MLN1117 in Combination With Docetaxel, Paclitaxel, and Other Investigational Anticancer Agents to Treat Participants With Gastric and Gastroesophageal Adenocarcinoma

• Sponsor: Millennium Pharmaceuticals, Inc. (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02551055
• Collaborator: (none)
• Enrollment: 32
• Locations: 6
• Arms: 7
• Actual Duration (Months): 16.1
• Patients Per Site: 5.3
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the maximum tolerated dose (MTD) or recommended Part 2 dose, safety and efficacy of MLN1117 (TAK-117) in combination with docetaxel, paclitaxel, investigational TAK-659 or investigational alisertib in adult participants with advanced and metastatic gastric or gastroesophageal adenocarcinoma. The study consists of a dose escalation phase (Part 1) and a dose expansion phase (Part 2).

Condition or Disease	Intervention/Treatment	Phase
Advanced and Metastatic Gastric or Gastroesophageal Adenocarcinoma	Drug: MLN1117; Drug: TAK-659; Drug: Alisertib; Drug: Paclitaxel; Drug: Docetaxel	Phase 1

Detailed Description

The drug being tested in this study is called MLN1117. MLN1117 is being tested to treat people who have locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma. This study will look at the dose-limiting toxicity and response to treatment in participants who take MLN1117 in combination with TAK-659, alisertib, paclitaxel, or docetaxel.

The study will enroll 32 participants in the dose escalation phase (Part 1) and 118 participants in the dose expansion phase (Part 2). Participants will be assigned to 1 of the 7 treatment groups:

• MLN1117 300 mg+Alisertib

• MLN1117 600 mg+Alisertib

• MLN1117 300 mg+Paclitaxel

• MLN1117 600 mg+Paclitaxel

• MLN1117 300 mg+TAK-659

• MLN1117 200 mg+Docetaxel

• MLN1117 300 mg+Docetaxel

In Part 1, the dose of MLN1117 will be increased step by step. All participants will be asked to take tablets of MLN1117 for 3 days on and 4 days off per week in 28-day treatment cycles or 21-day treatment cycles when given in combination with the other companion drugs.

This multi-center trial will be conducted in Spain and United States. The overall time to participate in this study is 10 months for Part 1 and 24 months for Part 2. Participants will make multiple visits to the clinic, and be contacted by telephone, e-mail or mail every 12 weeks for up to 6 months or 1 year after the last dose of study drug for a follow-up assessment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 32 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Umbrella Study to Evaluate MLN1117 in Combination With Taxanes (Docetaxel or Paclitaxel) and Other Investigational Anticancer Agents for the Treatment of Patients With Previously Treated Advanced and Metastatic Gastric and Gastroesophageal Adenocarcinoma
• Actual Study Start Date: Oct 15, 2015
• Actual Primary Completion Date: Feb 17, 2017
• Actual Study Completion Date: Feb 17, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: MLN1117 300 mg + Alisertib MLN1117 300 mg, tablets, orally, once daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15, 16, 17; 22, 23, and 24) and 4 days off per week and alisertib 40 mg, tablets, orally, twice daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15,16, and 17) and 4 days off per week on Weeks 1-3, and 1 week off in 28-day treatment cycles until PD or unacceptable toxicity.	Drug: MLN1117; MLN1117 Tablets; Other Names: TAK-117 ; Drug: Alisertib; Alisertib Tablets; Other Names: MLN8237
Experimental: MLN1117 600 mg + Alisertib MLN1117 600 mg, tablets, orally, once daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15, 16, 17; 22, 23, and 24) and 4 days off per week and alisertib 40 mg, tablets, orally, twice daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15,16, and 17) and 4 days off per week on Weeks 1-3, and 1 week off in 28-day treatment cycles until PD or unacceptable toxicity.	Drug: MLN1117; MLN1117 Tablets; Other Names: TAK-117 ; Drug: Alisertib; Alisertib Tablets; Other Names: MLN8237
Experimental: MLN1117 300 mg + Paclitaxel MLN1117 300 mg, tablets, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, 18; 23, 24, and 25) and 4 days off per week and paclitaxel 80 mg/m^2, infusion, intravenously, once weekly on (Days 1, 8, and 15) and 1 week off, in 28-day treatment cycles until PD or unacceptable toxicity.	Drug: MLN1117; MLN1117 Tablets; Other Names: TAK-117 ; Drug: Paclitaxel; Paclitaxel intravenous infusion
Experimental: MLN1117 600 mg + Paclitaxel MLN1117 600 mg, tablets, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, 18; 23, 24, and 25) and 4 days off per week and paclitaxel 80 mg/m^2, infusion, intravenously, once weekly on (Days 1, 8, and 15) and 1 week off, in 28-day treatment cycles until PD or unacceptable toxicity.	Drug: MLN1117; MLN1117 Tablets; Other Names: TAK-117 ; Drug: Paclitaxel; Paclitaxel intravenous infusion
Experimental: MLN1117 300 mg + TAK-659 MLN1117 300 mg, tablets, orally, once daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15, 16, 17; and 22, 23, and 24) and 4 days off per week and TAK-659 100 mg (as determined in study C34001 [NCT02000934]), tablets, orally, once daily, in 28-day treatment cycles until progressive disease (PD) or unacceptable toxicity.	Drug: MLN1117; MLN1117 Tablets; Other Names: TAK-117 ; Drug: TAK-659; TAK-659 Tablets; Drug: Docetaxel; Docetaxel intravenous infusion
Experimental: MLN1117 200 mg + Docetaxel MLN1117 200 mg, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, and 18) and 4 days off per week and docetaxel 75 mg/m^2, infusion, intravenously, on Day 1 once every 3 weeks in 21-day treatment cycles until PD or unacceptable toxicity.	Drug: MLN1117; MLN1117 Tablets; Other Names: TAK-117 ; Drug: Docetaxel; Docetaxel intravenous infusion
Experimental: MLN1117 300 mg + Docetaxel MLN1117 300 mg, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, and 18) and 4 days off per week and docetaxel 75 mg/m^2, infusion, intravenously, on Day 1 once every 3 weeks in 21-day treatment cycles until PD or unacceptable toxicity.	Drug: MLN1117; MLN1117 Tablets; Other Names: TAK-117

Outcome Measures

Primary Outcome Measures

1. Number of Participants Who Experienced Cycle 1 Dose Limiting Toxicity (DLT) in Part 1 [Up to Cycle 1 (28 days for MLN1117+TAK-659, MLN1117+Alisertib, MLN1117+Paclitaxel or 21 days for MLN1117+Docetaxel)]

   Toxicity according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0. DLT defined as any of following considered related to any of treatment by investigator: Grade 4 neutropenia (absolute neutrophil count <500 cells/mm^3) for >7 days; ≥ Grade 3 neutropenia with coincident fever or infection; Grade 4 thrombocytopenia for >7 days; Grade 3 thrombocytopenia with clinically significant bleeding; Platelet count <10,000/mm^3 at any time; Delay in initiation of subsequent therapy cycle by >7 days due to treatment-related toxicity; ≥Grade 3 nonhematological toxicity except Grade 3 arthralgia/myalgia, fatigue that lasts <1 month, diarrhea, fasting hyperglycemia lasting ≤14 days, rash lasting ≤7 days and any other Grade 3 nonhematological toxicity that could be safely, reliably controlled to ≤Grade 1 with appropriate treatment; ≥ Grade 2 nonhematologic toxicities that are considered by investigator to be related to study drugs and dose-limiting.

2. Number of Participants With at Least 1 Treatment-Emergent Adverse Event (TEAE) in Part 1 [From first dose of study drug through 30 days after the last dose of study drug (approximately up to 366 days)]

   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 Serious Adverse Event (SAE) A serious 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. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug.

3. Number of Participants With at Least 1 ≥ Grade 3 TEAE in Part 1 [From first dose of study drug through 30 days after the last dose of study drug (approximately up to 366 days)]

   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. TEAE is defined as an adverse event with an onset that occurs after receiving study drug. There are 5 grades of the CTCAE; "grade" refers to severity. Grade 5 is the most severe, grade 1 is the least severe. As per version 4.0 of the CTCAE, Grade 3 = AE with severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. Grade 4 = AE with life-threatening consequences; urgent intervention indicated and Grade 5 = Death related to AE.

4. Number of Participants With at Least 1 Treatment-Emergent Serious Adverse Event (SAE) in Part 1 [From first dose of study drug through 30 days after the last dose of study drug (approximately up to 366 days)]

   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 SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly/birth defect; or a medically important event. TEAE is defined as an adverse event with an onset that occurs after receiving study drug.

5. Number of Participants With at Least 1 Dose Modification Due to AE in Part 1 [From first dose of study drug through 30 days after the last dose of study drug (approximately up to 366 days)]

   A decision regarding which study drug requires dose modification is dependent upon the toxicity, its onset, and time course. The causal relationship of each AE should will be assessed in relation to MLN1117 and to the combination agent in each cohort so that dose modifications can be made accordingly. Intrapatient dose reductions of MLN1117 are not permitted during Part 1 Cycle 1 unless the participant experiences a DLT attributed to MLN1117. Per dose modification guidelines, participants who have the study drug held because of treatment related or possibly related AEs may resume study drug treatment after resolution of the AE but may either maintain the same dose level or have doses of study drug reduced (dose reduction) by at least 1 dose level and if needed, by 2 dose levels. When a dose reduction of MLN1117 occurs, the MLN1117 dose will be reduced to the next lower dose that has been established as a safe dose during dose escalation (Part 1).

6. Overall Response Rate in Part 2 [Days 25-28 for MLN1117+TAK-659, MLN1117+Alisertib, and MLN1117+Paclitaxel and Days 18-21 for MLN1117+Docetaxel of Cycles 2, 4, 6; every other cycle until study discontinuation due to disease progression, unacceptable toxicity, or death (up to 336 days)]

   Overall response is defined as complete response (CR) plus partial response (PR) according to Response Evaluation Criteria in Solid tumors (RECIST) version 1.1 criteria. According to RECIST: CR is defined as disappearance of all target lesions and PR is defined as 30% decrease in the sum of the longest diameter of target lesions.

Secondary Outcome Measures

1. Number of Participants With at Least 1 TEAE and Serious TEAE in Part 1 and 2 [From first dose of study drug through 30 days after the last dose of study drug (approximately up to 366 days)]

   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 SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly/birth defect; or a medically important event. TEAE is defined as an adverse event with an onset that occurs after receiving study drug.

2. Number of Participants With Dose Delays, Dose Reductions, and Dose Interruptions Due To AE in Part 1 and 2 [From first dose of study drug through 30 days after the last dose of study drug (approximately up to 366 days)]

   Per dose modification guidelines, participants who have the study drug held because of treatment related or possibly related AEs may resume study drug treatment after resolution of the AE but may either maintain the same dose level or have doses of study drug reduced (dose reduction) by at least 1 dose level and if needed, by 2 dose levels.

3. Progression-Free Survival (PFS) Based on RECIST Criteria V 1.1 Assessment in Part 2 [Days 25-28 for MLN1117+TAK-659, MLN1117+Alisertib, and MLN1117+Paclitaxel and Days 18-21 for MLN1117+Docetaxel of Cycles 2, 4, 6; every other cycle until study discontinuation due to disease progression, unacceptable toxicity, or death (up to 336 days)]

   PFS is defined as the time from the date of randomization to the date of first documentation of Progressive disease (PD) or death due to any cause, whichever occurs first. PD is defined as an increase of >=20% from the nadir (or baseline, if it represents the point at which the sum of target disease was lowest).

4. Percentage of Participants With Disease Control Based on RECIST Criteria V 1.1 Assessment in Part 2 [Days 25-28 for MLN1117+TAK-659, MLN1117+Alisertib, and MLN1117+Paclitaxel and Days 18-21 for MLN1117+Docetaxel of Cycles 2, 4, 6; every other cycle until study discontinuation due to disease progression, unacceptable toxicity, or death (up to 336 days)]

   Disease control rate is defined as the percentage of participants with complete response (CR) + Partial response (PR) + stable disease (SD) according to RECIST version 1.1 criteria. CR is defined as disappearance of all target lesions, PR is defined as 30% decrease in the sum of the longest diameter of target lesions and SD is defined as not qualifying for CR, PR, or PD.

5. Duration of Response (DOR) Based on RECIST Criteria V 1.1 Assessment in Part 2 [Days 25-28 for MLN1117+TAK-659, MLN1117+Alisertib, and MLN1117+Paclitaxel and Days 18-21 for MLN1117+Docetaxel of Cycles 2, 4, 6; every other cycle until study discontinuation due to disease progression, unacceptable toxicity, or death (up to 336 days)]

   DOR is defined as the time from the date of first documentation of a response to the date of first documentation of PD according to RECIST version 1.1 criteria. PD is defined as 20% increase in the sum of the longest diameter of target lesions for measurable neoplastic disease.

6. Time to Disease Progression (TTP) Based on RECIST Criteria V 1.1 Assessment in Part 2 [Days 25-28 for MLN1117+TAK-659, MLN1117+Alisertib, and MLN1117+Paclitaxel and Days 18-21 for MLN1117+Docetaxel of Cycles 2, 4, 6; every other cycle until study discontinuation due to disease progression, unacceptable toxicity, or death (up to 336 days)]

   TTP is defined as the time from the date of randomization to the date of first documentation of PD. PD is defined as 20% increase in the sum of the longest diameter of target lesions for measurable neoplastic disease.

7. Overall Survival (OS) Based on RECIST Criteria V 1.1 Assessment [From randomization up to end of Part 2, then every 12 weeks until participant death or until 1 year after the last dose of study drug, whichever occurs first (up to 336 days)]

   OS is defined as the time from the date of randomization to the date of death.

8. Plasma Concentration of MLN1117-1003 [MLN1117 300 mg + Alisertib arms: Cycle 1 Day 3; MLN1117 300 mg + Paclitaxel arms and MLN1117 200 mg + Docetaxel arms: Cycle 1 Day 2; MLN1117 300 mg + TAK-659 arm: Cycle 1 Days 1 and 17]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

Part 1 and Part 2

1. Is male or female aged 18 years or older at the time of consent.

2. Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 14 days before enrollment.

3. Has adequate organ and hematologic function as evidenced by the following laboratory values within 14 days before enrollment:

• Absolute neutrophil count (ANC) ≥1.5x10^9/L.

• Platelet count ≥100x10^9/L.

• Hemoglobin ≥9 g/dL (Transfusions are allowed to reach this hemoglobin level).

• Serum creatinine ≤1.5 times the upper limit of the normal range (ULN) or creatinine clearance ≥50 mL/min either as estimated by the Cockcroft-Gault equation or based on urine collection (12 or 24 hours).

• Total bilirubin ≤1.5×ULN.

• Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤2.5×ULN.

1. Female participants who:

• Are postmenopausal for at least 1 year before the screening visit, OR

• Are surgically sterile, OR

• If they are of childbearing potential, agree to practice 1 highly effective method and 1 additional effective (barrier) method of contraception at the same time, from the time of signing the informed consent form through 30 days after the last dose of study drug (with the exception of those participants assigned to TAK-659, for whom the duration required is 180 days), or for as long as mandated by local labeling for docetaxel and paclitaxel, OR

• Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant, from the time of signing the informed consent form through 30 days after the last dose of study drug (with the exception of those participants assigned to TAK-659, for whom the duration required is 180 days), or for as long as mandated by local labeling for docetaxel and paclitaxel. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)

Male participants, even if surgically sterilized (ie, status postvasectomy), who:

• Agree to practice effective barrier contraception during the entire study treatment period and through 120 days after the last dose of study drug (with the exception of those participants assigned to TAK-659, for whom the duration required is 180 days), or for as long as mandated by local labeling for docetaxel and paclitaxel, OR

• Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant during the entire study treatment period and through 120 days after the last dose of study drug (with the exception of those participants assigned to TAK-659, for whom the duration required is 180 days) or for as long as mandated by local labeling for docetaxel and paclitaxel. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods for the female partner] and withdrawal are not acceptable methods of contraception.)

1. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care.

2. Has suitable venous access for the study-required blood sampling (ie, pharmacokinetic (PK) sampling, circulating tumor deoxyribonucleic acid [DNA]).

Part 1 only

1. Has a histologically confirmed diagnosis of advanced solid tumor, including but not limited to gastric or gastroesophageal junction adenocarcinoma.

2. Has radiographically or clinically evaluable disease. Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 is not required.

3. Is relapsed or refractory with no effective therapeutic options available.

Part 2 only

1. Has a histologically confirmed diagnosis of metastatic or locally advanced adenocarcinoma of the stomach or gastroesophageal junction (Stage IIIb or IV according to International Union Against Cancer [UICC] tumor, node, metastases [TNM] classification, 7th edition).

2. Has at least 1 measurable tumor lesion per RECIST Version 1.1 by radiographic techniques (computed tomography [CT] or magnetic resonance imaging [MRI]).

3. Has receipt of 1 prior systemic chemotherapy regimen for advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction with documented progressive disease (PD).

4. Has archived or fresh tumor biopsy samples obtained during screening sufficient for Epstein-Barr virus (EBV) testing and genotyping.

Exclusion Criteria:

Part 1 and Part 2

1. Has received prior systemic anticancer therapies or other investigational agents within 2 weeks before the first administration of study drug or has failed to recover from the adverse drug effects of prior therapies (to ≤Grade 1 or to a level meeting inclusion criteria). For prior therapies with a half-life longer than 3 days, the interval must equal minimally 28 days before the first administration of study drug and the participant must have documented PD.

2. Has radiotherapy within 14 days before enrollment.

3. Has fasting glucose ≥130 mg/dL. Poorly controlled diabetes mellitus (glycosylated hemoglobin [HbA1c] >7.0%). Participants with a history of transient glucose intolerance due to corticosteroid administration are allowed.

4. Has received strong cytochrome P-450 (CYP) 3A4 inducers/inhibitors within 7 days before the first administration of study drug or has conditions that require the concomitant use of CYP3A4 inducers/inhibitors during the course of the study.

5. For TAK-659 (Cohort A) only: Is receiving treatment with medications that are known to be inhibitors or inducers of P-glycoprotein (P-gp). Baseline lipase >ULN. Participants not fulfilling these exclusion criteria can be enrolled in other cohorts (Part 1 only).

6. Has taken proton pump inhibitors within 7 days before the first administration of study drug or has conditions that require the concomitant use of proton pump inhibitors during the course of the study.

7. Has signs of peripheral neuropathy ≥ National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade 2.

8. Has symptomatic brain metastases or brain metastases with a stable neurologic status for <2 weeks after completion of the definitive therapy and steroids.

9. Has systemic infection requiring intravenous (IV) antibiotic therapy or other serious infection within 14 days before the first dose of study drug.

10. Has known or suspected human immunodeficiency virus (HIV) positive or hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection. Testing for these agents is not required in the absence of clinical findings or suspicion.

11. Has known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerability of orally administered study drug, including difficulty swallowing tablets; diarrhea >Grade 1 despite supportive therapy; or prior total gastrectomy.

12. Has clinically significant comorbidities, such as uncontrolled pulmonary disease, known impaired cardiac function or clinically significant cardiac disease, active central nervous system disease, or any other condition that could compromise the participant's participation in the study.

• Known impaired cardiac function or clinically significant cardiac disease includes: evidence of currently uncontrolled cardiovascular conditions (including arrhythmias, angina, pulmonary hypertension, acute ischemia or active conduction system abnormalities); current history of New York Heart Association Class III or IV heart failure; acute myocardial infarction within 6 months before starting study drug; baseline QT interval corrected for heart rate (QTc) ≥Grade 1 according to NCI CTCAE Version 4.03 criteria; or abnormalities on baseline 12-lead ECG that are considered clinically significant per the investigator.

1. Female participants who are lactating and breastfeeding or have a positive serum pregnancy test during the screening period or a positive urine pregnancy test on Day 1 before the first dose of study drug.

2. Participants with bilirubin >ULN, or AST and/or ALT >1.5 X ULN concomitant with alkaline phosphatase >2.5 X ULN cannot be allocated to Cohort D (MLN1117+docetaxel) in Part 1 and are not eligible for Part 2 if they are also EBV negative.

Part 2 only

1. Has prior treatment with any of the following:

• An Aurora A-targeted agent (not eligible for randomization in Cohorts B, C, or D, but eligible for Cohort A if EBV positive).

• A docetaxel- or paclitaxel-containing chemotherapy regimen (not eligible for randomization in Cohorts B, C, or D, but eligible for Cohort A if EBV positive).

• A spleen tyrosine kinase (SYK) inhibitor (MLN1117+TAK-659 arm only).

• A phosphoinositide 3-kinase (PI3K) or serine/threonine kinase, also known as protein kinase B or PKB (AKT) inhibitor.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Lake Success	New York	United States
2		New York	New York	United States
3		Philadelphia	Pennsylvania	United States
4		Dallas	Texas	United States
5		Houston	Texas	United States
6		Barcelona		Spain

Sponsors and Collaborators

• Millennium Pharmaceuticals, Inc.

Investigators

• Study Director: Medical Director, Takeda

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 25, 2016

More Information

Publications

None provided.

• Responsible Party: Millennium Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT02551055
• Other Study ID Numbers: C032-6001 (MLN1117-1003); 2015-001032-38; U1111-1166-8653; REec-2016-2039
• First Posted: Sep 16, 2015
• Last Update Posted: Sep 20, 2019
• Last Verified: Aug 1, 2019

• 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: Adenocarcinoma; Paclitaxel; Docetaxel; Serabelisib

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 3 investigative sites in Spain and the United States from 15 October 2015 to 18 January 2017.
Pre-assignment Detail	Participants with solid advanced tumors were enrolled in Part 1 to receive MLN1117 along with alisertib, paclitaxel, TAK-659 and docetaxel in 1 of 7 treatment regimens. In Part 2, participants with gastric or gastroesophageal junction adenocarcinoma were to be enrolled, however, study terminated before initiation of part 2.

Arm/Group Title	MLN1117 300 mg + Alisertib	MLN1117 600 mg + Alisertib	MLN1117 300 mg + Paclitaxel	MLN1117 600 mg + Paclitaxel	MLN1117 300 mg + TAK-659	MLN1117 200 mg + Docetaxel	MLN1117 300 mg + Docetaxel	Part 2
Arm/Group Description	MLN1117 300 mg, tablets, orally, once daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15, 16, 17; 22, 23, and 24) and 4 days off per week and alisertib 40 mg, tablets, orally, twice daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15,16, and 17) and 4 days off per week on Weeks 1-3, and 1 week off in 28-day treatment cycles until PD or unacceptable toxicity (up to 12 cycles).	MLN1117 600 mg, tablets, orally, once daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15, 16, 17; 22, 23, and 24) and 4 days off per week and alisertib 40 mg, tablets, orally, twice daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15,16, and 17) and 4 days off per week on Weeks 1-3, and 1 week off in 28-day treatment cycles until PD or unacceptable toxicity (up to 10 cycles).	MLN1117 300 mg, tablets, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, 18; 23, 24, and 25) and 4 days off per week and paclitaxel 80 mg/m^2, infusion, intravenously, once weekly on (Days 1, 8, and 15) and 1 week off, in 28-day treatment cycles until PD or unacceptable toxicity (up to 6 cycles).	MLN1117 600 mg, tablets, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, 18; 23, 24, and 25) and 4 days off per week and paclitaxel 80 mg/m^2, infusion, intravenously, once weekly on (Days 1, 8, and 15) and 1 week off, in 28-day treatment cycles until PD or unacceptable toxicity (up to 3 cycles).	MLN1117 300 mg, tablets, orally, once daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15, 16, 17; and 22, 23, and 24) and 4 days off per week and TAK-659 100 mg (as determined in study C34001 [NCT02000934]), tablets, orally, once daily, in 28-day treatment cycles until progressive disease (PD) or unacceptable toxicity (up to 3 cycles).	MLN1117 200 mg, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, and 18) and 4 days off per week and docetaxel 75 mg/m^2, infusion, intravenously, on Day 1 once every 3 weeks in 21-day treatment cycles until PD or unacceptable toxicity (up to 1 cycle).	MLN1117 300 mg, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, and 18) and 4 days off per week and docetaxel 75 mg/m^2, infusion, intravenously, on Day 1 once every 3 weeks in 21-day treatment cycles until PD or unacceptable toxicity (up to 2 cycles).	Participants entered Part 2 of the study were to be screened to determine EBV-positive or EBV-negative solid tumors. EBV-positive participants were to receive MLN1117+TAK-659 (Cohort A). EBV-negative participants were to be randomized to other treatment cohorts: MLN1117+alisertib (Cohort B), MLN1117+paclitaxel (Cohort C), or MLN1117+docetaxel (Cohort D).
Period Title: Overall Study
STARTED	4	6	3	6	7	2	4	0
COMPLETED	0	0	1	1	0	1	1	0
NOT COMPLETED	4	6	2	5	7	1	3	0

Baseline Characteristics

Arm/Group Title	MLN1117 300 mg + Alisertib	MLN1117 600 mg + Alisertib	MLN1117 300 mg + Paclitaxel	MLN1117 600 mg + Paclitaxel	MLN1117 300 mg + TAK-659	MLN1117 200 mg + Docetaxel	MLN1117 300 mg + Docetaxel	Total
Arm/Group Description	MLN1117 300 mg, tablets, orally, once daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15, 16, 17; 22, 23, and 24) and 4 days off per week and alisertib 40 mg, tablets, orally, twice daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15,16, and 17) and 4 days off per week on Weeks 1-3, and 1 week off in 28-day treatment cycles until PD or unacceptable toxicity (up to 12 cycles).	MLN1117 600 mg, tablets, orally, once daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15, 16, 17; 22, 23, and 24) and 4 days off per week and alisertib 40 mg, tablets, orally, twice daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15,16, and 17) and 4 days off per week on Weeks 1-3, and 1 week off in 28-day treatment cycles until PD or unacceptable toxicity (up to 10 cycles).	MLN1117 300 mg, tablets, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, 18; 23, 24, and 25) and 4 days off per week and paclitaxel 80 mg/m^2, infusion, intravenously, once weekly on (Days 1, 8, and 15) and 1 week off, in 28-day treatment cycles until PD or unacceptable toxicity (up to 6 cycles).	MLN1117 600 mg, tablets, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, 18; 23, 24, and 25) and 4 days off per week and paclitaxel 80 mg/m^2, infusion, intravenously, once weekly on (Days 1, 8, and 15) and 1 week off, in 28-day treatment cycles until PD or unacceptable toxicity (up to 3 cycles).	MLN1117 300 mg, tablets, orally, once daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15, 16, 17; and 22, 23, and 24) and 4 days off per week and TAK-659 100 mg (as determined in study C34001 [NCT02000934]), tablets, orally, once daily, in 28-day treatment cycles until progressive disease (PD) or unacceptable toxicity (up to 3 cycles).	MLN1117 200 mg, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, and 18) and 4 days off per week and docetaxel 75 mg/m^2, infusion, intravenously, on Day 1 once every 3 weeks in 21-day treatment cycles until PD or unacceptable toxicity (up to 1 cycle).	MLN1117 300 mg, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, and 18) and 4 days off per week and docetaxel 75 mg/m^2, infusion, intravenously, on Day 1 once every 3 weeks in 21-day treatment cycles until PD or unacceptable toxicity (up to 2 cycles).	Total of all reporting groups
Overall Participants	4	6	3	6	7	2	4	32
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.5 (7.94)	59.0 (4.86)	65.3 (13.28)	62.2 (11.82)	62.3 (9.16)	65.5 (4.95)	62.3 (9.95)	62.0 (8.61)
Sex: Female, Male (Count of Participants)
Female	3 75%	3 50%	3 100%	5 83.3%	7 100%	2 100%	2 50%	25 78.1%
Male	1 25%	3 50%	0 0%	1 16.7%	0 0%	0 0%	2 50%	7 21.9%
Race/Ethnicity, Customized (participants) [Number]
Hispanic or Latino	0 0%	0 0%	0 0%	1 16.7%	1 14.3%	0 0%	1 25%	3 9.4%
Not Hispanic or Latino	4 100%	6 100%	3 100%	5 83.3%	6 85.7%	2 100%	3 75%	29 90.6%
Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (participants) [Number]
White	4 100%	4 66.7%	2 66.7%	6 100%	6 85.7%	1 50%	4 100%	27 84.4%
Black or African American	0 0%	1 16.7%	1 33.3%	0 0%	1 14.3%	1 50%	0 0%	4 12.5%
Asian	0 0%	1 16.7%	0 0%	0 0%	0 0%	0 0%	0 0%	1 3.1%
Region of Enrollment (participants) [Number]
United States	4 100%	5 83.3%	3 100%	3 50%	6 85.7%	2 100%	4 100%	27 84.4%
Spain	0 0%	1 16.7%	0 0%	3 50%	1 14.3%	0 0%	0 0%	5 15.6%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	162.90 (14.178)	165.50 (10.145)	159.80 (4.513)	162.83 (15.108)	158.76 (6.662)	154.95 (7.142)	166.25 (16.674)	162.07 (10.939)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	77.75 (15.314)	71.63 (19.725)	74.07 (12.756)	82.38 (25.474)	65.53 (13.046)	75.45 (43.911)	68.28 (21.403)	73.13 (19.400)
Body Surface Area (m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [m^2]	1.825 (0.2814)	1.802 (0.2863)	1.809 (0.1638)	1.917 (0.3496)	1.694 (0.1790)	1.768 (0.5769)	1.767 (0.3734)	1.796 (0.2796)

Outcome Measures

1. Primary Outcome

Title	Number of Participants Who Experienced Cycle 1 Dose Limiting Toxicity (DLT) in Part 1
Description	Toxicity according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0. DLT defined as any of following considered related to any of treatment by investigator: Grade 4 neutropenia (absolute neutrophil count <500 cells/mm^3) for >7 days; ≥ Grade 3 neutropenia with coincident fever or infection; Grade 4 thrombocytopenia for >7 days; Grade 3 thrombocytopenia with clinically significant bleeding; Platelet count <10,000/mm^3 at any time; Delay in initiation of subsequent therapy cycle by >7 days due to treatment-related toxicity; ≥Grade 3 nonhematological toxicity except Grade 3 arthralgia/myalgia, fatigue that lasts <1 month, diarrhea, fasting hyperglycemia lasting ≤14 days, rash lasting ≤7 days and any other Grade 3 nonhematological toxicity that could be safely, reliably controlled to ≤Grade 1 with appropriate treatment; ≥ Grade 2 nonhematologic toxicities that are considered by investigator to be related to study drugs and dose-limiting.
Time Frame	Up to Cycle 1 (28 days for MLN1117+TAK-659, MLN1117+Alisertib, MLN1117+Paclitaxel or 21 days for MLN1117+Docetaxel)

Outcome Measure Data

Analysis Population Description

DLT-evaluable population defined as all participants in Part 1 of study who either experience DLT during Cycle 1 or complete treatment with at least 75% of the planned doses of MLN1117 and the combination partner, and have sufficient follow-up data for the investigators and sponsor to determine whether DLT occurred.

Arm/Group Title	MLN1117 300 mg + Alisertib	MLN1117 600 mg + Alisertib	MLN1117 300 mg + Paclitaxel	MLN1117 600 mg + Paclitaxel	MLN1117 300 mg + TAK-659	MLN1117 200 mg + Docetaxel	MLN1117 300 mg + Docetaxel
Arm/Group Description	MLN1117 300 mg, tablets, orally, once daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15, 16, 17; 22, 23, and 24) and 4 days off per week and alisertib 40 mg, tablets, orally, twice daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15,16, and 17) and 4 days off per week on Weeks 1-3, and 1 week off in 28-day treatment cycles until PD or unacceptable toxicity (up to 12 cycles).	MLN1117 600 mg, tablets, orally, once daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15, 16, 17; 22, 23, and 24) and 4 days off per week and alisertib 40 mg, tablets, orally, twice daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15,16, and 17) and 4 days off per week on Weeks 1-3, and 1 week off in 28-day treatment cycles until PD or unacceptable toxicity (up to 10 cycles).	MLN1117 300 mg, tablets, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, 18; 23, 24, and 25) and 4 days off per week and paclitaxel 80 mg/m^2, infusion, intravenously, once weekly on (Days 1, 8, and 15) and 1 week off, in 28-day treatment cycles until PD or unacceptable toxicity (up to 6 cycles).	MLN1117 600 mg, tablets, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, 18; 23, 24, and 25) and 4 days off per week and paclitaxel 80 mg/m^2, infusion, intravenously, once weekly on (Days 1, 8, and 15) and 1 week off, in 28-day treatment cycles until PD or unacceptable toxicity (up to 3 cycles).	MLN1117 300 mg, tablets, orally, once daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15, 16, 17; and 22, 23, and 24) and 4 days off per week and TAK-659 100 mg (as determined in study C34001 [NCT02000934]), tablets, orally, once daily, in 28-day treatment cycles until progressive disease (PD) or unacceptable toxicity (up to 3 cycles).	MLN1117 200 mg, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, and 18) and 4 days off per week and docetaxel 75 mg/m^2, infusion, intravenously, on Day 1 once every 3 weeks in 21-day treatment cycles until PD or unacceptable toxicity (up to 1 cycle).	MLN1117 300 mg, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, and 18) and 4 days off per week and docetaxel 75 mg/m^2, infusion, intravenously, on Day 1 once every 3 weeks in 21-day treatment cycles until PD or unacceptable toxicity (up to 2 cycles).
Measure Participants	4	6	3	6	7	2	4
Number [participants]	0 0%	1 16.7%	0 0%	0 0%	1 14.3%	0 0%	1 25%

2. Primary Outcome

Title	Number of Participants With at Least 1 Treatment-Emergent Adverse Event (TEAE) in Part 1
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 Serious Adverse Event (SAE) A serious 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. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug.
Time Frame	From first dose of study drug through 30 days after the last dose of study drug (approximately up to 366 days)

Outcome Measure Data

Analysis Population Description

Safety population is defined as all participants who received at least 1 dose of any study drug. Participants are analyzed according to the treatment actually received.

Arm/Group Title	MLN1117 300 mg + Alisertib	MLN1117 600 mg + Alisertib	MLN1117 300 mg + Paclitaxel	MLN1117 600 mg + Paclitaxel	MLN1117 300 mg + TAK-659	MLN1117 200 mg + Docetaxel	MLN1117 300 mg + Docetaxel
Arm/Group Description	MLN1117 300 mg, tablets, orally, once daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15, 16, 17; 22, 23, and 24) and 4 days off per week and alisertib 40 mg, tablets, orally, twice daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15,16, and 17) and 4 days off per week on Weeks 1-3, and 1 week off in 28-day treatment cycles until PD or unacceptable toxicity (up to 12 cycles).	MLN1117 600 mg, tablets, orally, once daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15, 16, 17; 22, 23, and 24) and 4 days off per week and alisertib 40 mg, tablets, orally, twice daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15,16, and 17) and 4 days off per week on Weeks 1-3, and 1 week off in 28-day treatment cycles until PD or unacceptable toxicity (up to 10 cycles).	MLN1117 300 mg, tablets, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, 18; 23, 24, and 25) and 4 days off per week and paclitaxel 80 mg/m^2, infusion, intravenously, once weekly on (Days 1, 8, and 15) and 1 week off, in 28-day treatment cycles until PD or unacceptable toxicity (up to 6 cycles).	MLN1117 600 mg, tablets, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, 18; 23, 24, and 25) and 4 days off per week and paclitaxel 80 mg/m^2, infusion, intravenously, once weekly on (Days 1, 8, and 15) and 1 week off, in 28-day treatment cycles until PD or unacceptable toxicity (up to 3 cycles).	MLN1117 300 mg, tablets, orally, once daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15, 16, 17; and 22, 23, and 24) and 4 days off per week and TAK-659 100 mg (as determined in study C34001 [NCT02000934]), tablets, orally, once daily, in 28-day treatment cycles until progressive disease (PD) or unacceptable toxicity (up to 3 cycles).	MLN1117 200 mg, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, and 18) and 4 days off per week and docetaxel 75 mg/m^2, infusion, intravenously, on Day 1 once every 3 weeks in 21-day treatment cycles until PD or unacceptable toxicity (up to 1 cycle).	MLN1117 300 mg, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, and 18) and 4 days off per week and docetaxel 75 mg/m^2, infusion, intravenously, on Day 1 once every 3 weeks in 21-day treatment cycles until PD or unacceptable toxicity (up to 2 cycles).
Measure Participants	4	6	3	6	7	2	4
Number [participants]	4 100%	6 100%	3 100%	6 100%	7 100%	2 100%	4 100%

3. Primary Outcome

Title	Number of Participants With at Least 1 ≥ Grade 3 TEAE in Part 1
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. TEAE is defined as an adverse event with an onset that occurs after receiving study drug. There are 5 grades of the CTCAE; "grade" refers to severity. Grade 5 is the most severe, grade 1 is the least severe. As per version 4.0 of the CTCAE, Grade 3 = AE with severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. Grade 4 = AE with life-threatening consequences; urgent intervention indicated and Grade 5 = Death related to AE.
Time Frame	From first dose of study drug through 30 days after the last dose of study drug (approximately up to 366 days)

Outcome Measure Data

Analysis Population Description

Safety population is defined as all participants who received at least 1 dose of any study drug. Participants are analyzed according to the treatment actually received.

Arm/Group Title	MLN1117 300 mg + Alisertib	MLN1117 600 mg + Alisertib	MLN1117 300 mg + Paclitaxel	MLN1117 600 mg + Paclitaxel	MLN1117 300 mg + TAK-659	MLN1117 200 mg + Docetaxel	MLN1117 300 mg + Docetaxel
Arm/Group Description	MLN1117 300 mg, tablets, orally, once daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15, 16, 17; 22, 23, and 24) and 4 days off per week and alisertib 40 mg, tablets, orally, twice daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15,16, and 17) and 4 days off per week on Weeks 1-3, and 1 week off in 28-day treatment cycles until PD or unacceptable toxicity (up to 12 cycles).	MLN1117 600 mg, tablets, orally, once daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15, 16, 17; 22, 23, and 24) and 4 days off per week and alisertib 40 mg, tablets, orally, twice daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15,16, and 17) and 4 days off per week on Weeks 1-3, and 1 week off in 28-day treatment cycles until PD or unacceptable toxicity (up to 10 cycles).	MLN1117 300 mg, tablets, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, 18; 23, 24, and 25) and 4 days off per week and paclitaxel 80 mg/m^2, infusion, intravenously, once weekly on (Days 1, 8, and 15) and 1 week off, in 28-day treatment cycles until PD or unacceptable toxicity (up to 6 cycles).	MLN1117 600 mg, tablets, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, 18; 23, 24, and 25) and 4 days off per week and paclitaxel 80 mg/m^2, infusion, intravenously, once weekly on (Days 1, 8, and 15) and 1 week off, in 28-day treatment cycles until PD or unacceptable toxicity (up to 3 cycles).	MLN1117 300 mg, tablets, orally, once daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15, 16, 17; and 22, 23, and 24) and 4 days off per week and TAK-659 100 mg (as determined in study C34001 [NCT02000934]), tablets, orally, once daily, in 28-day treatment cycles until progressive disease (PD) or unacceptable toxicity (up to 3 cycles).	MLN1117 200 mg, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, and 18) and 4 days off per week and docetaxel 75 mg/m^2, infusion, intravenously, on Day 1 once every 3 weeks in 21-day treatment cycles until PD or unacceptable toxicity (up to 1 cycle).	MLN1117 300 mg, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, and 18) and 4 days off per week and docetaxel 75 mg/m^2, infusion, intravenously, on Day 1 once every 3 weeks in 21-day treatment cycles until PD or unacceptable toxicity (up to 2 cycles).
Measure Participants	4	6	3	6	7	2	4
Number [participants]	4 100%	4 66.7%	2 66.7%	2 33.3%	6 85.7%	2 100%	4 100%

4. Primary Outcome

Title	Number of Participants With at Least 1 Treatment-Emergent Serious Adverse Event (SAE) in Part 1
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 SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly/birth defect; or a medically important event. TEAE is defined as an adverse event with an onset that occurs after receiving study drug.
Time Frame	From first dose of study drug through 30 days after the last dose of study drug (approximately up to 366 days)

Outcome Measure Data

Analysis Population Description

Safety population is defined as all participants who received at least 1 dose of any study drug. Participants are analyzed according to the treatment actually received.

Arm/Group Title	MLN1117 300 mg + Alisertib	MLN1117 600 mg + Alisertib	MLN1117 300 mg + Paclitaxel	MLN1117 600 mg + Paclitaxel	MLN1117 300 mg + TAK-659	MLN1117 200 mg + Docetaxel	MLN1117 300 mg + Docetaxel
Arm/Group Description	MLN1117 300 mg, tablets, orally, once daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15, 16, 17; 22, 23, and 24) and 4 days off per week and alisertib 40 mg, tablets, orally, twice daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15,16, and 17) and 4 days off per week on Weeks 1-3, and 1 week off in 28-day treatment cycles until PD or unacceptable toxicity (up to 12 cycles).	MLN1117 600 mg, tablets, orally, once daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15, 16, 17; 22, 23, and 24) and 4 days off per week and alisertib 40 mg, tablets, orally, twice daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15,16, and 17) and 4 days off per week on Weeks 1-3, and 1 week off in 28-day treatment cycles until PD or unacceptable toxicity (up to 10 cycles).	MLN1117 300 mg, tablets, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, 18; 23, 24, and 25) and 4 days off per week and paclitaxel 80 mg/m^2, infusion, intravenously, once weekly on (Days 1, 8, and 15) and 1 week off, in 28-day treatment cycles until PD or unacceptable toxicity (up to 6 cycles).	MLN1117 600 mg, tablets, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, 18; 23, 24, and 25) and 4 days off per week and paclitaxel 80 mg/m^2, infusion, intravenously, once weekly on (Days 1, 8, and 15) and 1 week off, in 28-day treatment cycles until PD or unacceptable toxicity (up to 3 cycles).	MLN1117 300 mg, tablets, orally, once daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15, 16, 17; and 22, 23, and 24) and 4 days off per week and TAK-659 100 mg (as determined in study C34001 [NCT02000934]), tablets, orally, once daily, in 28-day treatment cycles until progressive disease (PD) or unacceptable toxicity (up to 3 cycles).	MLN1117 200 mg, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, and 18) and 4 days off per week and docetaxel 75 mg/m^2, infusion, intravenously, on Day 1 once every 3 weeks in 21-day treatment cycles until PD or unacceptable toxicity (up to 1 cycle).	MLN1117 300 mg, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, and 18) and 4 days off per week and docetaxel 75 mg/m^2, infusion, intravenously, on Day 1 once every 3 weeks in 21-day treatment cycles until PD or unacceptable toxicity (up to 2 cycles).
Measure Participants	4	6	3	6	7	2	4
Number [participants]	2 50%	3 50%	1 33.3%	2 33.3%	5 71.4%	2 100%	4 100%

5. Primary Outcome

Title	Number of Participants With at Least 1 Dose Modification Due to AE in Part 1
Description	A decision regarding which study drug requires dose modification is dependent upon the toxicity, its onset, and time course. The causal relationship of each AE should will be assessed in relation to MLN1117 and to the combination agent in each cohort so that dose modifications can be made accordingly. Intrapatient dose reductions of MLN1117 are not permitted during Part 1 Cycle 1 unless the participant experiences a DLT attributed to MLN1117. Per dose modification guidelines, participants who have the study drug held because of treatment related or possibly related AEs may resume study drug treatment after resolution of the AE but may either maintain the same dose level or have doses of study drug reduced (dose reduction) by at least 1 dose level and if needed, by 2 dose levels. When a dose reduction of MLN1117 occurs, the MLN1117 dose will be reduced to the next lower dose that has been established as a safe dose during dose escalation (Part 1).
Time Frame	From first dose of study drug through 30 days after the last dose of study drug (approximately up to 366 days)

Outcome Measure Data

Analysis Population Description

Safety population is defined as all participants who received at least 1 dose of any study drug. Participants are analyzed according to the treatment actually received.

Arm/Group Title	MLN1117 300 mg + Alisertib	MLN1117 600 mg + Alisertib	MLN1117 300 mg + Paclitaxel	MLN1117 600 mg + Paclitaxel	MLN1117 300 mg + TAK-659	MLN1117 200 mg + Docetaxel	MLN1117 300 mg + Docetaxel
Arm/Group Description	MLN1117 300 mg, tablets, orally, once daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15, 16, 17; 22, 23, and 24) and 4 days off per week and alisertib 40 mg, tablets, orally, twice daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15,16, and 17) and 4 days off per week on Weeks 1-3, and 1 week off in 28-day treatment cycles until PD or unacceptable toxicity (up to 12 cycles).	MLN1117 600 mg, tablets, orally, once daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15, 16, 17; 22, 23, and 24) and 4 days off per week and alisertib 40 mg, tablets, orally, twice daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15,16, and 17) and 4 days off per week on Weeks 1-3, and 1 week off in 28-day treatment cycles until PD or unacceptable toxicity (up to 10 cycles).	MLN1117 300 mg, tablets, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, 18; 23, 24, and 25) and 4 days off per week and paclitaxel 80 mg/m^2, infusion, intravenously, once weekly on (Days 1, 8, and 15) and 1 week off, in 28-day treatment cycles until PD or unacceptable toxicity (up to 6 cycles).	MLN1117 600 mg, tablets, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, 18; 23, 24, and 25) and 4 days off per week and paclitaxel 80 mg/m^2, infusion, intravenously, once weekly on (Days 1, 8, and 15) and 1 week off, in 28-day treatment cycles until PD or unacceptable toxicity (up to 3 cycles).	MLN1117 300 mg, tablets, orally, once daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15, 16, 17; and 22, 23, and 24) and 4 days off per week and TAK-659 100 mg (as determined in study C34001 [NCT02000934]), tablets, orally, once daily, in 28-day treatment cycles until progressive disease (PD) or unacceptable toxicity (up to 3 cycles).	MLN1117 200 mg, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, and 18) and 4 days off per week and docetaxel 75 mg/m^2, infusion, intravenously, on Day 1 once every 3 weeks in 21-day treatment cycles until PD or unacceptable toxicity (up to 1 cycle).	MLN1117 300 mg, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, and 18) and 4 days off per week and docetaxel 75 mg/m^2, infusion, intravenously, on Day 1 once every 3 weeks in 21-day treatment cycles until PD or unacceptable toxicity (up to 2 cycles).
Measure Participants	4	6	3	6	7	2	4
Number [participants]	0 0%	1 16.7%	1 33.3%	0 0%	4 57.1%	0 0%	1 25%

6. Primary Outcome

Title	Overall Response Rate in Part 2
Description	Overall response is defined as complete response (CR) plus partial response (PR) according to Response Evaluation Criteria in Solid tumors (RECIST) version 1.1 criteria. According to RECIST: CR is defined as disappearance of all target lesions and PR is defined as 30% decrease in the sum of the longest diameter of target lesions.
Time Frame	Days 25-28 for MLN1117+TAK-659, MLN1117+Alisertib, and MLN1117+Paclitaxel and Days 18-21 for MLN1117+Docetaxel of Cycles 2, 4, 6; every other cycle until study discontinuation due to disease progression, unacceptable toxicity, or death (up to 336 days)

Outcome Measure Data

Analysis Population Description

Study was terminated before the initiation of Part 2 of the study.

Arm/Group Title	Part 2
Arm/Group Description	Participants entered Part 2 of the study were to be screened to determine EBV-positive or EBV-negative solid tumors. EBV-positive participants were to receive MLN1117+TAK-659 (Cohort A). EBV-negative participants were to be randomized to other treatment cohorts: MLN1117+alisertib (Cohort B), MLN1117+paclitaxel (Cohort C), or MLN1117+docetaxel (Cohort D).
Measure Participants	0

7. Secondary Outcome

Title	Number of Participants With at Least 1 TEAE and Serious TEAE in Part 1 and 2
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 SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly/birth defect; or a medically important event. TEAE is defined as an adverse event with an onset that occurs after receiving study drug.
Time Frame	From first dose of study drug through 30 days after the last dose of study drug (approximately up to 366 days)

Outcome Measure Data

Analysis Population Description

Safety population is defined as all participants who received at least 1 dose of any study drug. Participants are analyzed according to the treatment actually received.

Arm/Group Title	MLN1117 300 mg + Alisertib	MLN1117 600 mg + Alisertib	MLN1117 300 mg + Paclitaxel	MLN1117 600 mg + Paclitaxel	MLN1117 300 mg + TAK-659	MLN1117 200 mg + Docetaxel	MLN1117 300 mg + Docetaxel	Part 2
Arm/Group Description	MLN1117 300 mg, tablets, orally, once daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15, 16, 17; 22, 23, and 24) and 4 days off per week and alisertib 40 mg, tablets, orally, twice daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15,16, and 17) and 4 days off per week on Weeks 1-3, and 1 week off in 28-day treatment cycles until PD or unacceptable toxicity (up to 12 cycles).	MLN1117 600 mg, tablets, orally, once daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15, 16, 17; 22, 23, and 24) and 4 days off per week and alisertib 40 mg, tablets, orally, twice daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15,16, and 17) and 4 days off per week on Weeks 1-3, and 1 week off in 28-day treatment cycles until PD or unacceptable toxicity (up to 10 cycles).	MLN1117 300 mg, tablets, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, 18; 23, 24, and 25) and 4 days off per week and paclitaxel 80 mg/m^2, infusion, intravenously, once weekly on (Days 1, 8, and 15) and 1 week off, in 28-day treatment cycles until PD or unacceptable toxicity (up to 6 cycles).	MLN1117 600 mg, tablets, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, 18; 23, 24, and 25) and 4 days off per week and paclitaxel 80 mg/m^2, infusion, intravenously, once weekly on (Days 1, 8, and 15) and 1 week off, in 28-day treatment cycles until PD or unacceptable toxicity (up to 3 cycles).	MLN1117 300 mg, tablets, orally, once daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15, 16, 17; and 22, 23, and 24) and 4 days off per week and TAK-659 100 mg (as determined in study C34001 [NCT02000934]), tablets, orally, once daily, in 28-day treatment cycles until progressive disease (PD) or unacceptable toxicity (up to 3 cycles).	MLN1117 200 mg, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, and 18) and 4 days off per week and docetaxel 75 mg/m^2, infusion, intravenously, on Day 1 once every 3 weeks in 21-day treatment cycles until PD or unacceptable toxicity (up to 1 cycle).	MLN1117 300 mg, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, and 18) and 4 days off per week and docetaxel 75 mg/m^2, infusion, intravenously, on Day 1 once every 3 weeks in 21-day treatment cycles until PD or unacceptable toxicity (up to 2 cycles).	Participants entered Part 2 of the study were to be screened to determine EBV-positive or EBV-negative solid tumors. EBV-positive participants were to receive MLN1117+TAK-659 (Cohort A). EBV-negative participants were to be randomized to other treatment cohorts: MLN1117+alisertib (Cohort B), MLN1117+paclitaxel (Cohort C), or MLN1117+docetaxel (Cohort D).
Measure Participants	4	6	3	6	7	2	4	0
AE	4 100%	6 100%	3 100%	6 100%	7 100%	2 100%	4 100%
SAE	2 50%	3 50%	1 33.3%	2 33.3%	5 71.4%	2 100%	4 100%

8. Secondary Outcome

Title	Number of Participants With Dose Delays, Dose Reductions, and Dose Interruptions Due To AE in Part 1 and 2
Description	Per dose modification guidelines, participants who have the study drug held because of treatment related or possibly related AEs may resume study drug treatment after resolution of the AE but may either maintain the same dose level or have doses of study drug reduced (dose reduction) by at least 1 dose level and if needed, by 2 dose levels.
Time Frame	From first dose of study drug through 30 days after the last dose of study drug (approximately up to 366 days)

Outcome Measure Data

Analysis Population Description

Safety population is defined as all participants who received at least 1 dose of any study drug. Participants are analyzed according to the treatment actually received.

Arm/Group Title	MLN1117 300 mg + Alisertib	MLN1117 600 mg + Alisertib	MLN1117 300 mg + Paclitaxel	MLN1117 600 mg + Paclitaxel	MLN1117 300 mg + TAK-659	MLN1117 200 mg + Docetaxel	MLN1117 300 mg + Docetaxel	Part 2
Arm/Group Description	MLN1117 300 mg, tablets, orally, once daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15, 16, 17; 22, 23, and 24) and 4 days off per week and alisertib 40 mg, tablets, orally, twice daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15,16, and 17) and 4 days off per week on Weeks 1-3, and 1 week off in 28-day treatment cycles until PD or unacceptable toxicity (up to 12 cycles).	MLN1117 600 mg, tablets, orally, once daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15, 16, 17; 22, 23, and 24) and 4 days off per week and alisertib 40 mg, tablets, orally, twice daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15,16, and 17) and 4 days off per week on Weeks 1-3, and 1 week off in 28-day treatment cycles until PD or unacceptable toxicity (up to 10 cycles).	MLN1117 300 mg, tablets, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, 18; 23, 24, and 25) and 4 days off per week and paclitaxel 80 mg/m^2, infusion, intravenously, once weekly on (Days 1, 8, and 15) and 1 week off, in 28-day treatment cycles until PD or unacceptable toxicity (up to 6 cycles).	MLN1117 600 mg, tablets, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, 18; 23, 24, and 25) and 4 days off per week and paclitaxel 80 mg/m^2, infusion, intravenously, once weekly on (Days 1, 8, and 15) and 1 week off, in 28-day treatment cycles until PD or unacceptable toxicity (up to 3 cycles).	MLN1117 300 mg, tablets, orally, once daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15, 16, 17; and 22, 23, and 24) and 4 days off per week and TAK-659 100 mg (as determined in study C34001 [NCT02000934]), tablets, orally, once daily, in 28-day treatment cycles until progressive disease (PD) or unacceptable toxicity (up to 3 cycles).	MLN1117 200 mg, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, and 18) and 4 days off per week and docetaxel 75 mg/m^2, infusion, intravenously, on Day 1 once every 3 weeks in 21-day treatment cycles until PD or unacceptable toxicity (up to 1 cycle).	MLN1117 300 mg, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, and 18) and 4 days off per week and docetaxel 75 mg/m^2, infusion, intravenously, on Day 1 once every 3 weeks in 21-day treatment cycles until PD or unacceptable toxicity (up to 2 cycles).	Participants entered Part 2 of the study were to be screened to determine EBV-positive or EBV-negative solid tumors. EBV-positive participants were to receive MLN1117+TAK-659 (Cohort A). EBV-negative participants were to be randomized to other treatment cohorts: MLN1117+alisertib (Cohort B), MLN1117+paclitaxel (Cohort C), or MLN1117+docetaxel (Cohort D).
Measure Participants	4	6	3	6	7	2	4	0
Dose delay due to AE	0 0%	0 0%	0 0%	0 0%	1 14.3%	0 0%	0 0%
Dose reduction due to AE	0 0%	1 16.7%	1 33.3%	0 0%	4 57.1%	0 0%	1 25%
Dose interruption due to AE	0 0%	0 0%	1 33.3%	0 0%	0 0%	0 0%	0 0%

9. Secondary Outcome

Title	Progression-Free Survival (PFS) Based on RECIST Criteria V 1.1 Assessment in Part 2
Description	PFS is defined as the time from the date of randomization to the date of first documentation of Progressive disease (PD) or death due to any cause, whichever occurs first. PD is defined as an increase of >=20% from the nadir (or baseline, if it represents the point at which the sum of target disease was lowest).
Time Frame	Days 25-28 for MLN1117+TAK-659, MLN1117+Alisertib, and MLN1117+Paclitaxel and Days 18-21 for MLN1117+Docetaxel of Cycles 2, 4, 6; every other cycle until study discontinuation due to disease progression, unacceptable toxicity, or death (up to 336 days)

Outcome Measure Data

Analysis Population Description

Study was terminated before the initiation of Part 2 of the study.

Arm/Group Title	Part 2
Arm/Group Description	Participants entered Part 2 of the study were to be screened to determine EBV-positive or EBV-negative solid tumors. EBV-positive participants were to receive MLN1117+TAK-659 (Cohort A). EBV-negative participants were to be randomized to other treatment cohorts: MLN1117+alisertib (Cohort B), MLN1117+paclitaxel (Cohort C), or MLN1117+docetaxel (Cohort D).
Measure Participants	0

10. Secondary Outcome

Title	Percentage of Participants With Disease Control Based on RECIST Criteria V 1.1 Assessment in Part 2
Description	Disease control rate is defined as the percentage of participants with complete response (CR) + Partial response (PR) + stable disease (SD) according to RECIST version 1.1 criteria. CR is defined as disappearance of all target lesions, PR is defined as 30% decrease in the sum of the longest diameter of target lesions and SD is defined as not qualifying for CR, PR, or PD.
Time Frame	Days 25-28 for MLN1117+TAK-659, MLN1117+Alisertib, and MLN1117+Paclitaxel and Days 18-21 for MLN1117+Docetaxel of Cycles 2, 4, 6; every other cycle until study discontinuation due to disease progression, unacceptable toxicity, or death (up to 336 days)

Outcome Measure Data

Analysis Population Description

Study was terminated before the initiation of Part 2 of the study.

Arm/Group Title	Part 2
Arm/Group Description	Participants entered Part 2 of the study were to be screened to determine EBV-positive or EBV-negative solid tumors. EBV-positive participants were to receive MLN1117+TAK-659 (Cohort A). EBV-negative participants were to be randomized to other treatment cohorts: MLN1117+alisertib (Cohort B), MLN1117+paclitaxel (Cohort C), or MLN1117+docetaxel (Cohort D).
Measure Participants	0

11. Secondary Outcome

Title	Duration of Response (DOR) Based on RECIST Criteria V 1.1 Assessment in Part 2
Description	DOR is defined as the time from the date of first documentation of a response to the date of first documentation of PD according to RECIST version 1.1 criteria. PD is defined as 20% increase in the sum of the longest diameter of target lesions for measurable neoplastic disease.
Time Frame	Days 25-28 for MLN1117+TAK-659, MLN1117+Alisertib, and MLN1117+Paclitaxel and Days 18-21 for MLN1117+Docetaxel of Cycles 2, 4, 6; every other cycle until study discontinuation due to disease progression, unacceptable toxicity, or death (up to 336 days)

Outcome Measure Data

Analysis Population Description

Study was terminated before the initiation of Part 2 of the study.

Arm/Group Title	Part 2
Arm/Group Description	Participants entered Part 2 of the study were to be screened to determine EBV-positive or EBV-negative solid tumors. EBV-positive participants were to receive MLN1117+TAK-659 (Cohort A). EBV-negative participants were to be randomized to other treatment cohorts: MLN1117+alisertib (Cohort B), MLN1117+paclitaxel (Cohort C), or MLN1117+docetaxel (Cohort D).
Measure Participants	0

12. Secondary Outcome

Title	Time to Disease Progression (TTP) Based on RECIST Criteria V 1.1 Assessment in Part 2
Description	TTP is defined as the time from the date of randomization to the date of first documentation of PD. PD is defined as 20% increase in the sum of the longest diameter of target lesions for measurable neoplastic disease.
Time Frame	Days 25-28 for MLN1117+TAK-659, MLN1117+Alisertib, and MLN1117+Paclitaxel and Days 18-21 for MLN1117+Docetaxel of Cycles 2, 4, 6; every other cycle until study discontinuation due to disease progression, unacceptable toxicity, or death (up to 336 days)

Outcome Measure Data

Analysis Population Description

Study was terminated before the initiation of Part 2 of the study.

Arm/Group Title	Part 2
Arm/Group Description	Participants entered Part 2 of the study were to be screened to determine EBV-positive or EBV-negative solid tumors. EBV-positive participants were to receive MLN1117+TAK-659 (Cohort A). EBV-negative participants were to be randomized to other treatment cohorts: MLN1117+alisertib (Cohort B), MLN1117+paclitaxel (Cohort C), or MLN1117+docetaxel (Cohort D).
Measure Participants	0

13. Secondary Outcome

Title	Overall Survival (OS) Based on RECIST Criteria V 1.1 Assessment
Description	OS is defined as the time from the date of randomization to the date of death.
Time Frame	From randomization up to end of Part 2, then every 12 weeks until participant death or until 1 year after the last dose of study drug, whichever occurs first (up to 336 days)

Outcome Measure Data

Analysis Population Description

Study was terminated before the initiation of Part 2 of the study.

Arm/Group Title	Part 2
Arm/Group Description	Participants entered Part 2 of the study were to be screened to determine EBV-positive or EBV-negative solid tumors. EBV-positive participants were to receive MLN1117+TAK-659 (Cohort A). EBV-negative participants were to be randomized to other treatment cohorts: MLN1117+alisertib (Cohort B), MLN1117+paclitaxel (Cohort C), or MLN1117+docetaxel (Cohort D).
Measure Participants	0

14. Secondary Outcome

Title	Plasma Concentration of MLN1117-1003
Time Frame	MLN1117 300 mg + Alisertib arms: Cycle 1 Day 3; MLN1117 300 mg + Paclitaxel arms and MLN1117 200 mg + Docetaxel arms: Cycle 1 Day 2; MLN1117 300 mg + TAK-659 arm: Cycle 1 Days 1 and 17

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) evaluable population included all participants in Part 1 (dose escalation of the study for whom there were sufficient dosing and MLN1117 concentration-time data was available).

Arm/Group Title	MLN1117 300 mg + Alisertib	MLN1117 600 mg + Alisertib	MLN1117 300 mg + Paclitaxel	MLN1117 600 mg + Paclitaxel	MLN1117 300 mg + TAK-659	MLN1117 200 mg + Docetaxel	MLN1117 300 mg + Docetaxel
Arm/Group Description	MLN1117 300 mg, tablets, orally, once daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15, 16, 17; 22, 23, and 24) and 4 days off per week and alisertib 40 mg, tablets, orally, twice daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15,16, and 17) and 4 days off per week on Weeks 1-3, and 1 week off in 28-day treatment cycles until PD or unacceptable toxicity (up to 12 cycles).	MLN1117 600 mg, tablets, orally, once daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15, 16, 17; 22, 23, and 24) and 4 days off per week and alisertib 40 mg, tablets, orally, twice daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15,16, and 17) and 4 days off per week on Weeks 1-3, and 1 week off in 28-day treatment cycles until PD or unacceptable toxicity (up to 10 cycles).	MLN1117 300 mg, tablets, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, 18; 23, 24, and 25) and 4 days off per week and paclitaxel 80 mg/m^2, infusion, intravenously, once weekly on (Days 1, 8, and 15) and 1 week off, in 28-day treatment cycles until PD or unacceptable toxicity (up to 6 cycles).	MLN1117 600 mg, tablets, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, 18; 23, 24, and 25) and 4 days off per week and paclitaxel 80 mg/m^2, infusion, intravenously, once weekly on (Days 1, 8, and 15) and 1 week off, in 28-day treatment cycles until PD or unacceptable toxicity (up to 3 cycles).	MLN1117 300 mg, tablets, orally, once daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15, 16, 17; and 22, 23, and 24) and 4 days off per week and TAK-659 100 mg (as determined in study C34001 [NCT02000934]), tablets, orally, once daily, in 28-day treatment cycles until progressive disease (PD) or unacceptable toxicity (up to 3 cycles).	MLN1117 200 mg, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, and 18) and 4 days off per week and docetaxel 75 mg/m^2, infusion, intravenously, on Day 1 once every 3 weeks in 21-day treatment cycles until PD or unacceptable toxicity (up to 1 cycle).	MLN1117 300 mg, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, and 18) and 4 days off per week and docetaxel 75 mg/m^2, infusion, intravenously, on Day 1 once every 3 weeks in 21-day treatment cycles until PD or unacceptable toxicity (up to 2 cycles).
Measure Participants	4	6	3	6	7	2	4
Day 1: Predose	NA (NA)	NA (NA)	NA (NA)	NA (NA)	0.00 (0.000)	NA (NA)	NA (NA)
Day 1: 0.5 Hour Postdose	NA (NA)	NA (NA)	NA (NA)	NA (NA)	675.04 (816.641)	NA (NA)	NA (NA)
Day 1: 1 Hour Postdose	NA (NA)	NA (NA)	NA (NA)	NA (NA)	2171.00 (1840.041)	NA (NA)	NA (NA)
Day 1: 2 Hours Postdose	NA (NA)	NA (NA)	NA (NA)	NA (NA)	3054.14 (1811.084)	NA (NA)	NA (NA)
Day 1: 3 Hours Postdose	NA (NA)	NA (NA)	NA (NA)	NA (NA)	3315.29 (1521.130)	NA (NA)	NA (NA)
Day 1: 4 Hours Postdose	NA (NA)	NA (NA)	NA (NA)	NA (NA)	3164.71 (1522.096)	NA (NA)	NA (NA)
Day 1: 6 Hours Postdose	NA (NA)	NA (NA)	NA (NA)	NA (NA)	2726.71 (1259.976)	NA (NA)	NA (NA)
Day 1: 8 Hours Postdose	NA (NA)	NA (NA)	NA (NA)	NA (NA)	2466.29 (1112.350)	NA (NA)	NA (NA)
Day 1: 24 Hours Postdose	NA (NA)	NA (NA)	NA (NA)	NA (NA)	1045.17 (642.781)	NA (NA)	NA (NA)
Day 2: Predose	NA (NA)	NA (NA)	0.00 (0.000)	0.00 (0.000)	NA (NA)	0.00 (0.000)	0.00 (0.000)
Day 2: 0.5 Hour Postdose	NA (NA)	NA (NA)	1762.00 (1295.728)	1701.17 (1407.015)	NA (NA)	3240.00 (1230.366)	1333.05 (1970.336)
Day 2: 1 Hour Postdose	NA (NA)	NA (NA)	3840.00 (747.195)	3261.83 (2879.952)	NA (NA)	3165.00 (1859.691)	1554.00 (2042.092)
Day 2: 2 Hours Postdose	NA (NA)	NA (NA)	4066.67 (322.542)	3934.00 (3419.860)	NA (NA)	4615.00 (4433.560)	1456.23 (1577.178)
Day 2: 3 Hours Postdose	NA (NA)	NA (NA)	3653.33 (325.628)	3753.50 (3324.071)	NA (NA)	4355.00 (4362.849)	1598.75 (1269.397)
Day 2: 4 Hours Postdose	NA (NA)	NA (NA)	3206.67 (256.970)	3994.67 (3191.500)	NA (NA)	3725.00 (3542.605)	1475.75 (1062.242)
Day 2: 6 Hours Postdose	NA (NA)	NA (NA)	2720.00 (10.000)	4311.67 (2752.595)	NA (NA)	3085.00 (2920.351)	1417.75 (907.208)
Day 2: 8 Hours Postdose	NA (NA)	NA (NA)	2536.67 (87.369)	3246.00 (2026.285)	NA (NA)	3025.00 (2807.214)	1443.25 (992.241)
Day 2: 24 Hours Postdose	NA (NA)	NA (NA)	592.67 (38.527)	1279.83 (1238.550)	NA (NA)	717.00 (668.923)	420.80 (477.731)
Day 3: Predose	2177.50 (1453.717)	3178.82 (2696.065)	NA (NA)	NA (NA)	NA (NA)	NA (NA)	NA (NA)
Day 3: 0.5 Hour Postdose	3225.00 (693.229)	4554.80 (3431.547)	NA (NA)	NA (NA)	NA (NA)	NA (NA)	NA (NA)
Day 3: 1 Hour Postdose	5010.00 (1376.590)	5070.60 (3278.807)	NA (NA)	NA (NA)	NA (NA)	NA (NA)	NA (NA)
Day 3: 2 Hours Postdose	5007.50 (1192.347)	6235.80 (4139.804)	NA (NA)	NA (NA)	NA (NA)	NA (NA)	NA (NA)
Day 3: 3 Hours Postdose	4815.00 (810.535)	5650.00 (3995.103)	NA (NA)	NA (NA)	NA (NA)	NA (NA)	NA (NA)
Day 3: 4 Hours Postdose	4797.50 (1240.225)	4719.20 (3100.983)	NA (NA)	NA (NA)	NA (NA)	NA (NA)	NA (NA)
Day 3: 6 Hours Postdose	4777.50 (1753.024)	4501.80 (2904.730)	NA (NA)	NA (NA)	NA (NA)	NA (NA)	NA (NA)
Day 3: 8 Hours Postdose	4320.00 (1862.078)	4354.80 (2836.444)	NA (NA)	NA (NA)	NA (NA)	NA (NA)	NA (NA)
Day 3: 24 Hours Postdose	2217.33 (1604.245)	2357.42 (1806.031)	NA (NA)	NA (NA)	NA (NA)	NA (NA)	NA (NA)
Day 17: Predose	NA (NA)	NA (NA)	NA (NA)	NA (NA)	978.33 (1519.070)	NA (NA)	NA (NA)
Day 17: 0.5 Hour Postdose	NA (NA)	NA (NA)	NA (NA)	NA (NA)	2893.67 (1738.859)	NA (NA)	NA (NA)
Day 17: 1 Hour Postdose	NA (NA)	NA (NA)	NA (NA)	NA (NA)	5596.67 (387.599)	NA (NA)	NA (NA)
Day 17: 2 Hours Postdose	NA (NA)	NA (NA)	NA (NA)	NA (NA)	5583.33 (1146.575)	NA (NA)	NA (NA)
Day 17: 3 Hours Postdose	NA (NA)	NA (NA)	NA (NA)	NA (NA)	5116.67 (1608.426)	NA (NA)	NA (NA)
Day 17: 4 Hours Postdose	NA (NA)	NA (NA)	NA (NA)	NA (NA)	5066.67 (2009.784)	NA (NA)	NA (NA)
Day 17: 6 Hours Postdose	NA (NA)	NA (NA)	NA (NA)	NA (NA)	4293.33 (1654.398)	NA (NA)	NA (NA)
Day 17: 8 Hours Postdose	NA (NA)	NA (NA)	NA (NA)	NA (NA)	4330.00 (2606.971)	NA (NA)	NA (NA)

Adverse Events

Time Frame	From first dose of study drug through 30 days after the last dose of study drug. Related SAEs could be reported at any time after discontinuation.
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Laboratory finding that are considered clinically significant, drive dose modifications or the use of concomitant medications, are considered AEs.
Arm/Group Title	MLN1117 300 mg + Alisertib		MLN1117 600 mg + Alisertib		MLN1117 300 mg + Paclitaxel		MLN1117 600 mg + Paclitaxel		MLN1117 300 mg + TAK-659		MLN1117 200 mg + Docetaxel		MLN1117 300 mg + Docetaxel
Arm/Group Description	MLN1117 300 mg, tablets, orally, once daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15, 16, 17; 22, 23, and 24) and 4 days off per week and alisertib 40 mg, tablets, orally, twice daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15,16, and 17) and 4 days off per week on Weeks 1-3, and 1 week off in 28-day treatment cycles until PD or unacceptable toxicity (up to 12 cycles).		MLN1117 600 mg, tablets, orally, once daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15, 16, 17; 22, 23, and 24) and 4 days off per week and alisertib 40 mg, tablets, orally, twice daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15,16, and 17) and 4 days off per week on Weeks 1-3, and 1 week off in 28-day treatment cycles until PD or unacceptable toxicity (up to 10 cycles).		MLN1117 300 mg, tablets, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, 18; 23, 24, and 25) and 4 days off per week and paclitaxel 80 mg/m^2, infusion, intravenously, once weekly on (Days 1, 8, and 15) and 1 week off, in 28-day treatment cycles until PD or unacceptable toxicity (up to 6 cycles).		MLN1117 600 mg, tablets, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, 18; 23, 24, and 25) and 4 days off per week and paclitaxel 80 mg/m^2, infusion, intravenously, once weekly on (Days 1, 8, and 15) and 1 week off, in 28-day treatment cycles until PD or unacceptable toxicity (up to 3 cycles).		MLN1117 300 mg, tablets, orally, once daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15, 16, 17; and 22, 23, and 24) and 4 days off per week and TAK-659 100 mg (as determined in study C34001 [NCT02000934]), tablets, orally, once daily, in 28-day treatment cycles until progressive disease (PD) or unacceptable toxicity (up to 3 cycles).		MLN1117 200 mg, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, and 18) and 4 days off per week and docetaxel 75 mg/m^2, infusion, intravenously, on Day 1 once every 3 weeks in 21-day treatment cycles until PD or unacceptable toxicity (up to 1 cycle).		MLN1117 300 mg, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, and 18) and 4 days off per week and docetaxel 75 mg/m^2, infusion, intravenously, on Day 1 once every 3 weeks in 21-day treatment cycles until PD or unacceptable toxicity (up to 2 cycles).
All Cause Mortality
	MLN1117 300 mg + Alisertib		MLN1117 600 mg + Alisertib		MLN1117 300 mg + Paclitaxel		MLN1117 600 mg + Paclitaxel		MLN1117 300 mg + TAK-659		MLN1117 200 mg + Docetaxel		MLN1117 300 mg + Docetaxel
	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%)		0/6 (0%)		1/3 (33.3%)		1/6 (16.7%)		1/7 (14.3%)		1/2 (50%)		2/4 (50%)
Serious Adverse Events
	MLN1117 300 mg + Alisertib		MLN1117 600 mg + Alisertib		MLN1117 300 mg + Paclitaxel		MLN1117 600 mg + Paclitaxel		MLN1117 300 mg + TAK-659		MLN1117 200 mg + Docetaxel		MLN1117 300 mg + Docetaxel
	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%)		3/6 (50%)		1/3 (33.3%)		2/6 (33.3%)		5/7 (71.4%)		2/2 (100%)		4/4 (100%)
Blood and lymphatic system disorders
Febrile neutropenia	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		1/2 (50%)		2/4 (50%)
Haemorrhagic anaemia	1/4 (25%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Neutropenia	0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Gastrointestinal disorders
Abdominal pain	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		1/4 (25%)
Impaired gastric emptying	0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Ascites	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Oesophagitis	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Rectal haemorrhage	0/4 (0%)		0/6 (0%)		1/3 (33.3%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Small intestinal obstruction	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		1/4 (25%)
Upper gastrointestinal haemorrhage	1/4 (25%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Vomiting	0/4 (0%)		0/6 (0%)		0/3 (0%)		1/6 (16.7%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
General disorders
Pyrexia	1/4 (25%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Hepatobiliary disorders
Cholecystitis acute	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Infections and infestations
Sepsis	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		2/4 (50%)
Gastroenteritis	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Lung infection	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Osteomyelitis	0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Pelvic infection	0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Pneumonia	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		1/2 (50%)		0/4 (0%)
Investigations
Liver function test increased	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		1/2 (50%)		0/4 (0%)
Neutrophil count decreased	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		1/2 (50%)		0/4 (0%)
Metabolism and nutrition disorders
Dehydration	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Hypokalaemia	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Musculoskeletal and connective tissue disorders
Back pain	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		1/4 (25%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Ovarian cancer metastatic	0/4 (0%)		0/6 (0%)		0/3 (0%)		1/6 (16.7%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Lymphangiosis carcinomatosa	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		1/4 (25%)
Malignant neoplasm of ampulla of Vater	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		1/4 (25%)
Neuroendocrine carcinoma metastatic	0/4 (0%)		0/6 (0%)		1/3 (33.3%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Non-small cell lung cancer metastatic	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		1/4 (25%)
Reproductive system and breast disorders
Female genital tract fistula	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Vaginal haemorrhage	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion	0/4 (0%)		0/6 (0%)		0/3 (0%)		1/6 (16.7%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Vascular disorders
Deep vein thrombosis	0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Other (Not Including Serious) Adverse Events
	MLN1117 300 mg + Alisertib		MLN1117 600 mg + Alisertib		MLN1117 300 mg + Paclitaxel		MLN1117 600 mg + Paclitaxel		MLN1117 300 mg + TAK-659		MLN1117 200 mg + Docetaxel		MLN1117 300 mg + Docetaxel
	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%)		6/6 (100%)		3/3 (100%)		6/6 (100%)		7/7 (100%)		2/2 (100%)		4/4 (100%)
Blood and lymphatic system disorders
Neutropenia	2/4 (50%)		4/6 (66.7%)		1/3 (33.3%)		2/6 (33.3%)		0/7 (0%)		1/2 (50%)		4/4 (100%)
Anaemia	1/4 (25%)		2/6 (33.3%)		0/3 (0%)		1/6 (16.7%)		1/7 (14.3%)		0/2 (0%)		2/4 (50%)
Leukopenia	1/4 (25%)		0/6 (0%)		1/3 (33.3%)		0/6 (0%)		0/7 (0%)		1/2 (50%)		0/4 (0%)
Thrombocytopenia	0/4 (0%)		2/6 (33.3%)		1/3 (33.3%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Anaemia of chronic disease	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		1/4 (25%)
Haemorrhagic anaemia	0/4 (0%)		0/6 (0%)		1/3 (33.3%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Iron deficiency anaemia	0/4 (0%)		0/6 (0%)		1/3 (33.3%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Leukocytosis	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		1/4 (25%)
Cardiac disorders
Palpitations	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		1/2 (50%)		0/4 (0%)
Ear and labyrinth disorders
Ear pain	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Motion sickness	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Vertigo	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Eye disorders
Periorbital oedema	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		3/7 (42.9%)		0/2 (0%)		0/4 (0%)
Conjunctival haemorrhage	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Dry eye	0/4 (0%)		0/6 (0%)		1/3 (33.3%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Lacrimation increased	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Photophobia	0/4 (0%)		0/6 (0%)		1/3 (33.3%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Gastrointestinal disorders
Diarrhoea	0/4 (0%)		2/6 (33.3%)		1/3 (33.3%)		3/6 (50%)		3/7 (42.9%)		1/2 (50%)		2/4 (50%)
Nausea	0/4 (0%)		2/6 (33.3%)		2/3 (66.7%)		2/6 (33.3%)		4/7 (57.1%)		1/2 (50%)		1/4 (25%)
Vomiting	2/4 (50%)		2/6 (33.3%)		1/3 (33.3%)		3/6 (50%)		4/7 (57.1%)		0/2 (0%)		0/4 (0%)
Abdominal pain	1/4 (25%)		4/6 (66.7%)		1/3 (33.3%)		2/6 (33.3%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Constipation	2/4 (50%)		0/6 (0%)		2/3 (66.7%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		1/4 (25%)
Dyspepsia	1/4 (25%)		1/6 (16.7%)		1/3 (33.3%)		2/6 (33.3%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Stomatitis	1/4 (25%)		0/6 (0%)		1/3 (33.3%)		1/6 (16.7%)		0/7 (0%)		0/2 (0%)		1/4 (25%)
Mouth ulceration	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		2/7 (28.6%)		1/2 (50%)		0/4 (0%)
Abdominal pain lower	1/4 (25%)		1/6 (16.7%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Abdominal pain upper	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		1/2 (50%)		1/4 (25%)
Abdominal distension	0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Ascites	0/4 (0%)		0/6 (0%)		0/3 (0%)		1/6 (16.7%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Cheilitis	0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Colitis	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		1/4 (25%)
Dry mouth	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		1/2 (50%)		0/4 (0%)
Dysphagia	0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Flatulence	1/4 (25%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Gastrointestinal inflammation	0/4 (0%)		0/6 (0%)		1/3 (33.3%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Gastrooesophageal reflux disease	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		1/4 (25%)
Haemorrhoids	0/4 (0%)		0/6 (0%)		1/3 (33.3%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Impaired gastric emptying	0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Oesophagitis	1/4 (25%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Salivary hypersecretion	0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
General disorders
Fatigue	3/4 (75%)		3/6 (50%)		1/3 (33.3%)		0/6 (0%)		1/7 (14.3%)		1/2 (50%)		2/4 (50%)
Chills	0/4 (0%)		2/6 (33.3%)		1/3 (33.3%)		0/6 (0%)		2/7 (28.6%)		0/2 (0%)		0/4 (0%)
Oedema peripheral	1/4 (25%)		1/6 (16.7%)		2/3 (66.7%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Pyrexia	0/4 (0%)		2/6 (33.3%)		0/3 (0%)		0/6 (0%)		2/7 (28.6%)		0/2 (0%)		0/4 (0%)
Asthenia	0/4 (0%)		1/6 (16.7%)		0/3 (0%)		1/6 (16.7%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Malaise	0/4 (0%)		0/6 (0%)		0/3 (0%)		1/6 (16.7%)		2/7 (28.6%)		0/2 (0%)		0/4 (0%)
Face oedema	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Feeling jittery	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		1/2 (50%)		0/4 (0%)
Generalised oedema	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Influenza like illness	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Non-cardiac chest pain	0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Pain	0/4 (0%)		0/6 (0%)		1/3 (33.3%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Peripheral swelling	1/4 (25%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Hepatobiliary disorders
Hyperbilirubinaemia	1/4 (25%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Infections and infestations
Oral candidiasis	0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/6 (0%)		2/7 (28.6%)		0/2 (0%)		0/4 (0%)
Urinary tract infection	0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Bacteraemia	0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Cellulitis	0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Diverticulitis	0/4 (0%)		0/6 (0%)		1/3 (33.3%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Medical device site infection	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Respiratory tract infection	0/4 (0%)		0/6 (0%)		0/3 (0%)		1/6 (16.7%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Sinusitis	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Upper respiratory tract infection	0/4 (0%)		0/6 (0%)		1/3 (33.3%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Urinary tract infection bacterial	1/4 (25%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Injury, poisoning and procedural complications
Contusion	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Fall	0/4 (0%)		0/6 (0%)		0/3 (0%)		1/6 (16.7%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Infusion related reaction	0/4 (0%)		0/6 (0%)		1/3 (33.3%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Investigations
Weight decreased	0/4 (0%)		3/6 (50%)		0/3 (0%)		1/6 (16.7%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Aspartate aminotransferase increased	1/4 (25%)		0/6 (0%)		1/3 (33.3%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Alanine aminotransferase increased	0/4 (0%)		0/6 (0%)		1/3 (33.3%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Amylase increased	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		2/7 (28.6%)		0/2 (0%)		0/4 (0%)
Blood creatinine increased	0/4 (0%)		0/6 (0%)		1/3 (33.3%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Lipase increased	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		2/7 (28.6%)		0/2 (0%)		0/4 (0%)
Blood alkaline phosphatase increased	1/4 (25%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Blood bilirubin increased	0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Blood magnesium decreased	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		1/2 (50%)		0/4 (0%)
Blood potassium decreased	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		1/2 (50%)		0/4 (0%)
International normalised ratio increased	0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Transaminases increased	0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
White blood cell count decreased	0/4 (0%)		0/6 (0%)		0/3 (0%)		1/6 (16.7%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Metabolism and nutrition disorders
Dehydration	1/4 (25%)		0/6 (0%)		1/3 (33.3%)		2/6 (33.3%)		4/7 (57.1%)		0/2 (0%)		2/4 (50%)
Decreased appetite	0/4 (0%)		4/6 (66.7%)		0/3 (0%)		1/6 (16.7%)		2/7 (28.6%)		1/2 (50%)		1/4 (25%)
Hypokalaemia	0/4 (0%)		2/6 (33.3%)		1/3 (33.3%)		1/6 (16.7%)		2/7 (28.6%)		0/2 (0%)		2/4 (50%)
Hyperglycaemia	0/4 (0%)		1/6 (16.7%)		0/3 (0%)		1/6 (16.7%)		1/7 (14.3%)		0/2 (0%)		1/4 (25%)
Hypomagnesaemia	0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		2/4 (50%)
Hypophosphataemia	0/4 (0%)		0/6 (0%)		1/3 (33.3%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		2/4 (50%)
Hypocalcaemia	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		2/4 (50%)
Hyponatraemia	0/4 (0%)		0/6 (0%)		0/3 (0%)		1/6 (16.7%)		0/7 (0%)		0/2 (0%)		1/4 (25%)
Hypernatraemia	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		1/4 (25%)
Metabolic alkalosis	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Musculoskeletal and connective tissue disorders
Myalgia	0/4 (0%)		1/6 (16.7%)		1/3 (33.3%)		0/6 (0%)		1/7 (14.3%)		2/2 (100%)		0/4 (0%)
Back pain	0/4 (0%)		3/6 (50%)		1/3 (33.3%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Arthralgia	0/4 (0%)		0/6 (0%)		1/3 (33.3%)		0/6 (0%)		0/7 (0%)		1/2 (50%)		0/4 (0%)
Pain in extremity	0/4 (0%)		0/6 (0%)		1/3 (33.3%)		0/6 (0%)		0/7 (0%)		1/2 (50%)		0/4 (0%)
Bone pain	1/4 (25%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Muscular weakness	0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Musculoskeletal pain	1/4 (25%)		0/6 (0%)		1/3 (33.3%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		1/4 (25%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma of skin	0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Tumour pain	0/4 (0%)		0/6 (0%)		0/3 (0%)		1/6 (16.7%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Nervous system disorders
Dizziness	0/4 (0%)		2/6 (33.3%)		1/3 (33.3%)		0/6 (0%)		2/7 (28.6%)		0/2 (0%)		0/4 (0%)
Headache	0/4 (0%)		0/6 (0%)		1/3 (33.3%)		1/6 (16.7%)		2/7 (28.6%)		1/2 (50%)		0/4 (0%)
Neuropathy peripheral	0/4 (0%)		1/6 (16.7%)		1/3 (33.3%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		1/4 (25%)
Peripheral sensory neuropathy	0/4 (0%)		2/6 (33.3%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		1/4 (25%)
Syncope	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		1/7 (14.3%)		1/2 (50%)		0/4 (0%)
Balance disorder	0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Dysgeusia	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Mental impairment	0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Paraesthesia	0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Partial seizures	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Peripheral motor neuropathy	0/4 (0%)		0/6 (0%)		1/3 (33.3%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Restless legs syndrome	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Product Issues
Device occlusion	0/4 (0%)		0/6 (0%)		0/3 (0%)		1/6 (16.7%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Thrombosis in device	0/4 (0%)		0/6 (0%)		1/3 (33.3%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Psychiatric disorders
Insomnia	0/4 (0%)		2/6 (33.3%)		0/3 (0%)		0/6 (0%)		3/7 (42.9%)		0/2 (0%)		1/4 (25%)
Confusional state	0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Affect lability	0/4 (0%)		0/6 (0%)		0/3 (0%)		1/6 (16.7%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Agitation	0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Anxiety	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Depression	0/4 (0%)		0/6 (0%)		0/3 (0%)		1/6 (16.7%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Irritability	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Renal and urinary disorders
Acute kidney injury	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		1/7 (14.3%)		1/2 (50%)		1/4 (25%)
Dysuria	0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Haematuria	0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Micturition urgency	0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Pollakiuria	0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Urinary retention	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Reproductive system and breast disorders
Vaginal haemorrhage	0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	1/4 (25%)		0/6 (0%)		1/3 (33.3%)		0/6 (0%)		2/7 (28.6%)		0/2 (0%)		0/4 (0%)
Dyspnoea	0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		1/2 (50%)		2/4 (50%)
Pleural effusion	0/4 (0%)		1/6 (16.7%)		1/3 (33.3%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Pulmonary embolism	0/4 (0%)		1/6 (16.7%)		1/3 (33.3%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Dyspnoea exertional	0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Haemothorax	0/4 (0%)		0/6 (0%)		0/3 (0%)		1/6 (16.7%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Hiccups	0/4 (0%)		0/6 (0%)		1/3 (33.3%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Hypoxia	0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Nasal congestion	0/4 (0%)		0/6 (0%)		1/3 (33.3%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Oropharyngeal pain	0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Pneumonitis	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Productive cough	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		1/4 (25%)
Rhinorrhoea	0/4 (0%)		0/6 (0%)		1/3 (33.3%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Sinus congestion	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Sputum discoloured	0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Wheezing	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Skin and subcutaneous tissue disorders
Night sweats	0/4 (0%)		1/6 (16.7%)		2/3 (66.7%)		1/6 (16.7%)		2/7 (28.6%)		0/2 (0%)		0/4 (0%)
Alopecia	1/4 (25%)		1/6 (16.7%)		0/3 (0%)		2/6 (33.3%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Dry skin	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		2/7 (28.6%)		0/2 (0%)		0/4 (0%)
Rash	0/4 (0%)		0/6 (0%)		1/3 (33.3%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Rash pruritic	0/4 (0%)		0/6 (0%)		1/3 (33.3%)		1/6 (16.7%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Decubitus ulcer	0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Dermal cyst	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Onychomalacia	1/4 (25%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Pruritus	0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Rash maculo-papular	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Scab	1/4 (25%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Skin ulcer	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		1/4 (25%)
Vascular disorders
Deep vein thrombosis	0/4 (0%)		1/6 (16.7%)		1/3 (33.3%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)
Flushing	0/4 (0%)		0/6 (0%)		0/3 (0%)		1/6 (16.7%)		1/7 (14.3%)		1/2 (50%)		0/4 (0%)
Hot flush	0/4 (0%)		0/6 (0%)		1/3 (33.3%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		0/4 (0%)
Hypotension	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		0/7 (0%)		0/2 (0%)		1/4 (25%)
Orthostatic hypotension	0/4 (0%)		0/6 (0%)		0/3 (0%)		0/6 (0%)		1/7 (14.3%)		0/2 (0%)		0/4 (0%)

Limitations/Caveats

Due to the early termination of the study, the pharmacokinetic data collected was not processed further. Therefore, the planned secondary endpoints of PK summary statistics are not reported.

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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.