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Dose Escalation Study of MLN0128 in Participants With Advanced Malignancies

Sponsor
Millennium Pharmaceuticals, Inc. (Industry)
Overall Status
Completed
CT.gov ID
NCT01058707
Collaborator
(none)
198
Enrollment
16
Locations
7
Arms
109.1
Actual Duration (Months)
12.4
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a Phase I, open label, Dose Escalation study of oral administration of single agent MLN0128 in participants with Advanced Malignancies followed by an Expansion Phase in participants with renal cell carcinoma, endometrial cancer or urothelial cancer who have measurable disease.

Condition or Disease Intervention/Treatment Phase
Phase 1

Detailed Description

The drug being tested in this study is called MLN0128. MLN0128 is being tested to treat people who have Advanced Malignancies.

The study enrolled approximately 198 patients. Participants were assigned to one of the following dose regimens in the Dose Escalation Phase to establish the Maximum Tolerated Dose (MTD):

  • MLN0128 QD

  • MLN0128 QW

  • MLN0128 QDx3dQW

  • MLN0128 QDx5dQW

MLN0128 capsule, orally, once daily (QD) or Once weekly (QW) in the Dose Escalation Phase until MTD was established.

Once MTD was determined, participants were then enrolled in the Dose Expansion Phase to receive:

  • MLN0128 5 mg QD

  • MLN0128 30 mg QW

  • MLN0128 40 mg QW

This multi-centre trial was conducted worldwide. The overall time to participate in this study was approximately 244 weeks. Participants will make multiple visits to the clinic, and were contacted by telephone OR plus a final visit after last dose of study drug for a follow-up assessment.

Study Design

Study Type:
Interventional
Actual Enrollment :
198 participants
Allocation:
Non-Randomized
Intervention Model:
Sequential Assignment
Intervention Model Description:
The Escalation Phase was sequential and the Expansion Phase was parallel.The Escalation Phase was sequential and the Expansion Phase was parallel.
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase I, Open Label, Dose Escalation Study of Oral Administration of Single Agent INK128 in Subjects With Advanced Malignancies Followed by an Expansion in Subjects With Measurable Disease
Actual Study Start Date :
Jan 4, 2010
Actual Primary Completion Date :
Feb 7, 2019
Actual Study Completion Date :
Feb 7, 2019

Arms and Interventions

Arm Intervention/Treatment
Experimental: MLN0128 QD

MLN0128 2 mg, 4 mg, 6 mg or 7 mg, capsule, orally, once daily (QD) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 52.1 weeks).

Drug: MLN0128
MLN0128 capsules
Other Names:
  • INK128
  • TAK-128

    		•
    Experimental: MLN0128 QW

    MLN0128 7 mg, 10 mg, 15 mg, 20 mg, 30 mg or 40 mg capsule, orally, once weekly (QW) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 139.4 weeks).

    Drug: MLN0128
    MLN0128 capsules
    Other Names:
  • INK128
  • TAK-128

    		•
    Experimental: MLN0128 QDx3d QW

    MLN0128 6 mg, 9 mg, 12 mg, 16 mg or 20 mg capsule, orally, once daily every 3 days a week (QDx3d QW) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 129.4 weeks).

    Drug: MLN0128
    MLN0128 capsules
    Other Names:
  • INK128
  • TAK-128

    		•
    Experimental: MLN0128 QDx5d QW

    MLN0128 7 mg, 10 mg or 13 mg capsule, orally, once daily every 5 days a week (QDx5d QW) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 161.9 weeks).

    Drug: MLN0128
    MLN0128 capsules
    Other Names:
  • INK128
  • TAK-128

    		•
    Experimental: MLN0128 5 mg QD

    MLN0128 5 mg, capsule, orally, QD in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 98.3 weeks).

    Drug: MLN0128
    MLN0128 capsules
    Other Names:
  • INK128
  • TAK-128

    		•
    Experimental: MLN0128 30 mg QW

    MLN0128 30 mg, capsule, orally QW in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 240 weeks).

    Drug: MLN0128
    MLN0128 capsules
    Other Names:
  • INK128
  • TAK-128

    		•
    Experimental: MLN0128 40 mg QW

    MLN0128 40 mg, capsule, orally, QW in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 100.1 weeks).

    Drug: MLN0128
    MLN0128 capsules
    Other Names:
  • INK128
  • TAK-128

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Dose Escalation Phase: Maximum Tolerated Dose (MTD) [Cycle 1 (28 Days)]

      MTD was defined as the highest dose level of MLN0128 at which no more than 1 out of 6 evaluable participants experienced a DLT during the first cycle (28 days) of therapy.

    2. Dose Escalation Phase: Number of Participants With Dose Limiting Toxicities (DLTs) [Cycle 1 (28 days)]

      DLTs were defined as MLN0128-related treatment-emergent adverse events (TEAEs) that occurred within the Cycle 1 (first 28 days of treatment) as per Common Terminology Criteria for Adverse Events (CTCAE): Any ≥Grade 3 or non-hematologic toxicity except for Grade 3 nausea and/or vomiting and diarrhea, Grade 3 hyperglycemia lasting ≤ 14 days, Grade 3 rash lasting ≤ 3 days; Grade 4 neutropenia lasting >7 days in the absence of growth factor support; Grade 4 neutropenia of any duration associated with fever ≥38.5 degree celsius and/or systemic infection; Any other Grade 4 hematologic toxicity; Inability to administer at least 75% of planned doses of MLN0128 within Cycle 1 due to drug-related toxicity and any clinically significant occurrence that the investigators and sponsor agreed would place participants at an undue safety risk.

    3. Number of Participants Experiencing One or More Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug [First dose of study drug through 30 days after the administration of the last dose of study drug (Up to approximately 244 weeks)]

      An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. A serious adverse event is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant.

    4. Dose Expansion: Objective Response Rate (ORR) [From the first dose of study drug up to disease progression or death (Up to approximately 240 weeks)]

      ORR is defined as the percentage of participants who achieved complete response (CR) or partial response (PR based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. CR is defined as disappearance of all target lesions and PR was defined of at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD and for non-target lesions. Data was categorized as per type of cancer.

    5. Dose Expansion Phase: Duration of Objective Response [From the first dose of study drug up to disease progression or death (Up to approximately 240 weeks)]

      Duration of objective response is defined as the number of months from the start date of CR or PR (whichever occurred first) based on RECIST Criteria version 1.1 to the first date of objectively documented progressive disease (PD) for participants who achieved CR or PR. PD is 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).

    6. Dose Expansion: Duration of Stable Disease (SD) [From the first dose of study drug up to disease progression or death (Up to approximately 240 weeks)]

      Duration of SD was evaluated for participants with best response of SD and is defined as number of months from date of first dose to date of PD. As per RECIST 1.1, SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PR was defined of at least a 30% decrease in sum of longest diameter (LD) of target lesions, taking as reference the baseline sum LD and for non-target lesions. PD is defined as at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study (this includes baseline sum if that is smallest on study).

    Secondary Outcome Measures

    1. Cmax: Maximum Observed Plasma Concentration for MLN0128 [Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2]

    2. Ctrough: Observed Concentration at the End of a Dosing Interval [Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2]

    3. Terminal Phase Elimination Half-life (T1/2) for MLN0128 [Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2]

    4. AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN0128 [Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2]

    5. AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN0128 [Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2]

    6. Tmax: Time to Maximum Observed Plasma Concentration for MLN0128 [Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2]

    7. Percentage Area Under Plasma Concentration Time Curve Extrapolated [Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2]

    8. Percentage Change From Baseline in Eukaryotic Initiation Factor 4E-binding Protein 1 (P4EBP1), Serine/Threonine Protein Kinase B (PAKT) and Ribosomal Protein S6 (PS6) [Baseline, Cycle 1 Week 2]

      P4EBP, PAKT and PS6 were assayed in skin biopsies. A negative percentage change from Baseline indicates improvement.

    Eligibility Criteria

    Criteria

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

    • Voluntary written consent

    • Locally advanced or metastatic solid tumors with the exception of primary brain tumor, and have failed standard of care therapy

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

    • Ability to swallow oral medications

    • For women of child-bearing potential, negative serum or urine pregnancy test within 14 days prior to the first study drug administration and use of physician-approved method of birth control from 30 days prior to 90 days following the last study drug administration

    • Male participants must be surgically sterile or must agree to use physician-approved contraception during the study and for 90 days following the last study drug administration

    • Clinical laboratory values as specified in the protocol

    Additionally, to be eligible for the Dose Expansion portion of the study:

    • Participants must have evidence of measurable disease per response evaluation criteria in solid tumors (RECIST) version 1.1 by radiographic techniques or magnetic resonance imaging

    • Participants must have a pathologic diagnosis of advanced or recurrent endometrial adenocarcinoma and must have failed at least 1 prior line of standard chemotherapy

    • Participants must have a pathologic diagnosis of advanced/metastatic urothelial cancer (carcinoma of the bladder, ureter, and/or renal pelvis) and must have failed at least 1 line of prior therapy in the metastatic/unresectable setting

    • Participants must have a pathologic diagnosis of advanced renal cell carcinoma (RCC), with histological or cytological confirmation of RCC and must have failed at least 1 prior line of anti-vascular endothelial growth factor therapy (VEGF) therapy (including but not limited to sunitinib, and/or sorafenib, and/or bevacizumab and/or pazopanib, and/or axitinib) and must not have received prior therapy with a target of rapamycin complex 1 (TORC1) inhibitor (such as temsirolimus or everolimus); or

    • Participants must have a pathologic diagnosis of advanced renal cell carcinoma (RCC) and must have progressed on treatment with a TORC1 inhibitor (such as temsirolimus or everolimus).

    Exclusion Criteria:

    • Diagnosis of primary brain tumor

    • Have received prior cancer or other investigational therapy within 2 weeks prior to the first administration of study drug

    • Known impaired cardiac function or clinically significant cardiac disease

    • Known treatment with systemic corticosteroid within one week prior to the first administration of study drug

    • Diabetes mellitus

    • Human immunodeficiency virus (HIV) infection

    • Known active cardiovascular disease condition as specified in protocol

    • Failed to recover from the reversible effects of prior anticancer therapies

    • Pregnancy (positive serum or urine pregnancy test) or breast feeding

    • Malabsorption due to prior gastrointestinal (GI) surgery, GI disease

    • Other clinically significant co-morbidities

    Please note that there are additional inclusion and exclusion criteria. The study center will determine if you meet all of the criteria.

    Site personnel will explain the trial in detail and answer any question you may have if you do qualify for the study. You can then decide whether or not you wish to participate. If you do not qualify for the trial, site personnel will explain the reasons.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Scottsdale Arizona United States
    2 Los Angeles California United States
    3 Miami Florida United States
    4 Sarasota Florida United States
    5 Indianapolis Indiana United States
    6 Boston Massachusetts United States
    7 Ann Arbor Michigan United States
    8 Detroit Michigan United States
    9 Buffalo New York United States
    10 New York New York United States
    11 Cleveland Ohio United States
    12 Oklahoma City Oklahoma United States
    13 Philadelphia Pennsylvania United States
    14 Nashville Tennessee United States
    15 Barcelona Spain
    16 Valencia Spain

    Sponsors and Collaborators

    • Millennium Pharmaceuticals, Inc.

    Investigators

    • Study Director: Medical Monitor, Millennium Pharmaceuticals, Inc.

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Millennium Pharmaceuticals, Inc.
    ClinicalTrials.gov Identifier:
    NCT01058707
    Other Study ID Numbers:
    • INK128-001
    • 2009-017284-42
    • U1111-1187-4258
    First Posted:
    Jan 29, 2010
    Last Update Posted:
    Apr 1, 2020
    Last Verified:
    Mar 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.
    Solid tumors, MLN0128, TORC1/2 inhibitors
    Additional relevant MeSH terms:
    Neoplasms

    Study Results

    Participant Flow

    Recruitment Details Participants took part in the study at 15 investigative sites in Spain and the United States from 4 January 2010 to 7 February 2019.
    Pre-assignment Detail Participants with a diagnosis of advanced malignancies were enrolled and received rising doses of MLN0128 in the Dose Escalation Phase to determine Maximum Tolerated Dose (MTD). In the Dose Expansion Phase participants were enrolled to receive one of 3 dose regimens: MLN0128 5 mg once daily (QD), 30 mg once weekly (QW) or 40 mg QW.
    Arm/Group Title MLN0128 QD MLN0128 QW MLN0128 QDx3d QW MLN0128 QDx5d QW MLN0128 5 mg QD MLN0128 30 mg QW MLN0128 40 mg QW
    Arm/Group Description MLN0128 2 mg, 4 mg, 6 mg or 7 mg, capsule, orally, once daily (QD) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 52.1 weeks). MLN0128 7 mg, 10 mg, 15 mg, 20 mg, 30 mg or 40 mg capsule, orally, once weekly (QW) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 139.4 weeks). MLN0128 6 mg, 9 mg, 12 mg, 16 mg or 20 mg capsule, orally, once daily every 3 days a week (QDx3d QW) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 129.4 weeks). MLN0128 7 mg, 10 mg or 13 mg capsule, orally, once daily every 5 days a week (QDx5d QW) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 161.9 weeks). MLN0128 5 mg, capsule, orally, QD in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 98.3 weeks). MLN0128 30 mg, capsule, orally QW in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 240 weeks). MLN0128 40 mg, capsule, orally, QW in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 100.1 weeks).
    Period Title: Overall Study
    STARTED 31 30 33 22 39 17 26
    COMPLETED 0 0 0 0 0 0 0
    NOT COMPLETED 31 30 33 22 39 17 26

    Baseline Characteristics

    Arm/Group Title MLN0128 QD MLN0128 QW MLN0128 QDx3d QW MLN0128 QDx5d QW MLN0128 5 mg QD MLN0128 30 mg QW MLN0128 40 mg QW Total
    Arm/Group Description MLN0128 2 mg, 4 mg, 6 mg or 7 mg, capsule, orally, once daily (QD) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 52.1 weeks). MLN0128 7 mg, 10 mg, 15 mg, 20 mg, 30 mg or 40 mg capsule, orally, once weekly (QW) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 139.4 weeks). MLN0128 6 mg, 9 mg, 12 mg, 16 mg or 20 mg capsule, orally, once daily every 3 days a week (QDx3d QW) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 129.4 weeks). MLN0128 7 mg, 10 mg or 13 mg capsule, orally, once daily every 5 days a week (QDx5d QW) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 161.9 weeks). MLN0128 5 mg, capsule, orally, QD in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 98.3 weeks). MLN0128 30 mg, capsule, orally QW in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 240 weeks). MLN0128 40 mg, capsule, orally, QW in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 100.1 weeks). Total of all reporting groups
    Overall Participants 31 30 33 22 39 17 26 198
    Age (years) [Mean (Full Range) ]
    Mean (Full Range) [years]
    59.7
    53.8
    56.1
    58.1
    58.8
    59.7
    63.2
    58.31
    Sex: Female, Male (Count of Participants)
    Female
    16
    51.6%
    18
    60%
    22
    66.7%
    13
    59.1%
    16
    41%
    6
    35.3%
    14
    53.8%
    105
    53%
    Male
    15
    48.4%
    12
    40%
    11
    33.3%
    9
    40.9%
    23
    59%
    11
    64.7%
    12
    46.2%
    93
    47%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    11
    35.5%
    11
    36.7%
    7
    21.2%
    9
    40.9%
    8
    20.5%
    1
    5.9%
    2
    7.7%
    49
    24.7%
    Not Hispanic or Latino
    20
    64.5%
    19
    63.3%
    26
    78.8%
    13
    59.1%
    30
    76.9%
    16
    94.1%
    24
    92.3%
    148
    74.7%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    2.6%
    0
    0%
    0
    0%
    1
    0.5%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Asian
    1
    3.2%
    0
    0%
    0
    0%
    0
    0%
    1
    2.6%
    0
    0%
    0
    0%
    2
    1%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    2
    6.5%
    1
    3.3%
    3
    9.1%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    6
    3%
    White
    28
    90.3%
    29
    96.7%
    30
    90.9%
    22
    100%
    37
    94.9%
    17
    100%
    25
    96.2%
    188
    94.9%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    3.8%
    1
    0.5%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    2.6%
    0
    0%
    0
    0%
    1
    0.5%
    Region of Enrollment (Count of Participants)
    United States
    21
    67.7%
    18
    60%
    19
    57.6%
    12
    54.5%
    32
    82.1%
    15
    88.2%
    25
    96.2%
    142
    71.7%
    Spain
    10
    32.3%
    12
    40%
    14
    42.4%
    10
    45.5%
    7
    17.9%
    2
    11.8%
    1
    3.8%
    56
    28.3%

    Outcome Measures

    1. Primary Outcome
    Title Dose Escalation Phase: Maximum Tolerated Dose (MTD)
    Description MTD was defined as the highest dose level of MLN0128 at which no more than 1 out of 6 evaluable participants experienced a DLT during the first cycle (28 days) of therapy.
    Time Frame Cycle 1 (28 Days)

    Outcome Measure Data

    Analysis Population Description
    Dose Escalation-Evaluable Population included participants who received ≥ 75% or more of planned doses of MLN0128 in Cycle 1 or stopped study drug before receiving 75% of doses because of study drug-related AEs considered a DLT.
    Arm/Group Title MLN0128 QD MLN0128 QW MLN0128 QDx3d QW MLN0128 QDx5d QW
    Arm/Group Description MLN0128 2 mg, 4 mg, 6 mg or 7 mg, capsule, orally, once daily (QD) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 52.1 weeks). MLN0128 7 mg, 10 mg, 15 mg, 20 mg, 30 mg or 40 mg capsule, orally, once weekly (QW) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 139.4 weeks). MLN0128 6 mg, 9 mg, 12 mg, 16 mg or 20 mg capsule, orally, once daily every 3 days a week (QDx3d QW) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 129.4 weeks). MLN0128 7 mg, 10 mg or 13 mg capsule, orally, once daily every 5 days a week (QDx5d QW) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 161.9 weeks).
    Measure Participants 25 27 29 22
    Number [milligrams (mg)]
    6
    40
    9
    7
    2. Primary Outcome
    Title Dose Escalation Phase: Number of Participants With Dose Limiting Toxicities (DLTs)
    Description DLTs were defined as MLN0128-related treatment-emergent adverse events (TEAEs) that occurred within the Cycle 1 (first 28 days of treatment) as per Common Terminology Criteria for Adverse Events (CTCAE): Any ≥Grade 3 or non-hematologic toxicity except for Grade 3 nausea and/or vomiting and diarrhea, Grade 3 hyperglycemia lasting ≤ 14 days, Grade 3 rash lasting ≤ 3 days; Grade 4 neutropenia lasting >7 days in the absence of growth factor support; Grade 4 neutropenia of any duration associated with fever ≥38.5 degree celsius and/or systemic infection; Any other Grade 4 hematologic toxicity; Inability to administer at least 75% of planned doses of MLN0128 within Cycle 1 due to drug-related toxicity and any clinically significant occurrence that the investigators and sponsor agreed would place participants at an undue safety risk.
    Time Frame Cycle 1 (28 days)

    Outcome Measure Data

    Analysis Population Description
    Dose Escalation-Evaluable Population included participants who received ≥ 75% or more of planned doses of MLN0128 in Cycle 1 or stopped study drug before receiving 75% of doses because of study drug-related AEs considered a DLT.
    Arm/Group Title MLN0128 QD MLN0128 QW MLN0128 QDx3d QW MLN0128 QDx5d QW
    Arm/Group Description MLN0128 2 mg, 4 mg, 6 mg or 7 mg, capsule, orally, once daily (QD) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 52.1 weeks). MLN0128 7 mg, 10 mg, 15 mg, 20 mg, 30 mg or 40 mg capsule, orally, once weekly (QW) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 139.4 weeks). MLN0128 6 mg, 9 mg, 12 mg, 16 mg or 20 mg capsule, orally, once daily every 3 days a week (QDx3d QW) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 129.4 weeks). MLN0128 7 mg, 10 mg or 13 mg capsule, orally, once daily every 5 days a week (QDx5d QW) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 161.9 weeks).
    Measure Participants 25 27 29 22
    Count of Participants [Participants]
    7
    22.6%
    2
    6.7%
    6
    18.2%
    7
    31.8%
    3. Primary Outcome
    Title Number of Participants Experiencing One or More Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug
    Description An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. A serious adverse event is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant.
    Time Frame First dose of study drug through 30 days after the administration of the last dose of study drug (Up to approximately 244 weeks)

    Outcome Measure Data

    Analysis Population Description
    ASaT population included all participants who received at least 1 dose of MLN0128.
    Arm/Group Title MLN0128 QD MLN0128 QW MLN0128 QDx3d QW MLN0128 QDx5d QW MLN0128 5 mg QD MLN0128 30 mg QW MLN0128 40 mg QW
    Arm/Group Description MLN0128 2 mg, 4 mg, 6 mg or 7 mg, capsule, orally, once daily (QD) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 52.1 weeks). MLN0128 7 mg, 10 mg, 15 mg, 20 mg, 30 mg or 40 mg capsule, orally, once weekly (QW) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 139.4 weeks). MLN0128 6 mg, 9 mg, 12 mg, 16 mg or 20 mg capsule, orally, once daily every 3 days a week (QDx3d QW) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 129.4 weeks). MLN0128 7 mg, 10 mg or 13 mg capsule, orally, once daily every 5 days a week (QDx5d QW) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 161.9 weeks). MLN0128 5 mg, capsule, orally, QD in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 98.3 weeks). MLN0128 30 mg, capsule, orally QW in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 240 weeks). MLN0128 40 mg, capsule, orally, QW in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 100.1 weeks).
    Measure Participants 31 30 33 22 39 17 26
    TEAE
    31
    100%
    30
    100%
    33
    100%
    22
    100%
    39
    100%
    17
    100%
    26
    100%
    SAE
    13
    41.9%
    10
    33.3%
    17
    51.5%
    10
    45.5%
    19
    48.7%
    6
    35.3%
    9
    34.6%
    AEs Resulting in Discontinuation of MLN0128
    11
    35.5%
    4
    13.3%
    7
    21.2%
    6
    27.3%
    7
    17.9%
    3
    17.6%
    2
    7.7%
    Fatal AEs within 30 Days of Last Dose Study Drug
    1
    3.2%
    1
    3.3%
    2
    6.1%
    0
    0%
    0
    0%
    2
    11.8%
    1
    3.8%
    4. Primary Outcome
    Title Dose Expansion: Objective Response Rate (ORR)
    Description ORR is defined as the percentage of participants who achieved complete response (CR) or partial response (PR based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. CR is defined as disappearance of all target lesions and PR was defined of at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD and for non-target lesions. Data was categorized as per type of cancer.
    Time Frame From the first dose of study drug up to disease progression or death (Up to approximately 240 weeks)

    Outcome Measure Data

    Analysis Population Description
    Response-Evaluable Population included participants who received at least 1 dose of MLN0128, had measurable disease at Baseline, and underwent at least 1 post-Baseline disease assessment. Participants without a post-Baseline disease assessment but discontinued study drug due to symptomatic and/or clinical deterioration were included.
    Arm/Group Title MLN0128 5 mg QD MLN0128 30 mg QW MLN0128 40 mg QW
    Arm/Group Description MLN0128 5 mg, capsule, orally, QD in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 98.3 weeks). MLN0128 30 mg, capsule, orally QW in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 240 weeks). MLN0128 40 mg, capsule, orally, QW in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 100.1 weeks).
    Measure Participants 36 14 22
    Cancer Type: Renal
    15
    48.4%
    13
    43.3%
    15
    45.5%
    Cancer Type: Endometrial
    9
    29%
    0
    0%
    0
    0%
    Cancer Type: Bladder
    0
    0%
    0
    0%
    0
    0%
    5. Primary Outcome
    Title Dose Expansion Phase: Duration of Objective Response
    Description Duration of objective response is defined as the number of months from the start date of CR or PR (whichever occurred first) based on RECIST Criteria version 1.1 to the first date of objectively documented progressive disease (PD) for participants who achieved CR or PR. PD is 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).
    Time Frame From the first dose of study drug up to disease progression or death (Up to approximately 240 weeks)

    Outcome Measure Data

    Analysis Population Description
    Response-Evaluable Population:participants who received ≥1 dose of MLN0128,had measurable disease at Baseline,had ≥1 post-Baseline disease assessment.Participants without post-Baseline disease assessment but discontinued study drug due to symptomatic and/or clinical deterioration were included.CR/PR participants with available data were analyzed.
    Arm/Group Title MLN0128 5 mg QD MLN0128 30 mg QW MLN0128 40 mg QW
    Arm/Group Description MLN0128 5 mg, capsule, orally, QD in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 98.3 weeks). MLN0128 30 mg, capsule, orally QW in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 240 weeks). MLN0128 40 mg, capsule, orally, QW in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 100.1 weeks).
    Measure Participants 4 1 2
    Median (Full Range) [months]
    8.90
    56.05
    20.73
    6. Primary Outcome
    Title Dose Expansion: Duration of Stable Disease (SD)
    Description Duration of SD was evaluated for participants with best response of SD and is defined as number of months from date of first dose to date of PD. As per RECIST 1.1, SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PR was defined of at least a 30% decrease in sum of longest diameter (LD) of target lesions, taking as reference the baseline sum LD and for non-target lesions. PD is defined as at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study (this includes baseline sum if that is smallest on study).
    Time Frame From the first dose of study drug up to disease progression or death (Up to approximately 240 weeks)

    Outcome Measure Data

    Analysis Population Description
    Response-Evaluable Population: participants who received ≥1 dose of MLN0128, had measurable disease at Baseline (BL), underwent ≥1 post-BL disease assessment. Participants without post-BL disease assessment but discontinued study drug due to symptomatic and/or clinical deterioration were included. SD participants with available data were analyzed.
    Arm/Group Title MLN0128 5 mg QD MLN0128 30 mg QW MLN0128 40 mg QW
    Arm/Group Description MLN0128 5 mg, capsule, orally, QD in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 98.3 weeks). MLN0128 30 mg, capsule, orally QW in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 240 weeks). MLN0128 40 mg, capsule, orally, QW in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 100.1 weeks).
    Measure Participants 19 5 11
    Median (Full Range) [months]
    3.68
    2.20
    3.55
    7. Secondary Outcome
    Title Cmax: Maximum Observed Plasma Concentration for MLN0128
    Description
    Time Frame Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic (PK) population consisted of all participants included during the dose escalation phase of the study who received at least 1 dose of MLN0128. Number analyzed is the number of participants with data available for analysis at the given time-point.
    Arm/Group Title MLN0128 2 mg QD MLN0128 4 mg QD MLN0128 6 mg QD MLN0128 7 mg QD MLN0128 7 mg QW MLN0128 10 mg QW MLN0128 15 mg QW MLN0128 20 mg QW MLN0128 30 mg QW MLN0128 40 mg QW MLN0128 6 mg QDx3dQW MLN0128 9 mg QDx3d QW MLN0128 12 mg QDx3d QW MLN0128 16 mg QDx3d QW MLN0128 20 mg QDx3dQW MLN0128 7 mg QDx5dQW MLN0128 10 mg QDx5dQW MLN0128 13 mg QDx5dQW
    Arm/Group Description MLN0128 2 mg capsule, orally, QD in 28-day cycle (Up to 10.1 weeks). MLN0128 4 mg capsule, orally, QD in 28-day cycle (Up to 14.0 weeks) MLN0128 6 mg capsule, orally, QD in 28-day cycle (Up to 32.0 weeks). MLN0128 7 mg, capsule, orally QD in 28-day cycle (Up to 52.1 weeks). MLN0128 7 mg, capsule, orally QD in 28-day cycle (Up to 7.0 weeks). MLN0128 10 mg, capsule, orally QW in 28-day cycle (Up to 15.1 weeks). MLN0128 15 mg, capsule, orally QW in 28-day cycle (Up to 7.1 weeks). MLN0128 20 mg, capsule, orally QW in 28-day cycle (Up to 10.1 weeks). MLN0128 30 mg, capsule, orally QW in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 240 weeks). MLN0128 40 mg, capsule, orally, QW in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 100.1 weeks). MLN0128 6 mg, capsule, orally QDx3d QW in 28-day cycle (Up to 8.4 weeks). MLN0128 9 mg, capsule, orally QDx3d QW in 28-day cycle (Up to 129.4 weeks). MLN0128 12 mg, capsule, orally QDx3d QW in 28-day cycle (Up to 11.4 weeks). MLN0128 16 mg, capsule, orally QDx3d QW in 28-day cycle (Up to 31.4 weeks). MLN0128 20 mg, capsule, orally QDx3d QW in 28-day cycle (Up to 7.4 weeks). MLN0128 7 mg, capsule, orally QDx5d QW in 28-day cycle (Up to 15.9 weeks). MLN0128 10 mg, capsule, orally QDx5d QW in 28-day cycle (Up to 161.9 weeks). MLN0128 13 mg, capsule, orally QDx5d QW in 28-day cycle (Up to 7.7 weeks).
    Measure Participants 3 7 12 8 3 3 3 3 3 15 3 8 6 11 4 6 11 3
    Cycle 1 Day 1
    13.7
    20.5
    48.9
    67.8
    43.6
    75.9
    80.2
    136.6
    174.0
    193.8
    88.5
    82.9
    124.3
    78.5
    194.0
    46.9
    48.5
    110.1
    Cycle 2 Day 1
    16.2
    22.1
    39.4
    65.0
    66.7
    40.5
    66.9
    134.00
    142.6
    249.8
    60.0
    87.7
    115.1
    113.6
    183.00
    60.1
    60.0
    96.50
    8. Secondary Outcome
    Title Ctrough: Observed Concentration at the End of a Dosing Interval
    Description
    Time Frame Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2

    Outcome Measure Data

    Analysis Population Description
    PK population consisted of all participants included during the dose escalation phase of the study who received at least 1 dose of MLN0128. Number analyzed is the number of participants with data available for analysis at the given time-point.
    Arm/Group Title MLN0128 2 mg QD MLN0128 4 mg QD MLN0128 6 mg QD MLN0128 7 mg QD MLN0128 7 mg QW MLN0128 10 mg QW MLN0128 15 mg QW MLN0128 20 mg QW MLN0128 30 mg QW MLN0128 40 mg QW MLN0128 6 mg QDx3dQW MLN0128 9 mg QDx3d QW MLN0128 12 mg QDx3d QW MLN0128 16 mg QDx3d QW MLN0128 20 mg QDx3dQW MLN0128 7 mg QDx5dQW MLN0128 10 mg QDx5dQW MLN0128 13 mg QDx5dQW
    Arm/Group Description MLN0128 2 mg capsule, orally, QD in 28-day cycle (Up to 10.1 weeks). MLN0128 4 mg capsule, orally, QD in 28-day cycle (Up to 14.0 weeks) MLN0128 6 mg capsule, orally, QD in 28-day cycle (Up to 32.0 weeks). MLN0128 7 mg, capsule, orally QD in 28-day cycle (Up to 52.1 weeks). MLN0128 7 mg, capsule, orally QD in 28-day cycle (Up to 7.0 weeks). MLN0128 10 mg, capsule, orally QW in 28-day cycle (Up to 15.1 weeks). MLN0128 15 mg, capsule, orally QW in 28-day cycle (Up to 7.1 weeks). MLN0128 20 mg, capsule, orally QW in 28-day cycle (Up to 10.1 weeks). MLN0128 30 mg, capsule, orally QW in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 240 weeks). MLN0128 40 mg, capsule, orally, QW in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 100.1 weeks). MLN0128 6 mg, capsule, orally QDx3d QW in 28-day cycle (Up to 8.4 weeks). MLN0128 9 mg, capsule, orally QDx3d QW in 28-day cycle (Up to 129.4 weeks). MLN0128 12 mg, capsule, orally QDx3d QW in 28-day cycle (Up to 11.4 weeks). MLN0128 16 mg, capsule, orally QDx3d QW in 28-day cycle (Up to 31.4 weeks). MLN0128 20 mg, capsule, orally QDx3d QW in 28-day cycle (Up to 7.4 weeks). MLN0128 7 mg, capsule, orally QDx5d QW in 28-day cycle (Up to 15.9 weeks). MLN0128 10 mg, capsule, orally QDx5d QW in 28-day cycle (Up to 161.9 weeks). MLN0128 13 mg, capsule, orally QDx5d QW in 28-day cycle (Up to 7.7 weeks).
    Measure Participants 3 7 12 8 3 3 3 3 3 15 3 8 6 11 4 6 11 3
    Cycle 1 Day 1
    0.9
    1.2
    3.5
    4.4
    2.5
    6.8
    9.9
    8.1
    44.7
    3.1
    3.6
    21.7
    Cycle 2 Day 1
    4.5
    3.7
    4.5
    3.0
    10.3
    10.8
    4.4
    10.0
    11.40
    5.2
    3.0
    6.58
    9. Secondary Outcome
    Title Terminal Phase Elimination Half-life (T1/2) for MLN0128
    Description
    Time Frame Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2

    Outcome Measure Data

    Analysis Population Description
    PK population consisted of all participants included during the dose escalation phase of the study who received at least 1 dose of MLN0128. Number analyzed is the number of participants with data available for analysis at the given time-point.
    Arm/Group Title MLN0128 2 mg QD MLN0128 4 mg QD MLN0128 6 mg QD MLN0128 7 mg QD MLN0128 7 mg QW MLN0128 10 mg QW MLN0128 15 mg QW MLN0128 20 mg QW MLN0128 30 mg QW MLN0128 40 mg QW MLN0128 6 mg QDx3dQW MLN0128 9 mg QDx3d QW MLN0128 12 mg QDx3d QW MLN0128 16 mg QDx3d QW MLN0128 20 mg QDx3dQW MLN0128 7 mg QDx5dQW MLN0128 10 mg QDx5dQW MLN0128 13 mg QDx5dQW
    Arm/Group Description MLN0128 2 mg capsule, orally, QD in 28-day cycle (Up to 10.1 weeks). MLN0128 4 mg capsule, orally, QD in 28-day cycle (Up to 14.0 weeks) MLN0128 6 mg capsule, orally, QD in 28-day cycle (Up to 32.0 weeks). MLN0128 7 mg, capsule, orally QD in 28-day cycle (Up to 52.1 weeks). MLN0128 7 mg, capsule, orally QD in 28-day cycle (Up to 7.0 weeks). MLN0128 10 mg, capsule, orally QW in 28-day cycle (Up to 15.1 weeks). MLN0128 15 mg, capsule, orally QW in 28-day cycle (Up to 7.1 weeks). MLN0128 20 mg, capsule, orally QW in 28-day cycle (Up to 10.1 weeks). MLN0128 30 mg, capsule, orally QW in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 240 weeks). MLN0128 40 mg, capsule, orally, QW in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 100.1 weeks). MLN0128 6 mg, capsule, orally QDx3d QW in 28-day cycle (Up to 8.4 weeks). MLN0128 9 mg, capsule, orally QDx3d QW in 28-day cycle (Up to 129.4 weeks). MLN0128 12 mg, capsule, orally QDx3d QW in 28-day cycle (Up to 11.4 weeks). MLN0128 16 mg, capsule, orally QDx3d QW in 28-day cycle (Up to 31.4 weeks). MLN0128 20 mg, capsule, orally QDx3d QW in 28-day cycle (Up to 7.4 weeks). MLN0128 7 mg, capsule, orally QDx5d QW in 28-day cycle (Up to 15.9 weeks). MLN0128 10 mg, capsule, orally QDx5d QW in 28-day cycle (Up to 161.9 weeks). MLN0128 13 mg, capsule, orally QDx5d QW in 28-day cycle (Up to 7.7 weeks).
    Measure Participants 3 7 12 8 3 3 3 3 3 15 3 8 6 11 4 6 11 3
    Cycle 1 Day 1
    10.3
    7.4
    6.3
    6.2
    6.47
    5.8
    9.4
    5.7
    5.5
    7.1
    5.5
    7.9
    6.4
    7.2
    5.5
    7.8
    6.5
    8.7
    Cycle 2 Day 1
    8.1
    9.7
    7.9
    4.9
    5.6
    8.01
    4.57
    5.7
    5.6
    9.1
    7.0
    4.9
    6.4
    6.28
    6.8
    5.6
    6.42
    10. Secondary Outcome
    Title AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN0128
    Description
    Time Frame Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2

    Outcome Measure Data

    Analysis Population Description
    PK population consisted of all participants included during the dose escalation phase of the study who received at least 1 dose of MLN0128. Number analyzed is the number of participants with data available for analysis at the given time-point.
    Arm/Group Title MLN0128 2 mg QD MLN0128 4 mg QD MLN0128 6 mg QD MLN0128 7 mg QD MLN0128 7 mg QW MLN0128 10 mg QW MLN0128 15 mg QW MLN0128 20 mg QW MLN0128 30 mg QW MLN0128 40 mg QW MLN0128 6 mg QDx3dQW MLN0128 9 mg QDx3d QW MLN0128 12 mg QDx3d QW MLN0128 16 mg QDx3d QW MLN0128 20 mg QDx3dQW MLN0128 7 mg QDx5dQW MLN0128 10 mg QDx5dQW MLN0128 13 mg QDx5dQW
    Arm/Group Description MLN0128 2 mg capsule, orally, QD in 28-day cycle (Up to 10.1 weeks). MLN0128 4 mg capsule, orally, QD in 28-day cycle (Up to 14.0 weeks) MLN0128 6 mg capsule, orally, QD in 28-day cycle (Up to 32.0 weeks). MLN0128 7 mg, capsule, orally QD in 28-day cycle (Up to 52.1 weeks). MLN0128 7 mg, capsule, orally QD in 28-day cycle (Up to 7.0 weeks). MLN0128 10 mg, capsule, orally QW in 28-day cycle (Up to 15.1 weeks). MLN0128 15 mg, capsule, orally QW in 28-day cycle (Up to 7.1 weeks). MLN0128 20 mg, capsule, orally QW in 28-day cycle (Up to 10.1 weeks). MLN0128 30 mg, capsule, orally QW in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 240 weeks). MLN0128 40 mg, capsule, orally, QW in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 100.1 weeks). MLN0128 6 mg, capsule, orally QDx3d QW in 28-day cycle (Up to 8.4 weeks). MLN0128 9 mg, capsule, orally QDx3d QW in 28-day cycle (Up to 129.4 weeks). MLN0128 12 mg, capsule, orally QDx3d QW in 28-day cycle (Up to 11.4 weeks). MLN0128 16 mg, capsule, orally QDx3d QW in 28-day cycle (Up to 31.4 weeks). MLN0128 20 mg, capsule, orally QDx3d QW in 28-day cycle (Up to 7.4 weeks). MLN0128 7 mg, capsule, orally QDx5d QW in 28-day cycle (Up to 15.9 weeks). MLN0128 10 mg, capsule, orally QDx5d QW in 28-day cycle (Up to 161.9 weeks). MLN0128 13 mg, capsule, orally QDx5d QW in 28-day cycle (Up to 7.7 weeks).
    Measure Participants 3 7 12 8 3 3 3 3 3 15 3 8 6 11 4 6 11 3
    Cycle 1 Day 1
    185.00
    205.3
    390.6
    459.5
    440.00
    609.0
    1014.5
    1172.7
    1316.3
    2149.8
    494.0
    725.2
    922.8
    820.1
    1245.0
    326.2
    388.5
    941.5
    Cycle 2 Day 1
    371.0
    510.00
    1030.00
    1427.5
    2876.6
    11. Secondary Outcome
    Title AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN0128
    Description
    Time Frame Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2

    Outcome Measure Data

    Analysis Population Description
    PK population consisted of all participants included during the dose escalation phase of the study who received at least 1 dose of MLN0128. Number analyzed is the number of participants with data available for analysis at the given time-point.
    Arm/Group Title MLN0128 2 mg QD MLN0128 4 mg QD MLN0128 6 mg QD MLN0128 7 mg QD MLN0128 7 mg QW MLN0128 10 mg QW MLN0128 15 mg QW MLN0128 20 mg QW MLN0128 30 mg QW MLN0128 40 mg QW MLN0128 6 mg QDx3dQW MLN0128 9 mg QDx3d QW MLN0128 12 mg QDx3d QW MLN0128 16 mg QDx3d QW MLN0128 20 mg QDx3dQW MLN0128 7 mg QDx5dQW MLN0128 10 mg QDx5dQW MLN0128 13 mg QDx5dQW
    Arm/Group Description MLN0128 2 mg capsule, orally, QD in 28-day cycle (Up to 10.1 weeks). MLN0128 4 mg capsule, orally, QD in 28-day cycle (Up to 14.0 weeks) MLN0128 6 mg capsule, orally, QD in 28-day cycle (Up to 32.0 weeks). MLN0128 7 mg, capsule, orally QD in 28-day cycle (Up to 52.1 weeks). MLN0128 7 mg, capsule, orally QD in 28-day cycle (Up to 7.0 weeks). MLN0128 10 mg, capsule, orally QW in 28-day cycle (Up to 15.1 weeks). MLN0128 15 mg, capsule, orally QW in 28-day cycle (Up to 7.1 weeks). MLN0128 20 mg, capsule, orally QW in 28-day cycle (Up to 10.1 weeks). MLN0128 30 mg, capsule, orally QW in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 240 weeks). MLN0128 40 mg, capsule, orally, QW in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 100.1 weeks). MLN0128 6 mg, capsule, orally QDx3d QW in 28-day cycle (Up to 8.4 weeks). MLN0128 9 mg, capsule, orally QDx3d QW in 28-day cycle (Up to 129.4 weeks). MLN0128 12 mg, capsule, orally QDx3d QW in 28-day cycle (Up to 11.4 weeks). MLN0128 16 mg, capsule, orally QDx3d QW in 28-day cycle (Up to 31.4 weeks). MLN0128 20 mg, capsule, orally QDx3d QW in 28-day cycle (Up to 7.4 weeks). MLN0128 7 mg, capsule, orally QDx5d QW in 28-day cycle (Up to 15.9 weeks). MLN0128 10 mg, capsule, orally QDx5d QW in 28-day cycle (Up to 161.9 weeks). MLN0128 13 mg, capsule, orally QDx5d QW in 28-day cycle (Up to 7.7 weeks).
    Measure Participants 3 7 12 8 3 3 3 3 3 15 3 8 6 11 4 6 11 3
    Cycle 1 Day 1
    65.4
    65.3
    95.30
    72.80
    106.00
    162.00
    207.5
    130.2
    221.00
    Cycle 2 Day 1
    62.2
    105.00
    182.00
    197.00
    12. Secondary Outcome
    Title Tmax: Time to Maximum Observed Plasma Concentration for MLN0128
    Description
    Time Frame Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2

    Outcome Measure Data

    Analysis Population Description
    PK population consisted of all participants included during the dose escalation phase of the study who received at least 1 dose of MLN0128. Number analyzed is the number of participants with data available for analysis at the given time-point.
    Arm/Group Title MLN0128 2 mg QD MLN0128 4 mg QD MLN0128 6 mg QD MLN0128 7 mg QD MLN0128 7 mg QW MLN0128 10 mg QW MLN0128 15 mg QW MLN0128 20 mg QW MLN0128 30mg QW MLN0128 40 mg QW MLN0128 6 mg QDx3dQW MLN0128 9 mg QDx3d QW MLN0128 12 mg QDx3d QW MLN0128 16 mg QDx3d QW MLN0128 20 mg QDx3dQW MLN0128 7 mg QDx5dQW MLN0128 10 mg QDx5dQW MLN0128 13 mg QDx5dQW
    Arm/Group Description MLN0128 2 mg capsule, orally, QD in 28-day cycle (Up to 10.1 weeks). MLN0128 4 mg capsule, orally, QD in 28-day cycle (Up to 14.0 weeks) MLN0128 6 mg capsule, orally, QD in 28-day cycle (Up to 32.0 weeks). MLN0128 7 mg, capsule, orally QD in 28-day cycle (Up to 52.1 weeks). MLN0128 7 mg, capsule, orally QD in 28-day cycle (Up to 7.0 weeks). MLN0128 10 mg, capsule, orally QW in 28-day cycle (Up to 15.1 weeks). MLN0128 15 mg, capsule, orally QW in 28-day cycle (Up to 7.1 weeks). MLN0128 20 mg, capsule, orally QW in 28-day cycle (Up to 10.1 weeks). MLN0128 30 mg, capsule, orally QW in 28-day cycle (Up to 139.4 weeks). MLN0128 40 mg, capsule, orally, QW in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 100.1 weeks). MLN0128 6 mg, capsule, orally QDx3d QW in 28-day cycle (Up to 8.4 weeks). MLN0128 9 mg, capsule, orally QDx3d QW in 28-day cycle (Up to 129.4 weeks). MLN0128 12 mg, capsule, orally QDx3d QW in 28-day cycle (Up to 11.4 weeks). MLN0128 16 mg, capsule, orally QDx3d QW in 28-day cycle (Up to 31.4 weeks). MLN0128 20 mg, capsule, orally QDx3d QW in 28-day cycle (Up to 7.4 weeks). MLN0128 7 mg, capsule, orally QDx5d QW in 28-day cycle (Up to 15.9 weeks). MLN0128 10 mg, capsule, orally QDx5d QW in 28-day cycle (Up to 161.9 weeks). MLN0128 13 mg, capsule, orally QDx5d QW in 28-day cycle (Up to 7.7 weeks).
    Measure Participants 3 7 12 8 3 3 3 3 3 15 3 8 6 11 4 6 11 3
    Cycle 1 Day 1
    2.0
    2.0
    1.0
    1.5
    2.1
    1.0
    2.0
    2.0
    1.0
    2.4
    0.6
    1.1
    2.0
    2.1
    3.1
    1.2
    4.0
    2.1
    Cycle 2 Day 1
    2.0
    3.8
    2.0
    4.0
    1.02
    2.9
    2.0
    4.0
    4.0
    2.0
    4.0
    2.1
    3.7
    2.1
    1.0
    1.5
    2.0
    2.02
    13. Secondary Outcome
    Title Percentage Area Under Plasma Concentration Time Curve Extrapolated
    Description
    Time Frame Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2

    Outcome Measure Data

    Analysis Population Description
    The study was acquired from another organization and limited results data are available.
    Arm/Group Title MLN0128 2 mg QD MLN0128 4 mg QD MLN0128 6 mg QD MLN0128 7 mg QD MLN0128 7 mg QW MLN0128 10 mg QW MLN0128 15 mg QW MLN0128 20 mg QW MLN0128 30 mg QW MLN0128 40 mg QW MLN0128 6 mg QDx3dQW MLN0128 9 mg QDx3d QW MLN0128 12 mg QDx3d QW MLN0128 16 mg QDx3d QW MLN0128 20 mg QDx3dQW MLN0128 7 mg QDx5dQW MLN0128 10 mg QDx5dQW MLN0128 13 mg QDx5dQW
    Arm/Group Description MLN0128 2 mg capsule, orally, QD in 28-day cycle (Up to 10.1 weeks). MLN0128 4 mg capsule, orally, QD in 28-day cycle (Up to 14.0 weeks) MLN0128 6 mg capsule, orally, QD in 28-day cycle (Up to 32.0 weeks). MLN0128 7 mg, capsule, orally QD in 28-day cycle (Up to 52.1 weeks). MLN0128 7 mg, capsule, orally QD in 28-day cycle (Up to 7.0 weeks). MLN0128 10 mg, capsule, orally QW in 28-day cycle (Up to 15.1 weeks). MLN0128 15 mg, capsule, orally QW in 28-day cycle (Up to 7.1 weeks). MLN0128 20 mg, capsule, orally QW in 28-day cycle (Up to 10.1 weeks). MLN0128 30 mg, capsule, orally QW in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 240 weeks). MLN0128 40 mg, capsule, orally, QW in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 100.1 weeks). MLN0128 6 mg, capsule, orally QDx3d QW in 28-day cycle (Up to 8.4 weeks). MLN0128 9 mg, capsule, orally QDx3d QW in 28-day cycle (Up to 129.4 weeks). MLN0128 12 mg, capsule, orally QDx3d QW in 28-day cycle (Up to 11.4 weeks). MLN0128 16 mg, capsule, orally QDx3d QW in 28-day cycle (Up to 31.4 weeks). MLN0128 20 mg, capsule, orally QDx3d QW in 28-day cycle (Up to 7.4 weeks). MLN0128 7 mg, capsule, orally QDx5d QW in 28-day cycle (Up to 15.9 weeks). MLN0128 10 mg, capsule, orally QDx5d QW in 28-day cycle (Up to 161.9 weeks). MLN0128 13 mg, capsule, orally QDx5d QW in 28-day cycle (Up to 7.7 weeks).
    Measure Participants 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
    14. Secondary Outcome
    Title Percentage Change From Baseline in Eukaryotic Initiation Factor 4E-binding Protein 1 (P4EBP1), Serine/Threonine Protein Kinase B (PAKT) and Ribosomal Protein S6 (PS6)
    Description P4EBP, PAKT and PS6 were assayed in skin biopsies. A negative percentage change from Baseline indicates improvement.
    Time Frame Baseline, Cycle 1 Week 2

    Outcome Measure Data

    Analysis Population Description
    ASaT population included all participants who received at least 1 dose of MLN0128 in dose escalation phase. Participants with data at Baseline and Cycle 1 Week 2 are included. Number analyzed is the number of participants with data available at the given time-point.
    Arm/Group Title MLN0128 QD MLN0128 QW MLN0128 QDx3d QW MLN0128 QDx5d QW
    Arm/Group Description MLN0128 2 mg, 4 mg, 6 mg or 7 mg, capsule, orally, once daily (QD) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 52.1 weeks). MLN0128 7 mg, 10 mg, 15 mg, 20 mg, 30 mg or 40 mg capsule, orally, once weekly (QW) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 139.4 weeks). MLN0128 6 mg, 9 mg, 12 mg, 16 mg or 20 mg capsule, orally, once daily every 3 days a week (QDx3d QW) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 129.4 weeks). MLN0128 7 mg, 10 mg or 13 mg capsule, orally, once daily every 5 days a week (QDx5d QW) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 161.9 weeks).
    Measure Participants 31 30 33 22
    p4EBP1
    -64.1
    (47.65)
    -15.5
    (378.88)
    -99.5
    (2.75)
    87.4
    (43.83)
    pAKT
    27.1
    (73.78)
    26.9
    (139.75)
    73.3
    (115.55)
    168.9
    (514.88)
    pS6
    -50.2
    (43.89)
    -42.7
    (59.64)
    -68.2
    (37.98)
    -82.5
    (12.15)

    Adverse Events

    Time Frame All cause-mortality were collected throughout the study; SAEs and Other (non-serious) were collected from the first dose of study drug plus 30 days after last dose of study drug (Up to approximately 244 weeks)
    Adverse Event Reporting Description
    Arm/Group Title MLN0128 QD MLN0128 QW MLN0128 QDx3d QW MLN0128 QDx5d QW MLN0128 5 mg QD MLN0128 30 mg QW MLN0128 40 mg QW
    Arm/Group Description MLN0128 2 mg, 4 mg, 6 mg or 7 mg, capsule, orally, once daily (QD) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 52.1 weeks). MLN0128 7 mg, 10 mg, 15 mg, 20 mg, 30 mg or 40 mg capsule, orally, once weekly (QW) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 139.4 weeks). MLN0128 6 mg, 9 mg, 12 mg, 16 mg or 20 mg capsule, orally, once daily every 3 days a week (QDx3d QW) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 129.4 weeks). MLN0128 7 mg, 10 mg or 13 mg capsule, orally, once daily every 5 days a week (QDx5d QW) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 161.9 weeks). MLN0128 5 mg, capsule, orally, QD in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 98.3 weeks). MLN0128 30 mg, capsule, orally QW in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 240 weeks). MLN0128 40 mg, capsule, orally, QW in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 100.1 weeks).
    All Cause Mortality
    MLN0128 QD MLN0128 QW MLN0128 QDx3d QW MLN0128 QDx5d QW MLN0128 5 mg QD MLN0128 30 mg QW MLN0128 40 mg QW
    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 3/31 (9.7%) 2/30 (6.7%) 2/33 (6.1%) 0/22 (0%) 2/39 (5.1%) 2/17 (11.8%) 3/26 (11.5%)
    Serious Adverse Events
    MLN0128 QD MLN0128 QW MLN0128 QDx3d QW MLN0128 QDx5d QW MLN0128 5 mg QD MLN0128 30 mg QW MLN0128 40 mg QW
    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 13/31 (41.9%) 10/30 (33.3%) 17/33 (51.5%) 10/22 (45.5%) 19/39 (48.7%) 6/17 (35.3%) 9/26 (34.6%)
    Blood and lymphatic system disorders
    Anaemia 1/31 (3.2%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 1/39 (2.6%) 1/17 (5.9%) 2/26 (7.7%)
    Thrombocytopenia 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 1/39 (2.6%) 0/17 (0%) 1/26 (3.8%)
    Cardiac disorders
    Atrial fibrillation 0/31 (0%) 0/30 (0%) 0/33 (0%) 1/22 (4.5%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Cardiac arrest 1/31 (3.2%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Cardiac tamponade 0/31 (0%) 0/30 (0%) 0/33 (0%) 1/22 (4.5%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Supraventricular tachycardia 0/31 (0%) 0/30 (0%) 1/33 (3%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Ventricular fibrillation 1/31 (3.2%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Endocrine disorders
    Carcinoid syndrome 0/31 (0%) 1/30 (3.3%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Gastrointestinal disorders
    Stomatitis 0/31 (0%) 0/30 (0%) 4/33 (12.1%) 2/22 (9.1%) 0/39 (0%) 0/17 (0%) 1/26 (3.8%)
    Abdominal pain 1/31 (3.2%) 0/30 (0%) 0/33 (0%) 1/22 (4.5%) 3/39 (7.7%) 0/17 (0%) 0/26 (0%)
    Intestinal obstruction 1/31 (3.2%) 1/30 (3.3%) 0/33 (0%) 0/22 (0%) 1/39 (2.6%) 0/17 (0%) 0/26 (0%)
    Diarrhoea 1/31 (3.2%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 2/26 (7.7%)
    Dysphagia 0/31 (0%) 0/30 (0%) 1/33 (3%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Enterocutaneous fistula 1/31 (3.2%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Nausea 0/31 (0%) 0/30 (0%) 0/33 (0%) 1/22 (4.5%) 1/39 (2.6%) 1/17 (5.9%) 0/26 (0%)
    Oesophagitis 0/31 (0%) 0/30 (0%) 1/33 (3%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Pancreatitis acute 1/31 (3.2%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Vomiting 0/31 (0%) 0/30 (0%) 0/33 (0%) 1/22 (4.5%) 1/39 (2.6%) 1/17 (5.9%) 1/26 (3.8%)
    Abdominal pain upper 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 1/39 (2.6%) 0/17 (0%) 0/26 (0%)
    Constipation 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 1/17 (5.9%) 0/26 (0%)
    Small intestinal obstruction 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 1/17 (5.9%) 0/26 (0%)
    General disorders
    Asthenia 0/31 (0%) 0/30 (0%) 3/33 (9.1%) 1/22 (4.5%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    General physical health deterioration 0/31 (0%) 0/30 (0%) 1/33 (3%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Disease progression 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 1/26 (3.8%)
    Fatigue 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 1/17 (5.9%) 0/26 (0%)
    Pyrexia 0/31 (0%) 1/30 (3.3%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 1/26 (3.8%)
    Infections and infestations
    Pneumonia 1/31 (3.2%) 2/30 (6.7%) 1/33 (3%) 0/22 (0%) 2/39 (5.1%) 0/17 (0%) 0/26 (0%)
    Bacteraemia 0/31 (0%) 1/30 (3.3%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Cellulitis 1/31 (3.2%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Device related infection 1/31 (3.2%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Gastroenteritis 0/31 (0%) 0/30 (0%) 1/33 (3%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Osteomyelitis 0/31 (0%) 1/30 (3.3%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Sepsis 0/31 (0%) 1/30 (3.3%) 0/33 (0%) 0/22 (0%) 1/39 (2.6%) 1/17 (5.9%) 0/26 (0%)
    Urinary tract infection 0/31 (0%) 0/30 (0%) 1/33 (3%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 1/26 (3.8%)
    Cystitis 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 1/26 (3.8%)
    Respiratory tract infection 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 1/17 (5.9%) 0/26 (0%)
    Injury, poisoning and procedural complications
    Overdose 0/31 (0%) 0/30 (0%) 1/33 (3%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Post procedural haemorrhage 0/31 (0%) 0/30 (0%) 0/33 (0%) 1/22 (4.5%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Procedural haemorrhage 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 1/39 (2.6%) 0/17 (0%) 0/26 (0%)
    Investigations
    Ejection fraction decreased 0/31 (0%) 0/30 (0%) 0/33 (0%) 1/22 (4.5%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Metabolism and nutrition disorders
    Dehydration 0/31 (0%) 0/30 (0%) 1/33 (3%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 2/26 (7.7%)
    Hyperglycaemia 0/31 (0%) 0/30 (0%) 1/33 (3%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Hypokalaemia 0/31 (0%) 0/30 (0%) 1/33 (3%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Hypomagnesaemia 0/31 (0%) 0/30 (0%) 1/33 (3%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Hyponatraemia 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 1/17 (5.9%) 1/26 (3.8%)
    Hyperkalaemia 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 1/39 (2.6%) 0/17 (0%) 0/26 (0%)
    Musculoskeletal and connective tissue disorders
    Back pain 0/31 (0%) 1/30 (3.3%) 1/33 (3%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Pain in extremity 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 2/17 (11.8%) 1/26 (3.8%)
    Flank pain 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 1/39 (2.6%) 0/17 (0%) 0/26 (0%)
    Musculoskeletal chest pain 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 1/26 (3.8%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Gastric cancer 0/31 (0%) 1/30 (3.3%) 1/33 (3%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Breast cancer 0/31 (0%) 0/30 (0%) 1/33 (3%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Cancer pain 0/31 (0%) 0/30 (0%) 1/33 (3%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Intestinal adenocarcinoma 1/31 (3.2%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Malignant melanoma 1/31 (3.2%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Malignant pleural effusion 0/31 (0%) 0/30 (0%) 1/33 (3%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Metastases to central nervous system 1/31 (3.2%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Tumour pain 0/31 (0%) 1/30 (3.3%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Uterine cancer 0/31 (0%) 1/30 (3.3%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Transitional cell carcinoma 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 1/17 (5.9%) 1/26 (3.8%)
    Renal cell carcinoma 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 2/39 (5.1%) 0/17 (0%) 0/26 (0%)
    Nervous system disorders
    Brain oedema 0/31 (0%) 0/30 (0%) 0/33 (0%) 1/22 (4.5%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Hemiparesis 0/31 (0%) 0/30 (0%) 1/33 (3%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Seizure 0/31 (0%) 0/30 (0%) 0/33 (0%) 1/22 (4.5%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Encephalopathy 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 1/39 (2.6%) 0/17 (0%) 0/26 (0%)
    Psychiatric disorders
    Delirium 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 1/39 (2.6%) 0/17 (0%) 0/26 (0%)
    Mental status changes 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 1/39 (2.6%) 0/17 (0%) 2/26 (7.7%)
    Renal and urinary disorders
    Renal failure 1/31 (3.2%) 1/30 (3.3%) 1/33 (3%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Nephrolithiasis 0/31 (0%) 0/30 (0%) 0/33 (0%) 1/22 (4.5%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Acute kidney injury 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 3/39 (7.7%) 0/17 (0%) 2/26 (7.7%)
    Haematuria 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 2/39 (5.1%) 0/17 (0%) 0/26 (0%)
    Hydronephrosis 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 1/39 (2.6%) 0/17 (0%) 0/26 (0%)
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion 1/31 (3.2%) 0/30 (0%) 0/33 (0%) 1/22 (4.5%) 1/39 (2.6%) 0/17 (0%) 0/26 (0%)
    Bronchospasm 0/31 (0%) 0/30 (0%) 0/33 (0%) 1/22 (4.5%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Dyspnoea 1/31 (3.2%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 1/39 (2.6%) 1/17 (5.9%) 0/26 (0%)
    Pneumonitis 0/31 (0%) 1/30 (3.3%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Hypoxia 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 1/39 (2.6%) 0/17 (0%) 0/26 (0%)
    Pneumomediastinum 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 1/26 (3.8%)
    Respiratory failure 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 1/26 (3.8%)
    Skin and subcutaneous tissue disorders
    Rash maculo-papular 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 1/26 (3.8%)
    Vascular disorders
    Deep vein thrombosis 0/31 (0%) 1/30 (3.3%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 1/17 (5.9%) 0/26 (0%)
    Hypotension 0/31 (0%) 0/30 (0%) 1/33 (3%) 1/22 (4.5%) 1/39 (2.6%) 0/17 (0%) 0/26 (0%)
    Peripheral ischaemia 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 1/26 (3.8%)
    Other (Not Including Serious) Adverse Events
    MLN0128 QD MLN0128 QW MLN0128 QDx3d QW MLN0128 QDx5d QW MLN0128 5 mg QD MLN0128 30 mg QW MLN0128 40 mg QW
    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 31/31 (100%) 30/30 (100%) 33/33 (100%) 22/22 (100%) 39/39 (100%) 17/17 (100%) 26/26 (100%)
    Blood and lymphatic system disorders
    Anaemia 6/31 (19.4%) 5/30 (16.7%) 10/33 (30.3%) 3/22 (13.6%) 5/39 (12.8%) 2/17 (11.8%) 11/26 (42.3%)
    Lymphopenia 5/31 (16.1%) 4/30 (13.3%) 3/33 (9.1%) 2/22 (9.1%) 3/39 (7.7%) 0/17 (0%) 1/26 (3.8%)
    Thrombocytopenia 5/31 (16.1%) 1/30 (3.3%) 1/33 (3%) 1/22 (4.5%) 3/39 (7.7%) 1/17 (5.9%) 2/26 (7.7%)
    Coagulopathy 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 1/17 (5.9%) 0/26 (0%)
    Cardiac disorders
    Tachycardia 0/31 (0%) 0/30 (0%) 2/33 (6.1%) 1/22 (4.5%) 1/39 (2.6%) 0/17 (0%) 3/26 (11.5%)
    Palpitations 0/31 (0%) 0/30 (0%) 2/33 (6.1%) 0/22 (0%) 1/39 (2.6%) 1/17 (5.9%) 1/26 (3.8%)
    Pericardial effusion 0/31 (0%) 0/30 (0%) 0/33 (0%) 2/22 (9.1%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Ventricular extrasystoles 0/31 (0%) 2/30 (6.7%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Ear and labyrinth disorders
    Tinnitus 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 2/17 (11.8%) 1/26 (3.8%)
    Hypoacusis 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 2/39 (5.1%) 0/17 (0%) 0/26 (0%)
    Eye disorders
    Vision blurred 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 1/17 (5.9%) 2/26 (7.7%)
    Blindness transient 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 1/17 (5.9%) 0/26 (0%)
    Gastrointestinal disorders
    Nausea 16/31 (51.6%) 22/30 (73.3%) 24/33 (72.7%) 13/22 (59.1%) 21/39 (53.8%) 12/17 (70.6%) 20/26 (76.9%)
    Vomiting 12/31 (38.7%) 20/30 (66.7%) 20/33 (60.6%) 12/22 (54.5%) 12/39 (30.8%) 9/17 (52.9%) 20/26 (76.9%)
    Stomatitis 11/31 (35.5%) 10/30 (33.3%) 22/33 (66.7%) 13/22 (59.1%) 19/39 (48.7%) 9/17 (52.9%) 11/26 (42.3%)
    Diarrhoea 14/31 (45.2%) 10/30 (33.3%) 17/33 (51.5%) 9/22 (40.9%) 20/39 (51.3%) 9/17 (52.9%) 11/26 (42.3%)
    Dry mouth 8/31 (25.8%) 7/30 (23.3%) 3/33 (9.1%) 2/22 (9.1%) 5/39 (12.8%) 3/17 (17.6%) 7/26 (26.9%)
    Abdominal pain 3/31 (9.7%) 6/30 (20%) 4/33 (12.1%) 4/22 (18.2%) 8/39 (20.5%) 6/17 (35.3%) 4/26 (15.4%)
    Constipation 1/31 (3.2%) 6/30 (20%) 6/33 (18.2%) 3/22 (13.6%) 10/39 (25.6%) 8/17 (47.1%) 10/26 (38.5%)
    Abdominal pain upper 1/31 (3.2%) 2/30 (6.7%) 2/33 (6.1%) 2/22 (9.1%) 3/39 (7.7%) 2/17 (11.8%) 2/26 (7.7%)
    Abdominal distension 3/31 (9.7%) 2/30 (6.7%) 1/33 (3%) 0/22 (0%) 2/39 (5.1%) 3/17 (17.6%) 1/26 (3.8%)
    Dyspepsia 1/31 (3.2%) 2/30 (6.7%) 2/33 (6.1%) 0/22 (0%) 2/39 (5.1%) 3/17 (17.6%) 2/26 (7.7%)
    Gastrooesophageal reflux disease 0/31 (0%) 0/30 (0%) 3/33 (9.1%) 1/22 (4.5%) 0/39 (0%) 1/17 (5.9%) 1/26 (3.8%)
    Oral pain 0/31 (0%) 2/30 (6.7%) 1/33 (3%) 1/22 (4.5%) 2/39 (5.1%) 0/17 (0%) 5/26 (19.2%)
    Abdominal discomfort 0/31 (0%) 2/30 (6.7%) 0/33 (0%) 1/22 (4.5%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Haemorrhoids 0/31 (0%) 0/30 (0%) 2/33 (6.1%) 0/22 (0%) 0/39 (0%) 1/17 (5.9%) 0/26 (0%)
    Flatulence 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 1/39 (2.6%) 1/17 (5.9%) 3/26 (11.5%)
    Ascites 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 2/39 (5.1%) 1/17 (5.9%) 0/26 (0%)
    Retching 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 3/26 (11.5%)
    Tongue ulceration 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 2/39 (5.1%) 0/17 (0%) 1/26 (3.8%)
    Aphthous ulcer 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 1/39 (2.6%) 1/17 (5.9%) 0/26 (0%)
    Dysphagia 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 1/17 (5.9%) 1/26 (3.8%)
    Glossodynia 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 1/39 (2.6%) 1/17 (5.9%) 0/26 (0%)
    Hiatus hernia 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 1/39 (2.6%) 1/17 (5.9%) 0/26 (0%)
    Lip swelling 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 2/39 (5.1%) 0/17 (0%) 0/26 (0%)
    Oesophagitis 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 1/17 (5.9%) 1/26 (3.8%)
    Coeliac disease 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 1/17 (5.9%) 0/26 (0%)
    Haematemesis 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 1/17 (5.9%) 0/26 (0%)
    Oesophageal stenosis 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 1/17 (5.9%) 0/26 (0%)
    Oesophageal ulcer 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 1/17 (5.9%) 0/26 (0%)
    Rectal obstruction 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 1/17 (5.9%) 0/26 (0%)
    General disorders
    Asthenia 7/31 (22.6%) 15/30 (50%) 13/33 (39.4%) 10/22 (45.5%) 7/39 (17.9%) 2/17 (11.8%) 5/26 (19.2%)
    Fatigue 10/31 (32.3%) 9/30 (30%) 15/33 (45.5%) 7/22 (31.8%) 25/39 (64.1%) 11/17 (64.7%) 24/26 (92.3%)
    Pyrexia 2/31 (6.5%) 9/30 (30%) 8/33 (24.2%) 6/22 (27.3%) 8/39 (20.5%) 1/17 (5.9%) 5/26 (19.2%)
    Chills 1/31 (3.2%) 3/30 (10%) 3/33 (9.1%) 2/22 (9.1%) 2/39 (5.1%) 0/17 (0%) 3/26 (11.5%)
    Oedema peripheral 3/31 (9.7%) 4/30 (13.3%) 0/33 (0%) 1/22 (4.5%) 9/39 (23.1%) 1/17 (5.9%) 5/26 (19.2%)
    Chest pain 1/31 (3.2%) 1/30 (3.3%) 2/33 (6.1%) 1/22 (4.5%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Performance status decreased 0/31 (0%) 2/30 (6.7%) 0/33 (0%) 1/22 (4.5%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Malaise 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 2/17 (11.8%) 1/26 (3.8%)
    Pain 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 2/39 (5.1%) 0/17 (0%) 1/26 (3.8%)
    Early satiety 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 1/17 (5.9%) 0/26 (0%)
    Hepatobiliary disorders
    Hyperbilirubinaemia 0/31 (0%) 1/30 (3.3%) 2/33 (6.1%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Infections and infestations
    Urinary tract infection 4/31 (12.9%) 3/30 (10%) 6/33 (18.2%) 6/22 (27.3%) 6/39 (15.4%) 2/17 (11.8%) 8/26 (30.8%)
    Upper respiratory tract infection 1/31 (3.2%) 5/30 (16.7%) 1/33 (3%) 2/22 (9.1%) 0/39 (0%) 1/17 (5.9%) 3/26 (11.5%)
    Cellulitis 3/31 (9.7%) 2/30 (6.7%) 0/33 (0%) 0/22 (0%) 2/39 (5.1%) 0/17 (0%) 1/26 (3.8%)
    Nasopharyngitis 0/31 (0%) 1/30 (3.3%) 3/33 (9.1%) 1/22 (4.5%) 1/39 (2.6%) 1/17 (5.9%) 0/26 (0%)
    Oral herpes 0/31 (0%) 1/30 (3.3%) 4/33 (12.1%) 0/22 (0%) 2/39 (5.1%) 0/17 (0%) 0/26 (0%)
    Sinusitis 0/31 (0%) 2/30 (6.7%) 2/33 (6.1%) 1/22 (4.5%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Respiratory tract infection 0/31 (0%) 2/30 (6.7%) 2/33 (6.1%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Oral candidiasis 0/31 (0%) 2/30 (6.7%) 0/33 (0%) 1/22 (4.5%) 0/39 (0%) 1/17 (5.9%) 2/26 (7.7%)
    Catheter site infection 0/31 (0%) 0/30 (0%) 2/33 (6.1%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Oropharyngeal candidiasis 0/31 (0%) 0/30 (0%) 2/33 (6.1%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Conjunctivitis 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 2/39 (5.1%) 0/17 (0%) 0/26 (0%)
    Herpes zoster 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 1/39 (2.6%) 1/17 (5.9%) 0/26 (0%)
    Pneumonia 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 2/39 (5.1%) 0/17 (0%) 0/26 (0%)
    Clostridium difficile infection 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 1/17 (5.9%) 0/26 (0%)
    Injury, poisoning and procedural complications
    Contusion 2/31 (6.5%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Investigations
    Blood creatinine increased 9/31 (29%) 4/30 (13.3%) 3/33 (9.1%) 1/22 (4.5%) 6/39 (15.4%) 4/17 (23.5%) 5/26 (19.2%)
    Weight decreased 3/31 (9.7%) 3/30 (10%) 5/33 (15.2%) 2/22 (9.1%) 6/39 (15.4%) 3/17 (17.6%) 7/26 (26.9%)
    Blood urea increased 2/31 (6.5%) 2/30 (6.7%) 1/33 (3%) 1/22 (4.5%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Alanine aminotransferase increased 1/31 (3.2%) 1/30 (3.3%) 2/33 (6.1%) 1/22 (4.5%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Aspartate aminotransferase increased 1/31 (3.2%) 3/30 (10%) 0/33 (0%) 1/22 (4.5%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Gamma-glutamyltransferase increased 0/31 (0%) 2/30 (6.7%) 1/33 (3%) 1/22 (4.5%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Platelet count decreased 0/31 (0%) 1/30 (3.3%) 2/33 (6.1%) 1/22 (4.5%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Blood albumin decreased 0/31 (0%) 2/30 (6.7%) 0/33 (0%) 1/22 (4.5%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Blood triglycerides increased 0/31 (0%) 2/30 (6.7%) 0/33 (0%) 1/22 (4.5%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Blood urea decreased 0/31 (0%) 3/30 (10%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Lymphocyte count decreased 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 1/39 (2.6%) 0/17 (0%) 4/26 (15.4%)
    Blood alkaline phosphatase increased 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 3/26 (11.5%)
    Blood potassium increased 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 2/26 (7.7%)
    White blood cell count decreased 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 1/17 (5.9%) 0/26 (0%)
    Metabolism and nutrition disorders
    Hyperglycaemia 26/31 (83.9%) 18/30 (60%) 22/33 (66.7%) 12/22 (54.5%) 18/39 (46.2%) 12/17 (70.6%) 20/26 (76.9%)
    Decreased appetite 13/31 (41.9%) 12/30 (40%) 20/33 (60.6%) 9/22 (40.9%) 20/39 (51.3%) 7/17 (41.2%) 14/26 (53.8%)
    Dehydration 5/31 (16.1%) 6/30 (20%) 6/33 (18.2%) 1/22 (4.5%) 7/39 (17.9%) 4/17 (23.5%) 5/26 (19.2%)
    Hypokalaemia 2/31 (6.5%) 4/30 (13.3%) 2/33 (6.1%) 5/22 (22.7%) 6/39 (15.4%) 3/17 (17.6%) 1/26 (3.8%)
    Hypercholesterolaemia 5/31 (16.1%) 1/30 (3.3%) 4/33 (12.1%) 2/22 (9.1%) 0/39 (0%) 1/17 (5.9%) 0/26 (0%)
    Hypomagnesaemia 2/31 (6.5%) 3/30 (10%) 4/33 (12.1%) 3/22 (13.6%) 4/39 (10.3%) 1/17 (5.9%) 3/26 (11.5%)
    Hyponatraemia 2/31 (6.5%) 2/30 (6.7%) 4/33 (12.1%) 1/22 (4.5%) 3/39 (7.7%) 1/17 (5.9%) 2/26 (7.7%)
    Hypocalcaemia 3/31 (9.7%) 1/30 (3.3%) 2/33 (6.1%) 2/22 (9.1%) 3/39 (7.7%) 0/17 (0%) 1/26 (3.8%)
    Hypertriglyceridaemia 0/31 (0%) 0/30 (0%) 2/33 (6.1%) 1/22 (4.5%) 1/39 (2.6%) 1/17 (5.9%) 2/26 (7.7%)
    Hypocholesterolaemia 0/31 (0%) 2/30 (6.7%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Hypophosphataemia 0/31 (0%) 1/30 (3.3%) 8/33 (24.2%) 5/22 (22.7%) 4/39 (10.3%) 2/17 (11.8%) 5/26 (19.2%)
    Hyperkalaemia 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 3/39 (7.7%) 0/17 (0%) 2/26 (7.7%)
    Hypoalbuminaemia 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 1/39 (2.6%) 0/17 (0%) 4/26 (15.4%)
    Hypercalcaemia 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 1/17 (5.9%) 3/26 (11.5%)
    Musculoskeletal and connective tissue disorders
    Back pain 1/31 (3.2%) 13/30 (43.3%) 3/33 (9.1%) 1/22 (4.5%) 5/39 (12.8%) 2/17 (11.8%) 5/26 (19.2%)
    Pain in extremity 3/31 (9.7%) 2/30 (6.7%) 2/33 (6.1%) 3/22 (13.6%) 5/39 (12.8%) 0/17 (0%) 2/26 (7.7%)
    Arthralgia 2/31 (6.5%) 2/30 (6.7%) 2/33 (6.1%) 2/22 (9.1%) 2/39 (5.1%) 2/17 (11.8%) 7/26 (26.9%)
    Muscle spasms 1/31 (3.2%) 2/30 (6.7%) 4/33 (12.1%) 0/22 (0%) 2/39 (5.1%) 0/17 (0%) 2/26 (7.7%)
    Neck pain 3/31 (9.7%) 0/30 (0%) 2/33 (6.1%) 1/22 (4.5%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Muscular weakness 0/31 (0%) 2/30 (6.7%) 2/33 (6.1%) 1/22 (4.5%) 4/39 (10.3%) 1/17 (5.9%) 5/26 (19.2%)
    Myalgia 1/31 (3.2%) 1/30 (3.3%) 3/33 (9.1%) 0/22 (0%) 1/39 (2.6%) 1/17 (5.9%) 3/26 (11.5%)
    Musculoskeletal pain 0/31 (0%) 3/30 (10%) 0/33 (0%) 0/22 (0%) 2/39 (5.1%) 1/17 (5.9%) 3/26 (11.5%)
    Limb discomfort 2/31 (6.5%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Musculoskeletal chest pain 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 1/39 (2.6%) 2/17 (11.8%) 3/26 (11.5%)
    Osteitis 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 2/26 (7.7%)
    Pain in jaw 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 1/39 (2.6%) 1/17 (5.9%) 0/26 (0%)
    Joint swelling 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 1/17 (5.9%) 0/26 (0%)
    Flank pain 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 1/39 (2.6%) 1/17 (5.9%) 3/26 (11.5%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 1/17 (5.9%) 0/26 (0%)
    Seborrhoeic keratosis 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 1/17 (5.9%) 0/26 (0%)
    Nervous system disorders
    Headache 2/31 (6.5%) 8/30 (26.7%) 9/33 (27.3%) 5/22 (22.7%) 4/39 (10.3%) 3/17 (17.6%) 6/26 (23.1%)
    Dysgeusia 9/31 (29%) 4/30 (13.3%) 4/33 (12.1%) 4/22 (18.2%) 10/39 (25.6%) 4/17 (23.5%) 3/26 (11.5%)
    Dizziness 4/31 (12.9%) 3/30 (10%) 5/33 (15.2%) 1/22 (4.5%) 9/39 (23.1%) 1/17 (5.9%) 3/26 (11.5%)
    Tremor 2/31 (6.5%) 0/30 (0%) 3/33 (9.1%) 3/22 (13.6%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Neuropathy peripheral 0/31 (0%) 2/30 (6.7%) 2/33 (6.1%) 0/22 (0%) 2/39 (5.1%) 0/17 (0%) 0/26 (0%)
    Somnolence 3/31 (9.7%) 0/30 (0%) 1/33 (3%) 0/22 (0%) 2/39 (5.1%) 0/17 (0%) 1/26 (3.8%)
    Hypoaesthesia 0/31 (0%) 1/30 (3.3%) 2/33 (6.1%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Paraesthesia 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 2/39 (5.1%) 0/17 (0%) 3/26 (11.5%)
    Memory impairment 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 2/39 (5.1%) 0/17 (0%) 1/26 (3.8%)
    Disturbance in attention 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 1/17 (5.9%) 0/26 (0%)
    Sciatica 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 1/17 (5.9%) 0/26 (0%)
    Product Issues
    Device breakage 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 1/17 (5.9%) 0/26 (0%)
    Psychiatric disorders
    Confusional state 5/31 (16.1%) 1/30 (3.3%) 3/33 (9.1%) 2/22 (9.1%) 4/39 (10.3%) 0/17 (0%) 3/26 (11.5%)
    Insomnia 3/31 (9.7%) 1/30 (3.3%) 3/33 (9.1%) 3/22 (13.6%) 2/39 (5.1%) 3/17 (17.6%) 5/26 (19.2%)
    Anxiety 2/31 (6.5%) 2/30 (6.7%) 4/33 (12.1%) 1/22 (4.5%) 3/39 (7.7%) 3/17 (17.6%) 3/26 (11.5%)
    Depression 2/31 (6.5%) 0/30 (0%) 2/33 (6.1%) 0/22 (0%) 1/39 (2.6%) 4/17 (23.5%) 3/26 (11.5%)
    Agitation 0/31 (0%) 0/30 (0%) 0/33 (0%) 2/22 (9.1%) 0/39 (0%) 1/17 (5.9%) 0/26 (0%)
    Mental status changes 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 1/39 (2.6%) 0/17 (0%) 2/26 (7.7%)
    Renal and urinary disorders
    Haematuria 1/31 (3.2%) 3/30 (10%) 0/33 (0%) 2/22 (9.1%) 3/39 (7.7%) 1/17 (5.9%) 4/26 (15.4%)
    Dysuria 0/31 (0%) 1/30 (3.3%) 2/33 (6.1%) 2/22 (9.1%) 1/39 (2.6%) 0/17 (0%) 3/26 (11.5%)
    Proteinuria 0/31 (0%) 2/30 (6.7%) 2/33 (6.1%) 0/22 (0%) 0/39 (0%) 1/17 (5.9%) 3/26 (11.5%)
    Acute kidney injury 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 3/39 (7.7%) 0/17 (0%) 3/26 (11.5%)
    Pollakiuria 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 3/39 (7.7%) 0/17 (0%) 2/26 (7.7%)
    Azotaemia 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 1/17 (5.9%) 0/26 (0%)
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea 3/31 (9.7%) 7/30 (23.3%) 10/33 (30.3%) 4/22 (18.2%) 7/39 (17.9%) 3/17 (17.6%) 4/26 (15.4%)
    Cough 3/31 (9.7%) 5/30 (16.7%) 4/33 (12.1%) 4/22 (18.2%) 9/39 (23.1%) 6/17 (35.3%) 8/26 (30.8%)
    Oropharyngeal pain 1/31 (3.2%) 3/30 (10%) 1/33 (3%) 2/22 (9.1%) 4/39 (10.3%) 1/17 (5.9%) 9/26 (34.6%)
    Dysphonia 1/31 (3.2%) 0/30 (0%) 1/33 (3%) 3/22 (13.6%) 2/39 (5.1%) 2/17 (11.8%) 1/26 (3.8%)
    Dyspnoea exertional 3/31 (9.7%) 1/30 (3.3%) 1/33 (3%) 0/22 (0%) 3/39 (7.7%) 1/17 (5.9%) 3/26 (11.5%)
    Nasal dryness 0/31 (0%) 1/30 (3.3%) 0/33 (0%) 3/22 (13.6%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Productive cough 0/31 (0%) 3/30 (10%) 1/33 (3%) 0/22 (0%) 1/39 (2.6%) 1/17 (5.9%) 0/26 (0%)
    Nasal congestion 1/31 (3.2%) 0/30 (0%) 0/33 (0%) 2/22 (9.1%) 3/39 (7.7%) 2/17 (11.8%) 2/26 (7.7%)
    Epistaxis 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 5/39 (12.8%) 0/17 (0%) 3/26 (11.5%)
    Rhinorrhoea 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 2/39 (5.1%) 1/17 (5.9%) 2/26 (7.7%)
    Upper-airway cough syndrome 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 1/39 (2.6%) 0/17 (0%) 4/26 (15.4%)
    Wheezing 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 2/39 (5.1%) 0/17 (0%) 2/26 (7.7%)
    Haemoptysis 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 2/39 (5.1%) 0/17 (0%) 1/26 (3.8%)
    Pleural effusion 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 2/39 (5.1%) 0/17 (0%) 1/26 (3.8%)
    Hiccups 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 1/39 (2.6%) 1/17 (5.9%) 0/26 (0%)
    Nasal inflammation 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 1/39 (2.6%) 1/17 (5.9%) 0/26 (0%)
    Pharyngeal inflammation 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 2/26 (7.7%)
    Sneezing 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 1/17 (5.9%) 0/26 (0%)
    Skin and subcutaneous tissue disorders
    Rash 10/31 (32.3%) 4/30 (13.3%) 7/33 (21.2%) 4/22 (18.2%) 1/39 (2.6%) 0/17 (0%) 2/26 (7.7%)
    Pruritus generalised 10/31 (32.3%) 0/30 (0%) 6/33 (18.2%) 2/22 (9.1%) 12/39 (30.8%) 5/17 (29.4%) 3/26 (11.5%)
    Pruritus 3/31 (9.7%) 3/30 (10%) 1/33 (3%) 4/22 (18.2%) 10/39 (25.6%) 1/17 (5.9%) 4/26 (15.4%)
    Rash pruritic 4/31 (12.9%) 0/30 (0%) 3/33 (9.1%) 1/22 (4.5%) 3/39 (7.7%) 0/17 (0%) 3/26 (11.5%)
    Dry skin 2/31 (6.5%) 1/30 (3.3%) 1/33 (3%) 3/22 (13.6%) 3/39 (7.7%) 1/17 (5.9%) 2/26 (7.7%)
    Rash maculo-papular 3/31 (9.7%) 0/30 (0%) 1/33 (3%) 2/22 (9.1%) 17/39 (43.6%) 4/17 (23.5%) 3/26 (11.5%)
    Rash erythematous 1/31 (3.2%) 2/30 (6.7%) 1/33 (3%) 1/22 (4.5%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Rash generalised 0/31 (0%) 0/30 (0%) 1/33 (3%) 2/22 (9.1%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Dermatitis acneiform 0/31 (0%) 0/30 (0%) 0/33 (0%) 2/22 (9.1%) 1/39 (2.6%) 1/17 (5.9%) 0/26 (0%)
    Rash macular 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 4/39 (10.3%) 0/17 (0%) 2/26 (7.7%)
    Palmar-plantar erythrodysaesthesia syndrome 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 2/39 (5.1%) 2/17 (11.8%) 0/26 (0%)
    Alopecia 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 2/39 (5.1%) 0/17 (0%) 1/26 (3.8%)
    Hyperhidrosis 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 2/39 (5.1%) 1/17 (5.9%) 0/26 (0%)
    Blister 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 2/26 (7.7%)
    Night sweats 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 1/39 (2.6%) 1/17 (5.9%) 0/26 (0%)
    Decubitus ulcer 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 1/17 (5.9%) 0/26 (0%)
    Psoriasis 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 1/17 (5.9%) 0/26 (0%)
    Rash papular 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 1/17 (5.9%) 0/26 (0%)
    Vascular disorders
    Hypotension 0/31 (0%) 5/30 (16.7%) 2/33 (6.1%) 1/22 (4.5%) 1/39 (2.6%) 2/17 (11.8%) 0/26 (0%)
    Orthostatic hypotension 2/31 (6.5%) 0/30 (0%) 2/33 (6.1%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 0/26 (0%)
    Hypertension 0/31 (0%) 2/30 (6.7%) 1/33 (3%) 0/22 (0%) 1/39 (2.6%) 1/17 (5.9%) 2/26 (7.7%)
    Deep vein thrombosis 0/31 (0%) 0/30 (0%) 2/33 (6.1%) 0/22 (0%) 2/39 (5.1%) 0/17 (0%) 3/26 (11.5%)
    Flushing 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 1/17 (5.9%) 2/26 (7.7%)
    Phlebitis 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 0/17 (0%) 2/26 (7.7%)
    Lymphoedema 0/31 (0%) 0/30 (0%) 0/33 (0%) 0/22 (0%) 0/39 (0%) 1/17 (5.9%) 0/26 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

    Research Organization shall not publish any articles or papers nor make any presentations, nor assist any other person in publishing any articles or papers or in making any presentations relating or referring to the Study or any results, data or insights from or any data, information or materials obtained or generated in the performance of its obligations without the prior written consent of Takeda, which consent may be granted or withheld in Takeda's sole discretion.

    Results Point of Contact

    Name/Title Medical Director
    Organization Takeda
    Phone +1-866-835-2233
    Email GlobalOncologyMedinfo@takeda.com
    Responsible Party:
    Millennium Pharmaceuticals, Inc.
    ClinicalTrials.gov Identifier:
    NCT01058707
    Other Study ID Numbers:
    • INK128-001
    • 2009-017284-42
    • U1111-1187-4258
    First Posted:
    Jan 29, 2010
    Last Update Posted:
    Apr 1, 2020
    Last Verified:
    Mar 1, 2020