 neutropenia with fever >38.5 degrees Celsius and/or infection or neutropenia requiring colony-stimulating factor OR non-hematologic DLTs that were any Grade 3, 4, or 5 toxicity with the following exceptions: Grade 3 nausea, vomiting, diarrhea, and dehydration occurring in a setting of inadequate treatment; inadequately treated hypersensitivity reactions; Grade 3 elevated transaminases or urine electrolyte abnormality ≤1 week in duration; Grade 3 serum electrolyte abnormality ≤72 hours in duration. DLTs also included: drug-related adverse experience that lead to a dose modification; unresolved drug-related toxicity resulted in delay in initiation of Cycle 2.

    3. Maximum Tolerated Dose (MTD) for MLN2480 [Day 1, Cycle 1 up to 28 days]

    4. Recommended Phase 2 Dose (RP2D) of MLN2480 [Day 1, Cycle 1 up to 28 days]

    Secondary Outcome Measures

    1. Cmax : Maximum Observed Plasma Concentration for MLN2480 [Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose]

    2. Cmax: Maximum Observed Plasma Concentration for MLN0128 [Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose]

    3. Cmax: Maximum Observed Plasma Concentration for Alisertib [Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose]

    4. Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN2480 [Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose]

    5. Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0128 [Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose]

    6. Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Alisertib [Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose]

    7. AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for MLN2480 [Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose]

    8. AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for MLN0128 [Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose]

    9. AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for Alisertib [Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose]

    10. Cmax: Maximum Observed Plasma Concentration for Paclitaxel [Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose]

    11. AUC(0-last): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Paclitaxel [Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose]

    12. AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity, Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel [Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose]

    13. Terminal Elimination Half-life (T1/2) for Paclitaxel [Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose]

    14. Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) [Baseline then every 2 cycles beginning at Cycle 2, Day 27, until disease progression, death or end of study (Up to 13 months)]

      ORR was defined as the percentage of participants with complete response (CR) or partial response (PR) using Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. CR: Disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesions.

    15. Duration of Response [From first documented response until disease progression (Up to 13 months)]

      Duration of Response (DOR) was defined as the time in months from the first documented CR or PR per RECIST v. 1.1 to disease recurrence or disease progression (PD) whichever occurs first.

    16. Time to Response [From date of enrollment to the date of the first documentation of a confirmed response (Up to 13 months)]

      Time to response was defined as the time in months from the date of first dose of study treatment to the date of the first documentation of a PR or better response.

    17. Progression Free Survival (PFS) [Baseline then every 2 cycles beginning at Cycle 2, Day 27, until disease progression, death or end of study (Approximately up to 13 months)]

      PFS is defined as the time in months from the date of first study drug administration to the date of first documented PD or death due to any cause. PD was based on response evaluation criteria in solid tumors (RECIST V1.1), defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    All Treatment Arms:

    1. Male or female participants 18 years or older.

    2. Participants who, in the opinion of the treating physician, have failed standard therapies and for whom a phase 1 trial is an appropriate option.

    3. Radiographically or clinically evaluable tumor. For expansion phase: Tumors must be measurable and of the protocol specified genetic mutational status, where applicable.

    4. Recovered (ie, less than or equal to [<=] Grade 1 toxicity) from adverse effects (except alopecia) of prior therapy.

    5. Eastern Cooperative Oncology Group (ECOG) performance status 0-1.

    6. Expected survival time of at least 3 months in the opinion of the investigator.

    7. Block of banked tumor tissue and/or greater than or equal to (>=) 10 unstained slides. Participants who satisfy all other eligibility criteria but do not have banked tissue/slides may be asked to consent to baseline biopsy.

    8. Suitable vein access for the study-required blood sampling.

    9. Thyroid function tests consistent with stable thyroid function. Note: Participants on a stable dose of thyroid replacement therapy for a suggested minimum of 12 weeks before Cycle 1, Day 1 are eligible.

    10. Left ventricular ejection fraction (LVEF) of 50 percent (%) or greater, as measured by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA), within 28 days before the first dose of MLN2480

    11. Female participants who are post-menopausal for at least 1 year, surgically sterile, or agree to practice 2 effective methods of contraception through 120 days (4 months) after the last dose of study drug for participants in Arms 1, 2, and 5, and through 6 months for participants in Arms 3 and 4, or agree to practice true abstinence.

    12. Male participants who, even if surgically sterilized, agree to practice effective barrier contraception through 120 days (4 months) after the last dose of study drug for participants in Arms 1, 2, and 5, and through 6 months for participants in Arms 3, and 4, or agree to practice true abstinence.

    13. Additional inclusion criteria for arm 3 expansion only (MLN2480 + paclitaxel):

    1. Participants with Kirsten rat sarcoma viral oncogene homolog (KRAS) exon 2 or BRAF non-V600 mutation-positive non-small cell lung cancer (NSCLC) who have received a minimum of 1 but not more than 2 prior cytotoxic-approved regimens.
    1. Additional inclusion criteria for arms 4 and 5 expansion only (MLN2480 + cetuximab;
    MLN2480 + irinotecan):
    1. Participants with CRC who have received a minimum of 1 but not more than 2 prior cytotoxic-approved regimens.
    Exclusion Criteria:
    All treatment arms:

    1. Female participants who are pregnant or currently breastfeeding.

    2. History of any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with safe protocol completion.

    3. History of uncontrolled brain metastasis unless: previously treated with surgery, whole-brain radiation, or stereotactic radiosurgery; stable disease for >= 60 days without steroid use (or stable steroid dose established for >= 28 days before the first dose of MLN2480).

    4. Ongoing seizure disorder or a requirement for antiepileptics.

    5. Recent prior therapies, including: chemotherapy and hormonal therapy <= 4 weeks or 4 half lives, whichever occurs first, before administration of study drug; immunotherapy/monoclonal antibody use <= 4 weeks before administration of MLN2480; or radiation therapy <= 3 weeks before administration of study drug.

    6. Chronic therapeutic corticosteroid use with the exception of replacement therapy for adrenal insufficiency or corticosteroid inhalers.

    7. Known history of human immunodeficiency virus infection, hepatitis B, or hepatitis C; Prior allogeneic bone marrow or organ transplantation, or active condition of chronic immune suppression is not allowed.

    8. Concomitant use, or administration <= 14 days before first dose of study drug(s), of clinically significant enzyme inducers.

    9. Treatment with gemfibrozil (strong Cytochrome P4502C8 [CYP2C8] inhibitor) within 14 days before the first dose of MLN2480.

    10. History of or current illicit drug use, drug abuse, or alcohol abuse.

    11. Major surgery within 14 days before the first dose of study drug.

    12. Inability to comply with study requirements.

    13. Other unspecified reasons that, in the opinion of the investigator or Millennium, make the participant unsuitable for enrollment.

    14. Additional exclusion criteria for arms 3, 5, and 6 expansion only (MLN2480 + paclitaxel; MLN2480 + irinotecan; MLN2480 monotherapy):

    1. Prior treatment with rapidly accelerated fibrosarcoma (RAF), extracellular signal-regulated kinases (MEK), or other inhibitors of the mitogen-activated protein kinase (MAPK) pathway.
    1. Additional exclusion criteria for arm 2 only (MLN2480 + alisertib):
    1. History of uncontrolled sleep apnea syndrome and other conditions that could result in excessive daytime sleepiness, such as severe chronic obstructive pulmonary disease.
    1. Additional exclusion criteria for arm 3 only (MLN2480 + paclitaxel):
    1. Known hypersensitivity to paclitaxel, or its components or other drugs formulated in Cremophor® EL (polyoxyethylated castor oil).

    1. Additional exclusion criteria for arm 5 only (MLN2480 + irinotecan):

    2. Use of strong or moderate Cytochrome P4503A (CYP3A) inhibitors <= days of the first dose of irinotecan.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Massachusetts General Hospital Cancer Center Boston Massachusetts United States 2114
    2 Beth Israel Deaconess Medical Center Boston Massachusetts United States 2115
    3 Dana Farber Cancer Institute Boston Massachusetts United States 2115
    4 Fox Chase Cancer Center Philadelphia Pennsylvania United States 19111
    5 The University of Texas MD Anderson Cancer Center Houston Texas United States 77030
    6 Institut Bergonie Bordeaux cedex Gironde France 33076
    7 Institut Claudius Regaud-Oncopole Toulouse cedex 09 Haute Garonne France 31059
    8 Institut Gustave Roussy Villejuif cedex Val De Marne France 94805
    9 Hospital Universitari Vall d'Hebron Barcelona Spain 8035
    10 START Madrid. Fundacion Jimenez Diaz Madrid Spain 28040
    11 Hospital Clinico Universitario Virgen de la Victoria Malaga Spain 29010
    12 Sarah Cannon Research Institure UK London Greater London United Kingdom W1G 6AD
    13 The Chrisie Manchester Greater Manchester United Kingdom M20 4BX
    14 Churchill Hospital Oxford Oxfordshire United Kingdom OX3 7LJ

    Sponsors and Collaborators

    • Millennium Pharmaceuticals, Inc.

    Investigators

    • Study Director: Medical Director Clinical Science, Takeda

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Millennium Pharmaceuticals, Inc.
    ClinicalTrials.gov Identifier:
    NCT02327169
    Other Study ID Numbers:
    • C28002
    • 2014-003340-12
    • U1111-1159-5831
    First Posted:
    Dec 30, 2014
    Last Update Posted:
    Feb 25, 2020
    Last Verified:
    Feb 1, 2020
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Millennium Pharmaceuticals, Inc.
    Drug therapy
    Additional relevant MeSH terms:
    Neoplasms
    Paclitaxel
    Irinotecan
    Cetuximab

    Study Results

    Participant Flow

    Recruitment Details Participants took part in the study at 14 investigative sites in the United States, France, Spain, and United Kingdom from 14 September 2016 to 02 July 2018.
    Pre-assignment Detail Participants with a diagnosis of advanced nonhematologic malignancies were enrolled in one of the five arm groups: MLN2480 + MLN0128, MLN2480 + Alisertib, MLN2480 + Paclitaxel, MLN2480 + Cetuximab, MLN2480 + Irinotecan.
    Arm/Group Title MLN2480 100 mg + MLN0128 2 mg MLN2480 100 mg + Alisertib 30 mg MLN2480 160 mg + Alisertib 30 mg MLN2480 200 mg + Alisertib 30 mg MLN2480 100 mg + Alisertib 40 mg MLN2480 100 mg + Paclitaxel 80 mg/m^2 MLN2480 160 mg + Paclitaxel 80 mg/m^2 MLN2480 200 mg + Paclitaxel 80 mg/m^2 MLN2480 400 mg + Paclitaxel 80 mg/m^2 MLN2480 600 mg + Paclitaxel 80 mg/m^2 MLN2480 400 mg + Cetuximab 250 mg/m^2 MLN2480 600 mg + Cetuximab 250 mg/m^2 ML2480 300 mg + Irinotecan 180 mg/m^2 ML2480 400 mg + Irinotecan 180 mg/m^2 Dose Expansion: MLN2480 600 mg + Paclitaxel 80 mg/m^2
    Arm/Group Description Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 40 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 milligram per square meter (mg/m^2), intravenous (IV) infusion, once weekly (QW) for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and cetuximab administered intravenously at a loading dose of 400 mg/m^2 (cycle 1 Day 1), then at 250 mg/m^2 QW on Days 8, 15, and 22 of cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose was based on the standard of care. Dose Escalation Phase: MLN2480 600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and cetuximab administered intravenously at a loading dose of 400 mg/m^2 (cycle 1 Day 1), then at 250 mg/m^2 QW on Days 8, 15, and 22 of cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose was based on the standard of care. Dose Escalation Phase: MLN2480 300 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and irinotecan 180 mg/m^2, IV infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and irinotecan 180 mg/m^2, IV infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose was based on the standard of care. Dose Expansion Phase: MLN2480 600 mg, tablets, orally, once per week on Days 2, 9, 16 and 23 of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, once on 1, 8, and 15 of a 28-day cycle for up to 12 cycles.
    Period Title: Overall Study
    STARTED 4 3 7 3 8 4 3 4 6 8 6 7 1 7 10
    COMPLETED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
    NOT COMPLETED 4 3 7 3 8 4 3 4 6 8 6 7 1 7 10

    Baseline Characteristics

    Arm/Group Title MLN2480 100 mg + MLN0128 2 mg MLN2480 100 mg + Alisertib 30 mg MLN2480 160 mg + Alisertib 30 mg MLN2480 200 mg + Alisertib 30 mg MLN2480 100 mg + Alisertib 40 mg MLN2480 100 mg + Paclitaxel 80 mg/m^2 MLN2480 160 mg + Paclitaxel 80 mg/m^2 MLN2480 200 mg + Paclitaxel 80 mg/m^2 MLN2480 400 mg + Paclitaxel 80 mg/m^2 MLN2480 600 mg + Paclitaxel 80 mg/m^2 MLN2480 400 mg + Cetuximab 250 mg/m^2 MLN2480 600 mg + Cetuximab 250 mg/m^2 ML2480 300 mg + Irinotecan 180 mg/m^2 ML2480 400 mg + Irinotecan 180 mg/m^2 Dose Expansion: MLN2480 600 mg + Paclitaxel 80 mg/m^2 Total
    Arm/Group Description Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 40 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 milligram per square meter (mg/m^2), intravenous (IV) infusion, once weekly (QW) for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and cetuximab administered intravenously at a loading dose of 400 mg/m^2 (cycle 1 Day 1), then at 250 mg/m^2 QW on Days 8, 15, and 22 of cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose was based on the standard of care. Dose Escalation Phase: MLN2480 600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and cetuximab administered intravenously at a loading dose of 400 mg/m^2 (cycle 1 Day 1), then at 250 mg/m^2 QW on Days 8, 15, and 22 of cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose was based on the standard of care. Dose Escalation Phase: MLN2480 300 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and irinotecan 180 mg/m^2, IV infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and irinotecan 180 mg/m^2, IV infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose was based on the standard of care. Dose Expansion Phase: MLN2480 600 mg, tablets, orally, once per week on Days 2, 9, 16 and 23 of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, once on 1, 8, and 15 of a 28-day cycle for up to 12 cycles. Total of all reporting groups
    Overall Participants 4 3 7 3 8 4 3 4 6 8 6 7 1 7 10 81
    Age (years) [Mean (Full Range) ]
    Mean (Full Range) [years]
    57.5
    48.0
    60.9
    51.0
    68.0
    66.0
    60.3
    70.0
    54.2
    65.9
    52.8
    60.1
    62.0
    62.3
    63.9
    62.3
    Sex: Female, Male (Count of Participants)
    Female
    3
    75%
    3
    100%
    4
    57.1%
    1
    33.3%
    6
    75%
    2
    50%
    2
    66.7%
    3
    75%
    5
    83.3%
    4
    50%
    2
    33.3%
    4
    57.1%
    0
    0%
    3
    42.9%
    5
    50%
    47
    58%
    Male
    1
    25%
    0
    0%
    3
    42.9%
    2
    66.7%
    2
    25%
    2
    50%
    1
    33.3%
    1
    25%
    1
    16.7%
    4
    50%
    4
    66.7%
    3
    42.9%
    1
    100%
    4
    57.1%
    5
    50%
    34
    42%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    0
    0%
    0
    0%
    0
    0%
    1
    33.3%
    0
    0%
    0
    0%
    1
    33.3%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    2
    2.5%
    Not Hispanic or Latino
    4
    100%
    3
    100%
    7
    100%
    0
    0%
    8
    100%
    3
    75%
    1
    33.3%
    4
    100%
    5
    83.3%
    7
    87.5%
    5
    83.3%
    4
    57.1%
    1
    100%
    7
    100%
    6
    60%
    65
    80.2%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    2
    66.7%
    0
    0%
    1
    25%
    1
    33.3%
    0
    0%
    1
    16.7%
    1
    12.5%
    1
    16.7%
    3
    42.9%
    0
    0%
    0
    0%
    4
    40%
    14
    17.3%
    Race/Ethnicity, Customized (Count of Participants)
    White
    4
    100%
    3
    100%
    6
    85.7%
    1
    33.3%
    8
    100%
    4
    100%
    2
    66.7%
    4
    100%
    3
    50%
    6
    75%
    6
    100%
    4
    57.1%
    1
    100%
    7
    100%
    5
    50%
    64
    79%
    Black or African American
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    33.3%
    0
    0%
    1
    16.7%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    2
    2.5%
    Other
    0
    0%
    0
    0%
    1
    14.3%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    16.7%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    10%
    3
    3.7%
    Not Reported
    0
    0%
    0
    0%
    0
    0%
    2
    66.7%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    16.7%
    2
    25%
    0
    0%
    3
    42.9%
    0
    0%
    0
    0%
    4
    40%
    12
    14.8%
    Height (centimetres (cm)) [Mean (Full Range) ]
    Mean (Full Range) [centimetres (cm)]
    168.9
    163.4
    166.7
    160.3
    164.5
    167.0
    167.7
    166.3
    159.7
    167.3
    169.8
    167.4
    182.5
    172.3
    162.7
    164.7
    Weight (kilograms (kg)) [Mean (Full Range) ]
    Mean (Full Range) [kilograms (kg)]
    71.55
    80.53
    84.62
    74.15
    63.59
    86.63
    77.40
    65.45
    67.92
    65.79
    76.22
    71.39
    86.50
    74.97
    67.65
    70.31
    Body Surface Area (BSA) (square meters (m^2)) [Mean (Full Range) ]
    Mean (Full Range) [square meters (m^2)]
    1.818
    1.906
    1.961
    1.817
    1.698
    2.003
    1.884
    1.732
    1.726
    1.738
    1.893
    1.814
    2.094
    1.925
    1.740
    1.846

    Outcome Measures

    1. Primary Outcome
    Title Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
    Description An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with this treatment. An SAE means any untoward medical occurrence that at any dose results in death, is life-threatening, requires in patient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or is a medically important event.
    Time Frame From Day 1, Cycle 1 through 30 days after the last dose of study drug (up to 13 months)

    Outcome Measure Data

    Analysis Population Description
    Safety population was defined as all participants who received any amount of MLN2480.
    Arm/Group Title MLN2480 100 mg + MLN0128 2 mg MLN2480 100 mg + Alisertib 30 mg MLN2480 160 mg + Alisertib 30 mg MLN2480 200 mg + Alisertib 30 mg MLN2480 100 mg + Alisertib 40 mg MLN2480 100 mg + Paclitaxel 80 mg/m^2 MLN2480 160 mg + Paclitaxel 80 mg/m^2 MLN2480 200 mg + Paclitaxel 80 mg/m^2 MLN2480 400 mg + Paclitaxel 80 mg/m^2 MLN2480 600 mg + Paclitaxel 80 mg/m^2 MLN2480 400 mg + Cetuximab 250 mg/m^2 MLN2480 600 mg + Cetuximab 250 mg/m^2 ML2480 300 mg + Irinotecan 180 mg/m^2 ML2480 400 mg + Irinotecan 180 mg/m^2 Dose Expansion: MLN2480 600 mg + Paclitaxel 80 mg/m^2
    Arm/Group Description Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 40 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 milligram per square meter (mg/m^2), intravenous (IV) infusion, once weekly (QW) for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and cetuximab administered intravenously at a loading dose of 400 mg/m^2 (cycle 1 Day 1), then at 250 mg/m^2 QW on Days 8, 15, and 22 of cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose was based on the standard of care. Dose Escalation Phase: MLN2480 600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and cetuximab administered intravenously at a loading dose of 400 mg/m^2 (cycle 1 Day 1), then at 250 mg/m^2 QW on Days 8, 15, and 22 of cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose was based on the standard of care. Dose Escalation Phase: MLN2480 300 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and irinotecan 180 mg/m^2, IV infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and irinotecan 180 mg/m^2, IV infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose was based on the standard of care. Dose Expansion Phase: MLN2480 600 mg, tablets, orally, once per week on Days 2, 9, 16 and 23 of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, once on 1, 8, and 15 of a 28-day cycle for up to 12 cycles.
    Measure Participants 4 3 7 3 8 4 3 4 6 8 6 7 1 7 10
    AEs
    4
    100%
    3
    100%
    7
    100%
    3
    100%
    8
    100%
    4
    100%
    3
    100%
    4
    100%
    6
    100%
    8
    100%
    6
    100%
    7
    100%
    1
    100%
    7
    100%
    10
    100%
    SAEs
    2
    50%
    1
    33.3%
    5
    71.4%
    1
    33.3%
    3
    37.5%
    1
    25%
    1
    33.3%
    2
    50%
    3
    50%
    4
    50%
    2
    33.3%
    3
    42.9%
    0
    0%
    4
    57.1%
    7
    70%
    2. Primary Outcome
    Title Number of Participants With Dose-Limiting Toxicities (DLTs)
    Description DLT was defined using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 and included: any drug-related hematologic toxicity ≥Grade 4 with the exception of Grade 4 neutropenia <7 days duration; Grade 3 or 4 neutropenia with fever >38.5 degrees Celsius and/or infection or neutropenia requiring colony-stimulating factor OR non-hematologic DLTs that were any Grade 3, 4, or 5 toxicity with the following exceptions: Grade 3 nausea, vomiting, diarrhea, and dehydration occurring in a setting of inadequate treatment; inadequately treated hypersensitivity reactions; Grade 3 elevated transaminases or urine electrolyte abnormality ≤1 week in duration; Grade 3 serum electrolyte abnormality ≤72 hours in duration. DLTs also included: drug-related adverse experience that lead to a dose modification; unresolved drug-related toxicity resulted in delay in initiation of Cycle 2.
    Time Frame From Day 1, Cycle 1 through 30 days after the last dose in Cycle 1 (up to 8 weeks)

    Outcome Measure Data

    Analysis Population Description
    The DLT-evaluable population was defined as all participants in the dose escalation phase of the study who either experienced DLT during cycle 1, or completed at least 75% of the scheduled doses in cycle 1 without DLT.
    Arm/Group Title MLN2480 100 mg + MLN0128 2 mg MLN2480 100 mg + Alisertib 30 mg MLN2480 160 mg + Alisertib 30 mg MLN2480 200 mg + Alisertib 30 mg MLN2480 100 mg + Alisertib 40 mg MLN2480 100 mg + Paclitaxel 80 mg/m^2 MLN2480 160 mg + Paclitaxel 80 mg/m^2 MLN2480 200 mg + Paclitaxel 80 mg/m^2 MLN2480 400 mg + Paclitaxel 80 mg/m^2 MLN2480 600 mg + Paclitaxel 80 mg/m^2 MLN2480 400 mg + Cetuximab 250 mg/m^2 MLN2480 600 mg + Cetuximab 250 mg/m^2 ML2480 300 mg + Irinotecan 180 mg/m^2 ML2480 400 mg + Irinotecan 180 mg/m^2 Dose Expansion: MLN2480 600 mg + Paclitaxel 80 mg/m^2
    Arm/Group Description Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 40 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 milligram per square meter (mg/m^2), intravenous (IV) infusion, once weekly (QW) for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and cetuximab administered intravenously at a loading dose of 400 mg/m^2 (cycle 1 Day 1), then at 250 mg/m^2 QW on Days 8, 15, and 22 of cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose was based on the standard of care. Dose Escalation Phase: MLN2480 600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and cetuximab administered intravenously at a loading dose of 400 mg/m^2 (cycle 1 Day 1), then at 250 mg/m^2 QW on Days 8, 15, and 22 of cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose was based on the standard of care. Dose Escalation Phase: MLN2480 300 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and irinotecan 180 mg/m^2, IV infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and irinotecan 180 mg/m^2, IV infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose was based on the standard of care. Dose Expansion Phase: MLN2480 600 mg, tablets, orally, once per week on Days 2, 9, 16 and 23 of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, once on 1, 8, and 15 of a 28-day cycle for up to 12 cycles.
    Measure Participants 4 3 7 3 8 8 3 4 6 8 6 7 1 7 10
    Count of Participants [Participants]
    1
    25%
    0
    0%
    0
    0%
    0
    0%
    1
    12.5%
    0
    0%
    0
    0%
    0
    0%
    1
    16.7%
    1
    12.5%
    0
    0%
    1
    14.3%
    0
    0%
    1
    14.3%
    1
    10%
    3. Primary Outcome
    Title Maximum Tolerated Dose (MTD) for MLN2480
    Description
    Time Frame Day 1, Cycle 1 up to 28 days

    Outcome Measure Data

    Analysis Population Description
    The DLT-evaluable population was defined as all participants in the dose escalation phase of the study who either experienced DLT during cycle 1, or completed at least 75% of the scheduled doses in cycle 1 without DLT.
    Arm/Group Title MLN2480 100 mg + MLN0128 2 mg MLN2480 100 mg + Alisertib 30 mg MLN2480 160 mg + Alisertib 30 mg MLN2480 200 mg + Alisertib 30 mg MLN2480 100 mg + Alisertib 40 mg MLN2480 100 mg + Paclitaxel 80 mg/m^2 MLN2480 160 mg + Paclitaxel 80 mg/m^2 MLN2480 200 mg + Paclitaxel 80 mg/m^2 MLN2480 400 mg + Paclitaxel 80 mg/m^2 MLN2480 600 mg + Paclitaxel 80 mg/m^2 MLN2480 400 mg + Cetuximab 250 mg/m^2 MLN2480 600 mg + Cetuximab 250 mg/m^2 ML2480 300 mg + Irinotecan 180 mg/m^2 ML2480 400 mg + Irinotecan 180 mg/m^2 Dose Expansion: MLN2480 600 mg + Paclitaxel 80 mg/m^2
    Arm/Group Description Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 40 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 milligram per square meter (mg/m^2), intravenous (IV) infusion, once weekly (QW) for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and cetuximab administered intravenously at a loading dose of 400 mg/m^2 (cycle 1 Day 1), then at 250 mg/m^2 QW on Days 8, 15, and 22 of cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose was based on the standard of care. Dose Escalation Phase: MLN2480 600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and cetuximab administered intravenously at a loading dose of 400 mg/m^2 (cycle 1 Day 1), then at 250 mg/m^2 QW on Days 8, 15, and 22 of cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose was based on the standard of care. Dose Escalation Phase: MLN2480 300 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and irinotecan 180 mg/m^2, IV infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and irinotecan 180 mg/m^2, IV infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose was based on the standard of care. Dose Expansion Phase: MLN2480 600 mg, tablets, orally, once per week on Days 2, 9, 16 and 23 of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, once on 1, 8, and 15 of a 28-day cycle for up to 12 cycles.
    Measure Participants 4 3 7 3 8 8 3 4 6 8 6 7 1 7 10
    Number [mg]
    NA
    NA
    NA
    NA
    NA
    NA
    NA
    NA
    NA
    600
    NA
    NA
    NA
    NA
    NA
    4. Primary Outcome
    Title Recommended Phase 2 Dose (RP2D) of MLN2480
    Description
    Time Frame Day 1, Cycle 1 up to 28 days

    Outcome Measure Data

    Analysis Population Description
    The DLT-evaluable population was defined as all participants in the dose escalation phase of the study who either experienced DLT during cycle 1, or completed at least 75% of the scheduled doses in cycle 1 without DLT.
    Arm/Group Title MLN2480 100 mg + MLN0128 2 mg MLN2480 100 mg + Alisertib 30 mg MLN2480 160 mg + Alisertib 30 mg MLN2480 200 mg + Alisertib 30 mg MLN2480 100 mg + Alisertib 40 mg MLN2480 100 mg + Paclitaxel 80 mg/m^2 MLN2480 160 mg + Paclitaxel 80 mg/m^2 MLN2480 200 mg + Paclitaxel 80 mg/m^2 MLN2480 400 mg + Paclitaxel 80 mg/m^2 MLN2480 600 mg + Paclitaxel 80 mg/m^2 MLN2480 400 mg + Cetuximab 250 mg/m^2 MLN2480 600 mg + Cetuximab 250 mg/m^2 ML2480 300 mg + Irinotecan 180 mg/m^2 ML2480 400 mg + Irinotecan 180 mg/m^2 Dose Expansion: MLN2480 600 mg + Paclitaxel 80 mg/m^2
    Arm/Group Description Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 40 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 milligram per square meter (mg/m^2), intravenous (IV) infusion, once weekly (QW) for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and cetuximab administered intravenously at a loading dose of 400 mg/m^2 (cycle 1 Day 1), then at 250 mg/m^2 QW on Days 8, 15, and 22 of cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose was based on the standard of care. Dose Escalation Phase: MLN2480 600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and cetuximab administered intravenously at a loading dose of 400 mg/m^2 (cycle 1 Day 1), then at 250 mg/m^2 QW on Days 8, 15, and 22 of cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose was based on the standard of care. Dose Escalation Phase: MLN2480 300 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and irinotecan 180 mg/m^2, IV infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and irinotecan 180 mg/m^2, IV infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose was based on the standard of care. Dose Expansion Phase: MLN2480 600 mg, tablets, orally, once per week on Days 2, 9, 16 and 23 of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, once on 1, 8, and 15 of a 28-day cycle for up to 12 cycles.
    Measure Participants 4 3 7 3 8 8 3 4 6 8 6 7 1 7 10
    Number [mg]
    NA
    NA
    NA
    NA
    NA
    NA
    NA
    NA
    NA
    600
    NA
    NA
    NA
    NA
    NA
    5. Secondary Outcome
    Title Cmax : Maximum Observed Plasma Concentration for MLN2480
    Description
    Time Frame Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

    Outcome Measure Data

    Analysis Population Description
    The limited PK data did not allow to estimate the PK parameters defined in the protocol.
    Arm/Group Title MLN2480 100 mg + MLN0128 2 mg MLN2480 100 mg + Alisertib 30 mg MLN2480 160 mg + Alisertib 30 mg MLN2480 200 mg + Alisertib 30 mg MLN2480 100 mg + Alisertib 40 mg MLN2480 100 mg + Paclitaxel 80 mg/m^2 MLN2480 160 mg + Paclitaxel 80 mg/m^2 MLN2480 200 mg + Paclitaxel 80 mg/m^2 MLN2480 400 mg + Paclitaxel 80 mg/m^2 MLN2480 600 mg + Paclitaxel 80 mg/m^2 MLN2480 400 mg + Cetuximab 250 mg/m^2 MLN2480 600 mg + Cetuximab 250 mg/m^2 ML2480 300 mg + Irinotecan 180 mg/m^2 ML2480 400 mg + Irinotecan 180 mg/m^2 Dose Expansion: MLN2480 600 mg + Paclitaxel 80 mg/m^2
    Arm/Group Description Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 40 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 milligram per square meter (mg/m^2), intravenous (IV) infusion, once weekly (QW) for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and cetuximab administered intravenously at a loading dose of 400 mg/m^2 (cycle 1 Day 1), then at 250 mg/m^2 QW on Days 8, 15, and 22 of cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose was based on the standard of care. Dose Escalation Phase: MLN2480 600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and cetuximab administered intravenously at a loading dose of 400 mg/m^2 (cycle 1 Day 1), then at 250 mg/m^2 QW on Days 8, 15, and 22 of cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose was based on the standard of care. Dose Escalation Phase: MLN2480 300 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and irinotecan 180 mg/m^2, IV infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and irinotecan 180 mg/m^2, IV infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose was based on the standard of care. Dose Expansion Phase: MLN2480 600 mg, tablets, orally, once per week on Days 2, 9, 16 and 23 of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, once on 1, 8, and 15 of a 28-day cycle for up to 12 cycles.
    Measure Participants 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
    6. Secondary Outcome
    Title Cmax: Maximum Observed Plasma Concentration for MLN0128
    Description
    Time Frame Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

    Outcome Measure Data

    Analysis Population Description
    The limited PK data did not allow to estimate the PK parameters defined in the protocol.
    Arm/Group Title MLN2480 100 mg + MLN0128 2 mg
    Arm/Group Description Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles.
    Measure Participants 0
    7. Secondary Outcome
    Title Cmax: Maximum Observed Plasma Concentration for Alisertib
    Description
    Time Frame Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

    Outcome Measure Data

    Analysis Population Description
    The limited PK data did not allow to estimate the PK parameters defined in the protocol.
    Arm/Group Title MLN2480 100 mg + Alisertib 30 mg MLN2480 160 mg + Alisertib 30 mg MLN2480 200 mg + Alisertib 30 mg MLN2480 100 mg + Alisertib 40 mg
    Arm/Group Description Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 40 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.
    Measure Participants 0 0 0 0
    8. Secondary Outcome
    Title Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN2480
    Description
    Time Frame Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

    Outcome Measure Data

    Analysis Population Description
    The limited PK data did not allow to estimate the PK parameters defined in the protocol.
    Arm/Group Title MLN2480 100 mg + MLN0128 2 mg MLN2480 100 mg + Alisertib 30 mg MLN2480 160 mg + Alisertib 30 mg MLN2480 200 mg + Alisertib 30 mg MLN2480 100 mg + Alisertib 40 mg MLN2480 100 mg + Paclitaxel 80 mg/m^2 MLN2480 160 mg + Paclitaxel 80 mg/m^2 MLN2480 200 mg + Paclitaxel 80 mg/m^2 MLN2480 400 mg + Paclitaxel 80 mg/m^2 MLN2480 600 mg + Paclitaxel 80 mg/m^2 MLN2480 400 mg + Cetuximab 250 mg/m^2 MLN2480 600 mg + Cetuximab 250 mg/m^2 ML2480 300 mg + Irinotecan 180 mg/m^2 ML2480 400 mg + Irinotecan 180 mg/m^2 Dose Expansion: MLN2480 600 mg + Paclitaxel 80 mg/m^2
    Arm/Group Description Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 40 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 milligram per square meter (mg/m^2), intravenous (IV) infusion, once weekly (QW) for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and cetuximab administered intravenously at a loading dose of 400 mg/m^2 (cycle 1 Day 1), then at 250 mg/m^2 QW on Days 8, 15, and 22 of cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose was based on the standard of care. Dose Escalation Phase: MLN2480 600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and cetuximab administered intravenously at a loading dose of 400 mg/m^2 (cycle 1 Day 1), then at 250 mg/m^2 QW on Days 8, 15, and 22 of cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose was based on the standard of care. Dose Escalation Phase: MLN2480 300 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and irinotecan 180 mg/m^2, IV infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and irinotecan 180 mg/m^2, IV infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose was based on the standard of care. Dose Expansion Phase: MLN2480 600 mg, tablets, orally, once per week on Days 2, 9, 16 and 23 of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, once on 1, 8, and 15 of a 28-day cycle for up to 12 cycles.
    Measure Participants 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
    9. Secondary Outcome
    Title Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0128
    Description
    Time Frame Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

    Outcome Measure Data

    Analysis Population Description
    The limited PK data did not allow to estimate the PK parameters defined in the protocol.
    Arm/Group Title MLN2480 100 mg + MLN0128 2 mg
    Arm/Group Description Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles.
    Measure Participants 0
    10. Secondary Outcome
    Title Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Alisertib
    Description
    Time Frame Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

    Outcome Measure Data

    Analysis Population Description
    The limited PK data did not allow to estimate the PK parameters defined in the protocol.
    Arm/Group Title MLN2480 100 mg + Alisertib 30 mg MLN2480 160 mg + Alisertib 30 mg MLN2480 200 mg + Alisertib 30 mg MLN2480 100 mg + Alisertib 40 mg
    Arm/Group Description Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 40 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.
    Measure Participants 0 0 0 0
    11. Secondary Outcome
    Title AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for MLN2480
    Description
    Time Frame Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

    Outcome Measure Data

    Analysis Population Description
    The limited PK data did not allow to estimate the PK parameters defined in the protocol.
    Arm/Group Title MLN2480 100 mg + MLN0128 2 mg MLN2480 100 mg + Alisertib 30 mg MLN2480 160 mg + Alisertib 30 mg MLN2480 200 mg + Alisertib 30 mg MLN2480 100 mg + Alisertib 40 mg MLN2480 100 mg + Paclitaxel 80 mg/m^2 MLN2480 160 mg + Paclitaxel 80 mg/m^2 MLN2480 200 mg + Paclitaxel 80 mg/m^2 MLN2480 400 mg + Paclitaxel 80 mg/m^2 MLN2480 600 mg + Paclitaxel 80 mg/m^2 MLN2480 400 mg + Cetuximab 250 mg/m^2 MLN2480 600 mg + Cetuximab 250 mg/m^2 ML2480 300 mg + Irinotecan 180 mg/m^2 ML2480 400 mg + Irinotecan 180 mg/m^2 Dose Expansion: MLN2480 600 mg + Paclitaxel 80 mg/m^2
    Arm/Group Description Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 40 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 milligram per square meter (mg/m^2), intravenous (IV) infusion, once weekly (QW) for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and cetuximab administered intravenously at a loading dose of 400 mg/m^2 (cycle 1 Day 1), then at 250 mg/m^2 QW on Days 8, 15, and 22 of cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose was based on the standard of care. Dose Escalation Phase: MLN2480 600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and cetuximab administered intravenously at a loading dose of 400 mg/m^2 (cycle 1 Day 1), then at 250 mg/m^2 QW on Days 8, 15, and 22 of cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose was based on the standard of care. Dose Escalation Phase: MLN2480 300 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and irinotecan 180 mg/m^2, IV infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and irinotecan 180 mg/m^2, IV infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose was based on the standard of care. Dose Expansion Phase: MLN2480 600 mg, tablets, orally, once per week on Days 2, 9, 16 and 23 of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, once on 1, 8, and 15 of a 28-day cycle for up to 12 cycles.
    Measure Participants 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
    12. Secondary Outcome
    Title AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for MLN0128
    Description
    Time Frame Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

    Outcome Measure Data

    Analysis Population Description
    The limited PK data did not allow to estimate the PK parameters defined in the protocol.
    Arm/Group Title MLN2480 100 mg + MLN0128 2 mg
    Arm/Group Description Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles.
    Measure Participants 0
    13. Secondary Outcome
    Title AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for Alisertib
    Description
    Time Frame Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

    Outcome Measure Data

    Analysis Population Description
    The limited PK data did not allow to estimate the PK parameters defined in the protocol.
    Arm/Group Title MLN2480 100 mg + Alisertib 30 mg MLN2480 160 mg + Alisertib 30 mg MLN2480 200 mg + Alisertib 30 mg MLN2480 100 mg + Alisertib 40 mg
    Arm/Group Description Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 40 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.
    Measure Participants 0 0 0 0
    14. Secondary Outcome
    Title Cmax: Maximum Observed Plasma Concentration for Paclitaxel
    Description
    Time Frame Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

    Outcome Measure Data

    Analysis Population Description
    The limited PK data did not allow to estimate the PK parameters defined in the protocol.
    Arm/Group Title MLN2480 100 mg + Paclitaxel 80 mg/m^2 MLN2480 160 mg + Paclitaxel 80 mg/m^2 MLN2480 200 mg + Paclitaxel 80 mg/m^2 MLN2480 400 mg + Paclitaxel 80 mg/m^2 MLN2480 600 mg + Paclitaxel 80 mg/m^2 Dose Expansion: MLN2480 600 mg + Paclitaxel 80 mg/m^2
    Arm/Group Description Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 milligram per square meter (mg/m^2), intravenous (IV) infusion, once weekly (QW) for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Expansion Phase: MLN2480 600 mg, tablets, orally, once per week on Days 2, 9, 16 and 23 of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg, capsules, orally, once on 1, 8, and 15 of a 28-day cycle for up to 12 cycles.
    Measure Participants 0 0 0 0 0 0
    15. Secondary Outcome
    Title AUC(0-last): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Paclitaxel
    Description
    Time Frame Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

    Outcome Measure Data

    Analysis Population Description
    The limited PK data did not allow to estimate the PK parameters defined in the protocol.
    Arm/Group Title MLN2480 100 mg + Paclitaxel 80 mg/m^2 MLN2480 160 mg + Paclitaxel 80 mg/m^2 MLN2480 200 mg + Paclitaxel 80 mg/m^2 MLN2480 400 mg + Paclitaxel 80 mg/m^2 MLN2480 600 mg + Paclitaxel 80 mg/m^2 Dose Expansion: MLN2480 600 mg + Paclitaxel 80 mg/m^2
    Arm/Group Description Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 milligram per square meter (mg/m^2), intravenous (IV) infusion, once weekly (QW) for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Expansion Phase: MLN2480 600 mg, tablets, orally, once per week on Days 2, 9, 16 and 23 of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg, capsules, orally, once on 1, 8, and 15 of a 28-day cycle for up to 12 cycles.
    Measure Participants 0 0 0 0 0 0
    16. Secondary Outcome
    Title AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity, Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel
    Description
    Time Frame Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

    Outcome Measure Data

    Analysis Population Description
    The limited PK data did not allow to estimate the PK parameters defined in the protocol.
    Arm/Group Title MLN2480 100 mg + Paclitaxel 80 mg/m^2 MLN2480 160 mg + Paclitaxel 80 mg/m^2 MLN2480 200 mg + Paclitaxel 80 mg/m^2 MLN2480 400 mg + Paclitaxel 80 mg/m^2 MLN2480 600 mg + Paclitaxel 80 mg/m^2 Dose Expansion: MLN2480 600 mg + Paclitaxel 80 mg/m^2
    Arm/Group Description Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 milligram per square meter (mg/m^2), intravenous (IV) infusion, once weekly (QW) for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Expansion Phase: MLN2480 600 mg, tablets, orally, once per week on Days 2, 9, 16 and 23 of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg, capsules, orally, once on 1, 8, and 15 of a 28-day cycle for up to 12 cycles.
    Measure Participants 0 0 0 0 0 0
    17. Secondary Outcome
    Title Terminal Elimination Half-life (T1/2) for Paclitaxel
    Description
    Time Frame Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

    Outcome Measure Data

    Analysis Population Description
    The limited PK data did not allow to estimate the PK parameters defined in the protocol.
    Arm/Group Title MLN2480 100 mg + Paclitaxel 80 mg/m^2 MLN2480 160 mg + Paclitaxel 80 mg/m^2 MLN2480 200 mg + Paclitaxel 80 mg/m^2 MLN2480 400 mg + Paclitaxel 80 mg/m^2 MLN2480 600 mg + Paclitaxel 80 mg/m^2 Dose Expansion: MLN2480 600 mg + Paclitaxel 80 mg/m^2
    Arm/Group Description Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 milligram per square meter (mg/m^2), intravenous (IV) infusion, once weekly (QW) for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Expansion Phase: MLN2480 600 mg, tablets, orally, once per week on Days 2, 9, 16 and 23 of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg, capsules, orally, once on 1, 8, and 15 of a 28-day cycle for up to 12 cycles.
    Measure Participants 0 0 0 0 0 0
    18. Secondary Outcome
    Title Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST)
    Description ORR was defined as the percentage of participants with complete response (CR) or partial response (PR) using Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. CR: Disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesions.
    Time Frame Baseline then every 2 cycles beginning at Cycle 2, Day 27, until disease progression, death or end of study (Up to 13 months)

    Outcome Measure Data

    Analysis Population Description
    Response-evaluable population was defined as participants who received at least 1 dose of study drug, had measurable disease at baseline, and 1 postbaseline response assessment.
    Arm/Group Title MLN2480 100 mg + MLN0128 2 mg MLN2480 100 mg + Alisertib 30 mg MLN2480 160 mg + Alisertib 30 mg MLN2480 200 mg + Alisertib 30 mg MLN2480 100 mg + Alisertib 40 mg MLN2480 100 mg + Paclitaxel 80 mg/m^2 MLN2480 160 mg + Paclitaxel 80 mg/m^2 MLN2480 200 mg + Paclitaxel 80 mg/m^2 MLN2480 400 mg + Paclitaxel 80 mg/m^2 MLN2480 600 mg + Paclitaxel 80 mg/m^2 MLN2480 400 mg + Cetuximab 250 mg/m^2 MLN2480 600 mg + Cetuximab 250 mg/m^2 ML2480 300 mg + Irinotecan 180 mg/m^2 ML2480 400 mg + Irinotecan 180 mg/m^2 Dose Expansion: MLN2480 600 mg + Paclitaxel 80 mg/m^2
    Arm/Group Description Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 40 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 milligram per square meter (mg/m^2), intravenous (IV) infusion, once weekly (QW) for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and cetuximab administered intravenously at a loading dose of 400 mg/m^2 (cycle 1 Day 1), then at 250 mg/m^2 QW on Days 8, 15, and 22 of cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose was based on the standard of care. Dose Escalation Phase: MLN2480 600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and cetuximab administered intravenously at a loading dose of 400 mg/m^2 (cycle 1 Day 1), then at 250 mg/m^2 QW on Days 8, 15, and 22 of cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose was based on the standard of care. Dose Escalation Phase: MLN2480 300 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and irinotecan 180 mg/m^2, IV infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and irinotecan 180 mg/m^2, IV infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose was based on the standard of care. Dose Expansion Phase: MLN2480 600 mg, tablets, orally, once per week on Days 2, 9, 16 and 23 of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, once on 1, 8, and 15 of a 28-day cycle for up to 12 cycles.
    Measure Participants 1 3 7 3 6 4 3 3 5 6 6 5 1 5 8
    Number (95% Confidence Interval) [percentage of participants]
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    17
    212.5%
    75
    1875%
    0
    0%
    0
    0%
    40
    666.7%
    17
    212.5%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    38
    380%
    19. Secondary Outcome
    Title Duration of Response
    Description Duration of Response (DOR) was defined as the time in months from the first documented CR or PR per RECIST v. 1.1 to disease recurrence or disease progression (PD) whichever occurs first.
    Time Frame From first documented response until disease progression (Up to 13 months)

    Outcome Measure Data

    Analysis Population Description
    Responders from response-evaluable population was defined as participants who received at least 1 dose of study drug, had measurable disease at baseline, and 1 postbaseline response assessment. For a participant that has not progressed, DOR was censored at the last response assessment.
    Arm/Group Title MLN2480 100 mg + MLN0128 2 mg MLN2480 100 mg + Alisertib 30 mg MLN2480 160 mg + Alisertib 30 mg MLN2480 200 mg + Alisertib 30 mg MLN2480 100 mg + Alisertib 40 mg MLN2480 100 mg + Paclitaxel 80 mg/m^2 MLN2480 160 mg + Paclitaxel 80 mg/m^2 MLN2480 200 mg + Paclitaxel 80 mg/m^2 MLN2480 400 mg + Paclitaxel 80 mg/m^2 MLN2480 600 mg + Paclitaxel 80 mg/m^2 MLN2480 400 mg + Cetuximab 250 mg/m^2 MLN2480 600 mg + Cetuximab 250 mg/m^2 ML2480 300 mg + Irinotecan 180 mg/m^2 ML2480 400 mg + Irinotecan 180 mg/m^2 Dose Expansion: MLN2480 600 mg + Paclitaxel 80 mg/m^2
    Arm/Group Description Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 40 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 milligram per square meter (mg/m^2), intravenous (IV) infusion, once weekly (QW) for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and cetuximab administered intravenously at a loading dose of 400 mg/m^2 (cycle 1 Day 1), then at 250 mg/m^2 QW on Days 8, 15, and 22 of cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose was based on the standard of care. Dose Escalation Phase: MLN2480 600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and cetuximab administered intravenously at a loading dose of 400 mg/m^2 (cycle 1 Day 1), then at 250 mg/m^2 QW on Days 8, 15, and 22 of cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose was based on the standard of care. Dose Escalation Phase: MLN2480 300 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and irinotecan 180 mg/m^2, IV infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and irinotecan 180 mg/m^2, IV infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose was based on the standard of care. Dose Expansion Phase: MLN2480 600 mg, tablets, orally, once per week on Days 2, 9, 16 and 23 of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, once on 1, 8, and 15 of a 28-day cycle for up to 12 cycles.
    Measure Participants 0 0 0 0 1 3 0 0 2 1 0 0 0 0 3
    Median (95% Confidence Interval) [months]
    NA
    3.7
    6.5
    3.5
    11.5
    20. Secondary Outcome
    Title Time to Response
    Description Time to response was defined as the time in months from the date of first dose of study treatment to the date of the first documentation of a PR or better response.
    Time Frame From date of enrollment to the date of the first documentation of a confirmed response (Up to 13 months)

    Outcome Measure Data

    Analysis Population Description
    Response-evaluable population was defined as all participants with measurable disease at baseline who received any amount of MLN2480 and have at least 1 post baseline response assessment.
    Arm/Group Title MLN2480 100 mg + MLN0128 2 mg MLN2480 100 mg + Alisertib 30 mg MLN2480 160 mg + Alisertib 30 mg MLN2480 200 mg + Alisertib 30 mg MLN2480 100 mg + Alisertib 40 mg MLN2480 100 mg + Paclitaxel 80 mg/m^2 MLN2480 160 mg + Paclitaxel 80 mg/m^2 MLN2480 200 mg + Paclitaxel 80 mg/m^2 MLN2480 400 mg + Paclitaxel 80 mg/m^2 MLN2480 600 mg + Paclitaxel 80 mg/m^2 MLN2480 400 mg + Cetuximab 250 mg/m^2 MLN2480 600 mg + Cetuximab 250 mg/m^2 ML2480 300 mg + Irinotecan 180 mg/m^2 ML2480 400 mg + Irinotecan 180 mg/m^2 Dose Expansion: MLN2480 600 mg + Paclitaxel 80 mg/m^2
    Arm/Group Description Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 40 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 milligram per square meter (mg/m^2), intravenous (IV) infusion, once weekly (QW) for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and cetuximab administered intravenously at a loading dose of 400 mg/m^2 (cycle 1 Day 1), then at 250 mg/m^2 QW on Days 8, 15, and 22 of cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose was based on the standard of care. Dose Escalation Phase: MLN2480 600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and cetuximab administered intravenously at a loading dose of 400 mg/m^2 (cycle 1 Day 1), then at 250 mg/m^2 QW on Days 8, 15, and 22 of cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose was based on the standard of care. Dose Escalation Phase: MLN2480 300 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and irinotecan 180 mg/m^2, IV infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and irinotecan 180 mg/m^2, IV infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose was based on the standard of care. Dose Expansion Phase: MLN2480 600 mg, tablets, orally, once per week on Days 2, 9, 16 and 23 of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, once on 1, 8, and 15 of a 28-day cycle for up to 12 cycles.
    Measure Participants 0 0 0 0 1 3 0 0 2 1 0 0 0 0 3
    Median (95% Confidence Interval) [months]
    4.2
    3.7
    2.7
    1.8
    1.9
    21. Secondary Outcome
    Title Progression Free Survival (PFS)
    Description PFS is defined as the time in months from the date of first study drug administration to the date of first documented PD or death due to any cause. PD was based on response evaluation criteria in solid tumors (RECIST V1.1), defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
    Time Frame Baseline then every 2 cycles beginning at Cycle 2, Day 27, until disease progression, death or end of study (Approximately up to 13 months)

    Outcome Measure Data

    Analysis Population Description
    Safety population is defined as all participants who received any amount of MLN2480. For a participant that has not progressed and has not died, PFS was censored at the last response assessment that is SD or better. Participants with no response assessment were censored at the date of first dose.
    Arm/Group Title MLN2480 100 mg + MLN0128 2 mg MLN2480 100 mg + Alisertib 30 mg MLN2480 160 mg + Alisertib 30 mg MLN2480 200 mg + Alisertib 30 mg MLN2480 100 mg + Alisertib 40 mg MLN2480 100 mg + Paclitaxel 80 mg/m^2 MLN2480 160 mg + Paclitaxel 80 mg/m^2 MLN2480 200 mg + Paclitaxel 80 mg/m^2 MLN2480 400 mg + Paclitaxel 80 mg/m^2 MLN2480 600 mg + Paclitaxel 80 mg/m^2 MLN2480 400 mg + Cetuximab 250 mg/m^2 MLN2480 600 mg + Cetuximab 250 mg/m^2 ML2480 300 mg + Irinotecan 180 mg/m^2 ML2480 400 mg + Irinotecan 180 mg/m^2 Dose Expansion: MLN2480 600 mg + Paclitaxel 80 mg/m^2
    Arm/Group Description Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 40 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 milligram per square meter (mg/m^2), intravenous (IV) infusion, once weekly (QW) for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and cetuximab administered intravenously at a loading dose of 400 mg/m^2 (cycle 1 Day 1), then at 250 mg/m^2 QW on Days 8, 15, and 22 of cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose was based on the standard of care. Dose Escalation Phase: MLN2480 600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and cetuximab administered intravenously at a loading dose of 400 mg/m^2 (cycle 1 Day 1), then at 250 mg/m^2 QW on Days 8, 15, and 22 of cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose was based on the standard of care. Dose Escalation Phase: MLN2480 300 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and irinotecan 180 mg/m^2, IV infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and irinotecan 180 mg/m^2, IV infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose was based on the standard of care. Dose Expansion Phase: MLN2480 600 mg, tablets, orally, once per week on Days 2, 9, 16 and 23 of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, once on 1, 8, and 15 of a 28-day cycle for up to 12 cycles.
    Measure Participants 4 3 7 3 8 4 3 4 6 8 6 7 1 7 10
    Median (95% Confidence Interval) [months]
    0.5
    1.9
    3.7
    1.9
    9.5
    5.3
    5.5
    2.9
    7.6
    3.3
    2.2
    1.7
    3.6
    4.7
    5.7

    Adverse Events

    Time Frame AEs were recorded from the first dose of study drug through 30 days after the last dose of study drug or the start of subsequent antineoplastic therapy, whichever occurred first. SAEs were collected from the signing of Informed Consent through 30 days after the last dose of study drug (Up to 13 months)
    Adverse Event Reporting Description At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
    Arm/Group Title MLN2480 100 mg + MLN0128 2 mg MLN2480 100 mg + Alisertib 30 mg MLN2480 160 mg + Alisertib 30 mg MLN2480 200 mg + Alisertib 30 mg MLN2480 100 mg + Alisertib 40 mg MLN2480 100 mg + Paclitaxel 80 mg/m^2 MLN2480 160 mg + Paclitaxel 80 mg/m^2 MLN2480 200 mg + Paclitaxel 80 mg/m^2 MLN2480 400 mg + Paclitaxel 80 mg/m^2 MLN2480 600 mg + Paclitaxel 80 mg/m^2 MLN2480 400 mg + Cetuximab 250 mg/m^2 MLN2480 600 mg + Cetuximab 250 mg/m^2 ML2480 300 mg + Irinotecan 180 mg/m^2 ML2480 400 mg + Irinotecan 180 mg/m^2 Dose Expansion: MLN2480 600 mg + Paclitaxel 80 mg/m^2
    Arm/Group Description Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 40 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 milligram per square meter (mg/m^2), intravenous (IV) infusion, once weekly (QW) for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and cetuximab administered intravenously at a loading dose of 400 mg/m^2 (cycle 1 Day 1), then at 250 mg/m^2 QW on Days 8, 15, and 22 of cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose was based on the standard of care. Dose Escalation Phase: MLN2480 600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and cetuximab administered intravenously at a loading dose of 400 mg/m^2 (cycle 1 Day 1), then at 250 mg/m^2 QW on Days 8, 15, and 22 of cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose was based on the standard of care. Dose Escalation Phase: MLN2480 300 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and irinotecan 180 mg/m^2, IV infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose was based on the standard of care. Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and irinotecan 180 mg/m^2, IV infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose was based on the standard of care. Dose Expansion Phase: MLN2480 600 mg, tablets, orally, once per week on Days 2, 9, 16 and 23 of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, once on 1, 8, and 15 of a 28-day cycle for up to 12 cycles.
    All Cause Mortality
    MLN2480 100 mg + MLN0128 2 mg MLN2480 100 mg + Alisertib 30 mg MLN2480 160 mg + Alisertib 30 mg MLN2480 200 mg + Alisertib 30 mg MLN2480 100 mg + Alisertib 40 mg MLN2480 100 mg + Paclitaxel 80 mg/m^2 MLN2480 160 mg + Paclitaxel 80 mg/m^2 MLN2480 200 mg + Paclitaxel 80 mg/m^2 MLN2480 400 mg + Paclitaxel 80 mg/m^2 MLN2480 600 mg + Paclitaxel 80 mg/m^2 MLN2480 400 mg + Cetuximab 250 mg/m^2 MLN2480 600 mg + Cetuximab 250 mg/m^2 ML2480 300 mg + Irinotecan 180 mg/m^2 ML2480 400 mg + Irinotecan 180 mg/m^2 Dose Expansion: MLN2480 600 mg + Paclitaxel 80 mg/m^2
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/4 (0%) 0/3 (0%) 2/7 (28.6%) 0/3 (0%) 1/8 (12.5%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 2/6 (33.3%) 2/7 (28.6%) 0/1 (0%) 0/7 (0%) 2/10 (20%)
    Serious Adverse Events
    MLN2480 100 mg + MLN0128 2 mg MLN2480 100 mg + Alisertib 30 mg MLN2480 160 mg + Alisertib 30 mg MLN2480 200 mg + Alisertib 30 mg MLN2480 100 mg + Alisertib 40 mg MLN2480 100 mg + Paclitaxel 80 mg/m^2 MLN2480 160 mg + Paclitaxel 80 mg/m^2 MLN2480 200 mg + Paclitaxel 80 mg/m^2 MLN2480 400 mg + Paclitaxel 80 mg/m^2 MLN2480 600 mg + Paclitaxel 80 mg/m^2 MLN2480 400 mg + Cetuximab 250 mg/m^2 MLN2480 600 mg + Cetuximab 250 mg/m^2 ML2480 300 mg + Irinotecan 180 mg/m^2 ML2480 400 mg + Irinotecan 180 mg/m^2 Dose Expansion: MLN2480 600 mg + Paclitaxel 80 mg/m^2
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 2/4 (50%) 1/3 (33.3%) 5/7 (71.4%) 1/3 (33.3%) 3/8 (37.5%) 1/4 (25%) 1/3 (33.3%) 2/4 (50%) 3/6 (50%) 4/8 (50%) 2/6 (33.3%) 3/7 (42.9%) 0/1 (0%) 4/7 (57.1%) 7/10 (70%)
    Blood and lymphatic system disorders
    Anaemia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 1/7 (14.3%) 2/10 (20%)
    Febrile neutropenia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/8 (12.5%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 2/7 (28.6%) 0/10 (0%)
    Neutropenia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 1/7 (14.3%) 0/10 (0%)
    Splenic haemorrhage 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 1/3 (33.3%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Cardiac disorders
    Atrial fibrillation 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 1/7 (14.3%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Atrial flutter 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Arrhythmia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Gastrointestinal disorders
    Abdominal pain 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 0/8 (0%) 1/4 (25%) 0/3 (0%) 1/4 (25%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 1/7 (14.3%) 0/10 (0%)
    Nausea 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/1 (0%) 2/7 (28.6%) 0/10 (0%)
    Vomiting 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Post-tussive vomiting 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Small intestinal obstruction 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Gastrointestinal haemorrhage 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Upper gastrointestinal haemorrhage 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/8 (12.5%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Pancreatitis acute 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/8 (12.5%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Diarrhoea 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 1/7 (14.3%) 0/10 (0%)
    Intestinal obstruction 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Gastrointestinal perforation 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Oesophagitis ulcerative 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Ascites 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    General disorders
    Pyrexia 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 1/7 (14.3%) 0/10 (0%)
    General physical health deterioration 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Hepatobiliary disorders
    Cholangitis 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Cholelithiasis 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/8 (12.5%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Hyperbilirubinaemia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Bile duct obstruction 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Infections and infestations
    Pneumonia 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 1/3 (33.3%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Lung infection 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Respiratory tract infection 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Sepsis 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Cellulitis 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Abdominal infection 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Urinary tract infection 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Injury, poisoning and procedural complications
    Subdural haematoma 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Metabolism and nutrition disorders
    Hypophosphataemia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Fluid overload 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 1/4 (25%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Musculoskeletal and connective tissue disorders
    Pain in extremity 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colorectal cancer 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Gastrointestinal carcinoma 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Malignant neoplasm progression 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Neoplasm progression 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Lung adenocarcinoma 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Tumour pain 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Metastatic malignant melanoma 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Renal and urinary disorders
    Haematuria 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 1/7 (14.3%) 2/10 (20%)
    Chronic obstructive pulmonary disease 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 2/10 (20%)
    Haemoptysis 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 1/7 (14.3%) 0/10 (0%)
    Pneumonia aspiration 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Pulmonary oedema 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 1/4 (25%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Skin and subcutaneous tissue disorders
    Rash maculo-papular 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Vascular disorders
    Deep vein thrombosis 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Other (Not Including Serious) Adverse Events
    MLN2480 100 mg + MLN0128 2 mg MLN2480 100 mg + Alisertib 30 mg MLN2480 160 mg + Alisertib 30 mg MLN2480 200 mg + Alisertib 30 mg MLN2480 100 mg + Alisertib 40 mg MLN2480 100 mg + Paclitaxel 80 mg/m^2 MLN2480 160 mg + Paclitaxel 80 mg/m^2 MLN2480 200 mg + Paclitaxel 80 mg/m^2 MLN2480 400 mg + Paclitaxel 80 mg/m^2 MLN2480 600 mg + Paclitaxel 80 mg/m^2 MLN2480 400 mg + Cetuximab 250 mg/m^2 MLN2480 600 mg + Cetuximab 250 mg/m^2 ML2480 300 mg + Irinotecan 180 mg/m^2 ML2480 400 mg + Irinotecan 180 mg/m^2 Dose Expansion: MLN2480 600 mg + Paclitaxel 80 mg/m^2
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 4/4 (100%) 3/3 (100%) 7/7 (100%) 3/3 (100%) 8/8 (100%) 4/4 (100%) 3/3 (100%) 4/4 (100%) 6/6 (100%) 8/8 (100%) 6/6 (100%) 7/7 (100%) 1/1 (100%) 7/7 (100%) 10/10 (100%)
    Blood and lymphatic system disorders
    Anaemia 1/4 (25%) 0/3 (0%) 5/7 (71.4%) 0/3 (0%) 5/8 (62.5%) 0/4 (0%) 3/3 (100%) 3/4 (75%) 4/6 (66.7%) 4/8 (50%) 0/6 (0%) 3/7 (42.9%) 1/1 (100%) 5/7 (71.4%) 5/10 (50%)
    Neutropenia 0/4 (0%) 1/3 (33.3%) 1/7 (14.3%) 1/3 (33.3%) 2/8 (25%) 0/4 (0%) 1/3 (33.3%) 1/4 (25%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 2/7 (28.6%) 1/10 (10%)
    Iron deficiency anaemia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 2/10 (20%)
    Leukocytosis 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 2/10 (20%)
    Lymphadenopathy 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/8 (12.5%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Thrombocytopenia 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 1/8 (12.5%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Febrile neutropenia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/8 (12.5%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Lymphopenia 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Cardiac disorders
    Atrial fibrillation 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 2/8 (25%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 1/7 (14.3%) 1/10 (10%)
    Palpitations 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 1/4 (25%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 1/1 (100%) 0/7 (0%) 0/10 (0%)
    Tachycardia 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 1/3 (33.3%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Atrial flutter 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Atrial tachycardia 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Atrial thrombosis 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Left ventricular dysfunction 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Pericardial effusion 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Arrhythmia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Sinus Tachycardia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Ventricular fibrillation 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Ear and labyrinth disorders
    Deafness unilateral 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Ear pain 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Endocrine disorders
    Hyperthyroidism 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Adrenal insufficiency 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Hypopituitarism 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Hypothyroidism 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/8 (12.5%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Thyroiditis 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Eye disorders
    Vision blurred 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 0/8 (0%) 2/4 (50%) 0/3 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Eyelid oedema 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 2/10 (20%)
    Dry eye 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 2/10 (20%)
    Eye haemorrhage 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/8 (12.5%) 0/4 (0%) 0/3 (0%) 1/4 (25%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Eye pain 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 1/4 (25%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 1/1 (100%) 0/7 (0%) 0/10 (0%)
    Cataract 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Eye inflammation 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Ocular hyperaemia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 1/3 (33.3%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Periorbital oedema 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Retinal haemorrhage 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 1/3 (33.3%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Gastrointestinal disorders
    Nausea 2/4 (50%) 1/3 (33.3%) 3/7 (42.9%) 1/3 (33.3%) 3/8 (37.5%) 3/4 (75%) 1/3 (33.3%) 3/4 (75%) 3/6 (50%) 1/8 (12.5%) 0/6 (0%) 2/7 (28.6%) 1/1 (100%) 4/7 (57.1%) 6/10 (60%)
    Diarrhoea 0/4 (0%) 1/3 (33.3%) 2/7 (28.6%) 0/3 (0%) 3/8 (37.5%) 1/4 (25%) 1/3 (33.3%) 1/4 (25%) 4/6 (66.7%) 3/8 (37.5%) 1/6 (16.7%) 2/7 (28.6%) 0/1 (0%) 2/7 (28.6%) 3/10 (30%)
    Constipation 0/4 (0%) 2/3 (66.7%) 3/7 (42.9%) 0/3 (0%) 4/8 (50%) 2/4 (50%) 1/3 (33.3%) 3/4 (75%) 2/6 (33.3%) 0/8 (0%) 0/6 (0%) 3/7 (42.9%) 0/1 (0%) 2/7 (28.6%) 3/10 (30%)
    Vomiting 0/4 (0%) 1/3 (33.3%) 2/7 (28.6%) 1/3 (33.3%) 3/8 (37.5%) 2/4 (50%) 0/3 (0%) 1/4 (25%) 2/6 (33.3%) 3/8 (37.5%) 1/6 (16.7%) 1/7 (14.3%) 0/1 (0%) 4/7 (57.1%) 4/10 (40%)
    Abdominal pain 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 1/8 (12.5%) 1/4 (25%) 0/3 (0%) 1/4 (25%) 3/6 (50%) 1/8 (12.5%) 1/6 (16.7%) 2/7 (28.6%) 1/1 (100%) 2/7 (28.6%) 2/10 (20%)
    Abdominal distension 0/4 (0%) 2/3 (66.7%) 0/7 (0%) 0/3 (0%) 2/8 (25%) 0/4 (0%) 1/3 (33.3%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 2/7 (28.6%) 0/10 (0%)
    Stomatitis 1/4 (25%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 2/8 (25%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/6 (16.7%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 1/7 (14.3%) 0/10 (0%)
    Dry mouth 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 1/4 (25%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/1 (0%) 1/7 (14.3%) 1/10 (10%)
    Dyspepsia 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 1/4 (25%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 2/7 (28.6%) 1/10 (10%)
    Gastrooesophageal reflux disease 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 1/4 (25%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Haematochezia 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/6 (16.7%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 1/7 (14.3%) 0/10 (0%)
    Dysphagia 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 1/7 (14.3%) 0/10 (0%)
    Mouth ulceration 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 1/4 (25%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Retching 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 1/4 (25%) 0/3 (0%) 1/4 (25%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Abdominal pain upper 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Ascites 0/4 (0%) 2/3 (66.7%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Epigastric discomfort 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/8 (12.5%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Gingival bleeding 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/8 (12.5%) 0/4 (0%) 1/3 (33.3%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Rectal haemorrhage 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 1/7 (14.3%) 0/10 (0%)
    Abdominal discomfort 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Abdominal mass 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 1/7 (14.3%) 0/10 (0%)
    Abdominal pain lower 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Abdominal tenderness 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Anal fistula 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Aphthous ulcer 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Colitis 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Faecal vomiting 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Faeces discoloured 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/8 (12.5%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Gastric haemorrhage 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Glossitis 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Haemorrhoidal haemorrhage 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Ileus 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 1/7 (14.3%) 0/10 (0%)
    Mouth haemorrhage 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Oral pain 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Pancreatitis 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Proctalgia 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Tongue coated 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Toothache 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 1/4 (25%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    General disorders
    Fatigue 3/4 (75%) 3/3 (100%) 5/7 (71.4%) 1/3 (33.3%) 5/8 (62.5%) 2/4 (50%) 2/3 (66.7%) 1/4 (25%) 3/6 (50%) 3/8 (37.5%) 0/6 (0%) 2/7 (28.6%) 1/1 (100%) 3/7 (42.9%) 2/10 (20%)
    Asthenia 0/4 (0%) 0/3 (0%) 2/7 (28.6%) 1/3 (33.3%) 1/8 (12.5%) 1/4 (25%) 1/3 (33.3%) 1/4 (25%) 2/6 (33.3%) 1/8 (12.5%) 1/6 (16.7%) 1/7 (14.3%) 0/1 (0%) 4/7 (57.1%) 5/10 (50%)
    Pyrexia 2/4 (50%) 1/3 (33.3%) 2/7 (28.6%) 1/3 (33.3%) 3/8 (37.5%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/6 (16.7%) 2/8 (25%) 0/6 (0%) 1/7 (14.3%) 0/1 (0%) 2/7 (28.6%) 1/10 (10%)
    Oedema peripheral 0/4 (0%) 0/3 (0%) 2/7 (28.6%) 1/3 (33.3%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 4/6 (66.7%) 1/8 (12.5%) 0/6 (0%) 1/7 (14.3%) 0/1 (0%) 0/7 (0%) 2/10 (20%)
    Chills 1/4 (25%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 1/8 (12.5%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 2/6 (33.3%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 1/1 (100%) 1/7 (14.3%) 0/10 (0%)
    Face oedema 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 0/8 (0%) 0/4 (0%) 1/3 (33.3%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 2/10 (20%)
    Non-cardiac chest pain 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 1/3 (33.3%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/6 (16.7%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Pain 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 2/6 (33.3%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Catheter site pain 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Localised oedema 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/8 (12.5%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Administration site extravasation 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Catheter site oedema 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Chest pain 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 1/7 (14.3%) 0/10 (0%)
    Early satiety 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Inflammation 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Infusion site pain 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 1/3 (33.3%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Malaise 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/8 (12.5%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Unevaluable event 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Vaccination site reaction 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Hepatobiliary disorders
    Hyperbilirubinaemia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 1/4 (25%) 0/3 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 2/7 (28.6%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Cholestasis 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Hepatocellular injury 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Immune system disorders
    Drug hypersensitivity 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Food allergy 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Sarcoidosis 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Infections and infestations
    Urinary tract infection 1/4 (25%) 0/3 (0%) 1/7 (14.3%) 1/3 (33.3%) 0/8 (0%) 1/4 (25%) 0/3 (0%) 1/4 (25%) 0/6 (0%) 1/8 (12.5%) 1/6 (16.7%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Upper respiratory tract infection 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 1/3 (33.3%) 1/8 (12.5%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 1/7 (14.3%) 0/10 (0%)
    Bronchitis 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/8 (12.5%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 4/10 (40%)
    Viral upper respiratory tract infection 0/4 (0%) 1/3 (33.3%) 1/7 (14.3%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 1/7 (14.3%) 0/10 (0%)
    Influenza 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Lung infection 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Rash pustular 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 2/6 (33.3%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Breast abscess 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Conjunctivitis viral 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Furuncle 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Gastroenteritis viral 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Herpes zoster 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Infective exacerbation of chronic obstructive airways disease 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Laryngitis 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Nail infection 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Oral fungal infection 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Paronychia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Pneumonia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 1/3 (33.3%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Pyelonephritis 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Sinusitis 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 1/4 (25%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Tongue fungal infection 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Injury, poisoning and procedural complications
    Wound 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Fall 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Incision site pain 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Infusion related reaction 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Stoma site haemorrhage 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Investigations
    Weight decreased 1/4 (25%) 1/3 (33.3%) 0/7 (0%) 1/3 (33.3%) 1/8 (12.5%) 0/4 (0%) 1/3 (33.3%) 0/4 (0%) 2/6 (33.3%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 1/7 (14.3%) 2/10 (20%)
    Aspartate aminotransferase increased 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 2/3 (66.7%) 0/8 (0%) 1/4 (25%) 1/3 (33.3%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Neutrophil count decreased 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 1/3 (33.3%) 2/8 (25%) 1/4 (25%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Transaminases increased 0/4 (0%) 0/3 (0%) 0/7 (0%) 2/3 (66.7%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 1/4 (25%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Blood bilirubin increased 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 1/3 (33.3%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Blood calcium decreased 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 2/10 (20%)
    Gamma-glutamyltransferase increased 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 1/4 (25%) 0/3 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Haemoglobin decreased 1/4 (25%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 1/8 (12.5%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Vitamin D decreased 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 1/6 (16.7%) 1/7 (14.3%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Weight increased 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 1/3 (33.3%) 0/4 (0%) 1/6 (16.7%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Adjusted calcium decreased 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Alanine aminotransferase increased 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 1/4 (25%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Blood phosphorus decreased 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 2/10 (20%)
    Blood potassium decreased 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Electrocardiogram QT prolonged 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    International normalised ratio increased 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 1/7 (14.3%) 0/10 (0%)
    Blood alkaline phosphatase increased 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Blood magnesium decreased 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Blood triglycerides increased 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Blood urea increased 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Blood urine present 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Breath sounds abnormal 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Lipase increased 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Platelet count decreased 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Platelet count increased 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Prothrombin level decreased 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Troponin increased 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    White blood cell count decreased 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/8 (12.5%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    White blood cell count increased 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Blood creatine phosphokinase increased 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 2/3 (66.7%) 0/8 (0%) 0/4 (0%) 2/3 (66.7%) 1/4 (25%) 0/6 (0%) 3/8 (37.5%) 1/6 (16.7%) 2/7 (28.6%) 0/1 (0%) 0/7 (0%) 2/10 (20%)
    Metabolism and nutrition disorders
    Hypophosphataemia 1/4 (25%) 0/3 (0%) 6/7 (85.7%) 2/3 (66.7%) 1/8 (12.5%) 0/4 (0%) 3/3 (100%) 2/4 (50%) 4/6 (66.7%) 7/8 (87.5%) 6/6 (100%) 4/7 (57.1%) 0/1 (0%) 5/7 (71.4%) 6/10 (60%)
    Decreased appetite 2/4 (50%) 1/3 (33.3%) 5/7 (71.4%) 1/3 (33.3%) 5/8 (62.5%) 2/4 (50%) 2/3 (66.7%) 1/4 (25%) 2/6 (33.3%) 1/8 (12.5%) 0/6 (0%) 1/7 (14.3%) 1/1 (100%) 2/7 (28.6%) 5/10 (50%)
    Hypocalcaemia 1/4 (25%) 1/3 (33.3%) 1/7 (14.3%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 3/6 (50%) 2/8 (25%) 0/6 (0%) 3/7 (42.9%) 0/1 (0%) 1/7 (14.3%) 4/10 (40%)
    Hypokalaemia 1/4 (25%) 1/3 (33.3%) 0/7 (0%) 1/3 (33.3%) 1/8 (12.5%) 0/4 (0%) 1/3 (33.3%) 0/4 (0%) 2/6 (33.3%) 0/8 (0%) 2/6 (33.3%) 0/7 (0%) 0/1 (0%) 2/7 (28.6%) 1/10 (10%)
    Hypomagnesaemia 0/4 (0%) 1/3 (33.3%) 1/7 (14.3%) 0/3 (0%) 1/8 (12.5%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 2/6 (33.3%) 1/8 (12.5%) 1/6 (16.7%) 4/7 (57.1%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Dehydration 1/4 (25%) 1/3 (33.3%) 0/7 (0%) 1/3 (33.3%) 0/8 (0%) 1/4 (25%) 1/3 (33.3%) 0/4 (0%) 0/6 (0%) 3/8 (37.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 1/7 (14.3%) 0/10 (0%)
    Hyperglycaemia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 1/3 (33.3%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 2/10 (20%)
    Hypoalbuminaemia 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 2/7 (28.6%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Hypercholesterolaemia 1/4 (25%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 3/8 (37.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Hyperuricaemia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 2/3 (66.7%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Hyponatraemia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/8 (12.5%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Vitamin D deficiency 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Hyperkalaemia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Hypoglycaemia 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Lactic acidosis 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Malnutrition 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Musculoskeletal and connective tissue disorders
    Back pain 1/4 (25%) 1/3 (33.3%) 2/7 (28.6%) 2/3 (66.7%) 1/8 (12.5%) 1/4 (25%) 0/3 (0%) 1/4 (25%) 2/6 (33.3%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 2/10 (20%)
    Myalgia 2/4 (50%) 0/3 (0%) 1/7 (14.3%) 1/3 (33.3%) 1/8 (12.5%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 3/6 (50%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 3/10 (30%)
    Arthralgia 2/4 (50%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 1/3 (33.3%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 1/7 (14.3%) 0/1 (0%) 1/7 (14.3%) 1/10 (10%)
    Muscle spasms 0/4 (0%) 1/3 (33.3%) 1/7 (14.3%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 2/10 (20%)
    Flank pain 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 1/3 (33.3%) 0/8 (0%) 1/4 (25%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 1/7 (14.3%) 0/10 (0%)
    Groin pain 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 0/8 (0%) 1/4 (25%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Musculoskeletal chest pain 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/8 (12.5%) 0/4 (0%) 0/3 (0%) 1/4 (25%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Neck pain 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 1/4 (25%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Pain in extremity 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Arthropathy 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/8 (12.5%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Bone pain 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Clubbing 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Fibromyalgia 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Muscular weakness 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Osteopenia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Musculoskeletal pain 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 1/8 (12.5%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Melanocytic naevus 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 1/4 (25%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Tumour pain 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 1/7 (14.3%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Cancer pain 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Metastases to skin 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Seborrhoeic keratosis 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 1/3 (33.3%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Nervous system disorders
    Headache 0/4 (0%) 1/3 (33.3%) 1/7 (14.3%) 1/3 (33.3%) 2/8 (25%) 1/4 (25%) 0/3 (0%) 1/4 (25%) 2/6 (33.3%) 3/8 (37.5%) 0/6 (0%) 1/7 (14.3%) 0/1 (0%) 1/7 (14.3%) 0/10 (0%)
    Dizziness 1/4 (25%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/8 (0%) 2/4 (50%) 0/3 (0%) 0/4 (0%) 1/6 (16.7%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 2/7 (28.6%) 1/10 (10%)
    Neuropathy peripheral 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/8 (0%) 1/4 (25%) 0/3 (0%) 0/4 (0%) 2/6 (33.3%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 4/10 (40%)
    Peripheral sensory neuropathy 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/8 (0%) 2/4 (50%) 0/3 (0%) 0/4 (0%) 3/6 (50%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Dysgeusia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 2/8 (25%) 2/4 (50%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Aphasia 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 1/4 (25%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Lethargy 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Paraesthesia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 2/10 (20%)
    Somnolence 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 2/8 (25%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Ataxia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 1/4 (25%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Hyperaesthesia 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Memory impairment 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Motor dysfunction 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Neurotoxicity 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Peripheral motor neuropathy 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Peripheral sensorimotor neuropathy 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Restless legs syndrome 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 1/4 (25%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Sciatica 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Vocal cord paralysis 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 1/4 (25%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Product Issues
    Device occlusion 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Psychiatric disorders
    Insomnia 3/4 (75%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 1/8 (12.5%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 1/7 (14.3%) 1/10 (10%)
    Depression 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 1/4 (25%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Confusional state 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Anxiety 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Renal and urinary disorders
    Acute kidney injury 1/4 (25%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 1/3 (33.3%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Dysuria 1/4 (25%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/8 (0%) 1/4 (25%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Haematuria 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Hydronephrosis 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 1/8 (12.5%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Pollakiuria 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 1/4 (25%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Proteinuria 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Renal hypertension 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Urinary incontinence 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Urinary tract obstruction 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Reproductive system and breast disorders
    Vaginal haemorrhage 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Female genital tract fistula 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Vaginal discharge 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 1/4 (25%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Vulvovaginal discomfort 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Respiratory, thoracic and mediastinal disorders
    Cough 1/4 (25%) 2/3 (66.7%) 1/7 (14.3%) 1/3 (33.3%) 5/8 (62.5%) 2/4 (50%) 2/3 (66.7%) 0/4 (0%) 2/6 (33.3%) 1/8 (12.5%) 0/6 (0%) 2/7 (28.6%) 0/1 (0%) 2/7 (28.6%) 3/10 (30%)
    Dyspnoea 1/4 (25%) 0/3 (0%) 2/7 (28.6%) 1/3 (33.3%) 3/8 (37.5%) 1/4 (25%) 0/3 (0%) 0/4 (0%) 2/6 (33.3%) 3/8 (37.5%) 0/6 (0%) 1/7 (14.3%) 0/1 (0%) 2/7 (28.6%) 4/10 (40%)
    Dyspnoea exertional 0/4 (0%) 2/3 (66.7%) 1/7 (14.3%) 1/3 (33.3%) 1/8 (12.5%) 2/4 (50%) 1/3 (33.3%) 2/4 (50%) 2/6 (33.3%) 0/8 (0%) 1/6 (16.7%) 0/7 (0%) 0/1 (0%) 2/7 (28.6%) 0/10 (0%)
    Oropharyngeal pain 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 1/3 (33.3%) 1/8 (12.5%) 1/4 (25%) 1/3 (33.3%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 1/7 (14.3%) 0/10 (0%)
    Pleural effusion 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 2/7 (28.6%) 1/10 (10%)
    Upper-airway cough syndrome 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 1/8 (12.5%) 1/4 (25%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 1/7 (14.3%) 0/10 (0%)
    Wheezing 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 2/10 (20%)
    Dysphonia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 1/4 (25%) 1/3 (33.3%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Epistaxis 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 1/7 (14.3%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Nasal congestion 0/4 (0%) 1/3 (33.3%) 1/7 (14.3%) 0/3 (0%) 1/8 (12.5%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Sinus congestion 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 1/8 (12.5%) 1/4 (25%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Haemoptysis 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 1/3 (33.3%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Hypoxia 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 1/3 (33.3%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 1/7 (14.3%) 0/10 (0%)
    Acute respiratory failure 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Hiccups 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 1/7 (14.3%) 0/10 (0%)
    Oropharyngeal discomfort 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 1/4 (25%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Painful respiration 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Pneumonia aspiration 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Productive cough 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Rales 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Respiratory tract congestion 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 1/7 (14.3%) 0/10 (0%)
    Rhinorrhoea 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 1/1 (100%) 0/7 (0%) 0/10 (0%)
    Skin and subcutaneous tissue disorders
    Alopecia 0/4 (0%) 2/3 (66.7%) 1/7 (14.3%) 1/3 (33.3%) 3/8 (37.5%) 3/4 (75%) 1/3 (33.3%) 2/4 (50%) 3/6 (50%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 1/1 (100%) 1/7 (14.3%) 3/10 (30%)
    Rash maculo-papular 2/4 (50%) 0/3 (0%) 2/7 (28.6%) 1/3 (33.3%) 1/8 (12.5%) 1/4 (25%) 0/3 (0%) 3/4 (75%) 1/6 (16.7%) 2/8 (25%) 2/6 (33.3%) 1/7 (14.3%) 0/1 (0%) 0/7 (0%) 2/10 (20%)
    Dermatitis acneiform 0/4 (0%) 1/3 (33.3%) 1/7 (14.3%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 1/3 (33.3%) 0/4 (0%) 1/6 (16.7%) 1/8 (12.5%) 0/6 (0%) 4/7 (57.1%) 0/1 (0%) 1/7 (14.3%) 2/10 (20%)
    Pruritus 1/4 (25%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 0/8 (0%) 1/4 (25%) 1/3 (33.3%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 2/10 (20%)
    Rash 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 0/8 (0%) 0/4 (0%) 1/3 (33.3%) 0/4 (0%) 1/6 (16.7%) 3/8 (37.5%) 1/6 (16.7%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Rash papular 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 1/4 (25%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Skin lesion 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 1/4 (25%) 1/3 (33.3%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Actinic keratosis 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 1/3 (33.3%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Dermatitis contact 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Dry skin 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Ephelides 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Erythema 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Hair colour changes 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Keratosis pilaris 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Miliaria 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Nail disorder 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Night sweats 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Nodular rash 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Onychoclasis 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Onycholysis 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Petechiae 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Pigmentation disorder 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 1/4 (25%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Rash erythematous 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Systemic lupus erythematosus rash 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Urticaria 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Vascular disorders
    Hypotension 2/4 (50%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 1/8 (12.5%) 1/4 (25%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 2/8 (25%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Flushing 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 2/8 (25%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Hot flush 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Haematoma 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 1/10 (10%)
    Hypertension 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/6 (16.7%) 0/8 (0%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Pallor 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 0/8 (0%) 0/6 (0%) 1/7 (14.3%) 0/1 (0%) 0/7 (0%) 0/10 (0%)
    Vena cava thrombosis 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/8 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/6 (0%) 1/8 (12.5%) 0/6 (0%) 0/7 (0%) 0/1 (0%) 0/7 (0%) 0/10 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    In general, Investigators may publish clinical data after the earlier of (i) publication by the Sponsor or (ii) 12 months following the abandonment, early termination or database lock; provided a copy of the publication provided to Sponsor at least 30 days ahead of publication, the Sponsor's confidential information is removed as may be requested by Sponsor and Investigator defers publication for up to 60 days in the event Sponsor provides notice that it intends to file a patent application.

    Results Point of Contact

    Name/Title Takeda Study Registration Call Center
    Organization Takeda
    Phone +1-866-835-2233
    Email GlobalOncologyMedinfo@takeda.com
    Responsible Party:
    Millennium Pharmaceuticals, Inc.
    ClinicalTrials.gov Identifier:
    NCT02327169
    Other Study ID Numbers:
    • C28002
    • 2014-003340-12
    • U1111-1159-5831
    First Posted:
    Dec 30, 2014
    Last Update Posted:
    Feb 25, 2020
    Last Verified:
    Feb 1, 2020