Advanced and Metastatic Gastric or Gastroesophageal Adenocarcinoma
Conditions
Keywords
Drug Therapy
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).
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.
Interventions
Sponsors
Millennium Pharmaceuticals, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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. 4. 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.) 5. 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. 6. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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). |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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 | — |
| 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. |
| 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). |
| 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. |
| 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. |
| 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. |
Countries
Spain, United States
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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 (up to 12 cycles). | 4 |
| 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 (up to 10 cycles). | 6 |
| 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 (up to 6 cycles). | 3 |
| 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 (up to 3 cycles). | 6 |
| 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 (up to 3 cycles). | 7 |
| 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 (up to 1 cycle). | 2 |
| 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 (up to 2 cycles). | 4 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Death | 2 | 4 | 2 | 2 | 2 | 1 | 2 | 0 |
| Overall Study | Reason not specified | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 |
| Overall Study | Study Terminated by Sponsor | 1 | 1 | 0 | 2 | 2 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 0 | 1 | 2 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | 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 |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 62.0 years STANDARD_DEVIATION 8.61 | 61.5 years STANDARD_DEVIATION 7.94 | 59.0 years STANDARD_DEVIATION 4.86 | 65.3 years STANDARD_DEVIATION 13.28 | 62.2 years STANDARD_DEVIATION 11.82 | 62.3 years STANDARD_DEVIATION 9.16 | 65.5 years STANDARD_DEVIATION 4.95 | 62.3 years STANDARD_DEVIATION 9.95 |
| Body Surface Area | 1.796 m^2 STANDARD_DEVIATION 0.2796 | 1.825 m^2 STANDARD_DEVIATION 0.2814 | 1.802 m^2 STANDARD_DEVIATION 0.2863 | 1.809 m^2 STANDARD_DEVIATION 0.1638 | 1.917 m^2 STANDARD_DEVIATION 0.3496 | 1.694 m^2 STANDARD_DEVIATION 0.179 | 1.768 m^2 STANDARD_DEVIATION 0.5769 | 1.767 m^2 STANDARD_DEVIATION 0.3734 |
| Height | 162.07 cm STANDARD_DEVIATION 10.939 | 162.90 cm STANDARD_DEVIATION 14.178 | 165.50 cm STANDARD_DEVIATION 10.145 | 159.80 cm STANDARD_DEVIATION 4.513 | 162.83 cm STANDARD_DEVIATION 15.108 | 158.76 cm STANDARD_DEVIATION 6.662 | 154.95 cm STANDARD_DEVIATION 7.142 | 166.25 cm STANDARD_DEVIATION 16.674 |
| Race/Ethnicity, Customized Asian | 1 participants | 0 participants | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Black or African American | 4 participants | 0 participants | 1 participants | 1 participants | 0 participants | 1 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 3 participants | 0 participants | 0 participants | 0 participants | 1 participants | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 29 participants | 4 participants | 6 participants | 3 participants | 5 participants | 6 participants | 2 participants | 3 participants |
| Race/Ethnicity, Customized Not Reported | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized White | 27 participants | 4 participants | 4 participants | 2 participants | 6 participants | 6 participants | 1 participants | 4 participants |
| Region of Enrollment Spain | 5 participants | 0 participants | 1 participants | 0 participants | 3 participants | 1 participants | 0 participants | 0 participants |
| Region of Enrollment United States | 27 participants | 4 participants | 5 participants | 3 participants | 3 participants | 6 participants | 2 participants | 4 participants |
| Sex: Female, Male Female | 25 Participants | 3 Participants | 3 Participants | 3 Participants | 5 Participants | 7 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Male | 7 Participants | 1 Participants | 3 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Weight | 73.13 kg STANDARD_DEVIATION 19.4 | 77.75 kg STANDARD_DEVIATION 15.314 | 71.63 kg STANDARD_DEVIATION 19.725 | 74.07 kg STANDARD_DEVIATION 12.756 | 82.38 kg STANDARD_DEVIATION 25.474 | 65.53 kg STANDARD_DEVIATION 13.046 | 75.45 kg STANDARD_DEVIATION 43.911 | 68.28 kg STANDARD_DEVIATION 21.403 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 6 | 1 / 3 | 1 / 6 | 1 / 7 | 1 / 2 | 2 / 4 |
| other Total, other adverse events | 4 / 4 | 6 / 6 | 3 / 3 | 6 / 6 | 7 / 7 | 2 / 2 | 4 / 4 |
| serious Total, serious adverse events | 2 / 4 | 3 / 6 | 1 / 3 | 2 / 6 | 5 / 7 | 2 / 2 | 4 / 4 |
Outcome results
Primary
Number of Participants Who Experienced Cycle 1 Dose Limiting Toxicity (DLT) in Part 1
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)
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| MLN1117 300 mg + Alisertib | Number of Participants Who Experienced Cycle 1 Dose Limiting Toxicity (DLT) in Part 1 | 0 participants |
| MLN1117 600 mg + Alisertib | Number of Participants Who Experienced Cycle 1 Dose Limiting Toxicity (DLT) in Part 1 | 1 participants |
| MLN1117 300 mg + Paclitaxel | Number of Participants Who Experienced Cycle 1 Dose Limiting Toxicity (DLT) in Part 1 | 0 participants |
| MLN1117 600 mg + Paclitaxel | Number of Participants Who Experienced Cycle 1 Dose Limiting Toxicity (DLT) in Part 1 | 0 participants |
| MLN1117 300 mg + TAK-659 | Number of Participants Who Experienced Cycle 1 Dose Limiting Toxicity (DLT) in Part 1 | 1 participants |
| MLN1117 200 mg + Docetaxel | Number of Participants Who Experienced Cycle 1 Dose Limiting Toxicity (DLT) in Part 1 | 0 participants |
| MLN1117 300 mg + Docetaxel | Number of Participants Who Experienced Cycle 1 Dose Limiting Toxicity (DLT) in Part 1 | 1 participants |
Primary
Number of Participants With at Least 1 Dose Modification Due to AE in Part 1
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)
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| MLN1117 300 mg + Alisertib | Number of Participants With at Least 1 Dose Modification Due to AE in Part 1 | 0 participants |
| MLN1117 600 mg + Alisertib | Number of Participants With at Least 1 Dose Modification Due to AE in Part 1 | 1 participants |
| MLN1117 300 mg + Paclitaxel | Number of Participants With at Least 1 Dose Modification Due to AE in Part 1 | 1 participants |
| MLN1117 600 mg + Paclitaxel | Number of Participants With at Least 1 Dose Modification Due to AE in Part 1 | 0 participants |
| MLN1117 300 mg + TAK-659 | Number of Participants With at Least 1 Dose Modification Due to AE in Part 1 | 4 participants |
| MLN1117 200 mg + Docetaxel | Number of Participants With at Least 1 Dose Modification Due to AE in Part 1 | 0 participants |
| MLN1117 300 mg + Docetaxel | Number of Participants With at Least 1 Dose Modification Due to AE in Part 1 | 1 participants |
Primary
Number of Participants With at Least 1 ≥ Grade 3 TEAE in Part 1
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)
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| MLN1117 300 mg + Alisertib | Number of Participants With at Least 1 ≥ Grade 3 TEAE in Part 1 | 4 participants |
| MLN1117 600 mg + Alisertib | Number of Participants With at Least 1 ≥ Grade 3 TEAE in Part 1 | 4 participants |
| MLN1117 300 mg + Paclitaxel | Number of Participants With at Least 1 ≥ Grade 3 TEAE in Part 1 | 2 participants |
| MLN1117 600 mg + Paclitaxel | Number of Participants With at Least 1 ≥ Grade 3 TEAE in Part 1 | 2 participants |
| MLN1117 300 mg + TAK-659 | Number of Participants With at Least 1 ≥ Grade 3 TEAE in Part 1 | 6 participants |
| MLN1117 200 mg + Docetaxel | Number of Participants With at Least 1 ≥ Grade 3 TEAE in Part 1 | 2 participants |
| MLN1117 300 mg + Docetaxel | Number of Participants With at Least 1 ≥ Grade 3 TEAE in Part 1 | 4 participants |
Primary
Number of Participants With at Least 1 Treatment-Emergent Adverse Event (TEAE) in Part 1
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)
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| MLN1117 300 mg + Alisertib | Number of Participants With at Least 1 Treatment-Emergent Adverse Event (TEAE) in Part 1 | 4 participants |
| MLN1117 600 mg + Alisertib | Number of Participants With at Least 1 Treatment-Emergent Adverse Event (TEAE) in Part 1 | 6 participants |
| MLN1117 300 mg + Paclitaxel | Number of Participants With at Least 1 Treatment-Emergent Adverse Event (TEAE) in Part 1 | 3 participants |
| MLN1117 600 mg + Paclitaxel | Number of Participants With at Least 1 Treatment-Emergent Adverse Event (TEAE) in Part 1 | 6 participants |
| MLN1117 300 mg + TAK-659 | Number of Participants With at Least 1 Treatment-Emergent Adverse Event (TEAE) in Part 1 | 7 participants |
| MLN1117 200 mg + Docetaxel | Number of Participants With at Least 1 Treatment-Emergent Adverse Event (TEAE) in Part 1 | 2 participants |
| MLN1117 300 mg + Docetaxel | Number of Participants With at Least 1 Treatment-Emergent Adverse Event (TEAE) in Part 1 | 4 participants |
Primary
Number of Participants With at Least 1 Treatment-Emergent Serious Adverse Event (SAE) in Part 1
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)
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| MLN1117 300 mg + Alisertib | Number of Participants With at Least 1 Treatment-Emergent Serious Adverse Event (SAE) in Part 1 | 2 participants |
| MLN1117 600 mg + Alisertib | Number of Participants With at Least 1 Treatment-Emergent Serious Adverse Event (SAE) in Part 1 | 3 participants |
| MLN1117 300 mg + Paclitaxel | Number of Participants With at Least 1 Treatment-Emergent Serious Adverse Event (SAE) in Part 1 | 1 participants |
| MLN1117 600 mg + Paclitaxel | Number of Participants With at Least 1 Treatment-Emergent Serious Adverse Event (SAE) in Part 1 | 2 participants |
| MLN1117 300 mg + TAK-659 | Number of Participants With at Least 1 Treatment-Emergent Serious Adverse Event (SAE) in Part 1 | 5 participants |
| MLN1117 200 mg + Docetaxel | Number of Participants With at Least 1 Treatment-Emergent Serious Adverse Event (SAE) in Part 1 | 2 participants |
| MLN1117 300 mg + Docetaxel | Number of Participants With at Least 1 Treatment-Emergent Serious Adverse Event (SAE) in Part 1 | 4 participants |
Primary
Overall Response Rate in Part 2
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)
Population: Study was terminated before the initiation of Part 2 of the study.
Secondary
Duration of Response (DOR) Based on RECIST Criteria V 1.1 Assessment in Part 2
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)
Population: Study was terminated before the initiation of Part 2 of the study.
Secondary
Number of Participants With at Least 1 TEAE and Serious TEAE in Part 1 and 2
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)
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MLN1117 300 mg + Alisertib | Number of Participants With at Least 1 TEAE and Serious TEAE in Part 1 and 2 | AE | 4 participants |
| MLN1117 300 mg + Alisertib | Number of Participants With at Least 1 TEAE and Serious TEAE in Part 1 and 2 | SAE | 2 participants |
| MLN1117 600 mg + Alisertib | Number of Participants With at Least 1 TEAE and Serious TEAE in Part 1 and 2 | AE | 6 participants |
| MLN1117 600 mg + Alisertib | Number of Participants With at Least 1 TEAE and Serious TEAE in Part 1 and 2 | SAE | 3 participants |
| MLN1117 300 mg + Paclitaxel | Number of Participants With at Least 1 TEAE and Serious TEAE in Part 1 and 2 | AE | 3 participants |
| MLN1117 300 mg + Paclitaxel | Number of Participants With at Least 1 TEAE and Serious TEAE in Part 1 and 2 | SAE | 1 participants |
| MLN1117 600 mg + Paclitaxel | Number of Participants With at Least 1 TEAE and Serious TEAE in Part 1 and 2 | AE | 6 participants |
| MLN1117 600 mg + Paclitaxel | Number of Participants With at Least 1 TEAE and Serious TEAE in Part 1 and 2 | SAE | 2 participants |
| MLN1117 300 mg + TAK-659 | Number of Participants With at Least 1 TEAE and Serious TEAE in Part 1 and 2 | AE | 7 participants |
| MLN1117 300 mg + TAK-659 | Number of Participants With at Least 1 TEAE and Serious TEAE in Part 1 and 2 | SAE | 5 participants |
| MLN1117 200 mg + Docetaxel | Number of Participants With at Least 1 TEAE and Serious TEAE in Part 1 and 2 | AE | 2 participants |
| MLN1117 200 mg + Docetaxel | Number of Participants With at Least 1 TEAE and Serious TEAE in Part 1 and 2 | SAE | 2 participants |
| MLN1117 300 mg + Docetaxel | Number of Participants With at Least 1 TEAE and Serious TEAE in Part 1 and 2 | AE | 4 participants |
| MLN1117 300 mg + Docetaxel | Number of Participants With at Least 1 TEAE and Serious TEAE in Part 1 and 2 | SAE | 4 participants |
Secondary
Number of Participants With Dose Delays, Dose Reductions, and Dose Interruptions Due To AE in Part 1 and 2
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)
Population: 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 | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MLN1117 300 mg + Alisertib | Number of Participants With Dose Delays, Dose Reductions, and Dose Interruptions Due To AE in Part 1 and 2 | Dose interruption due to AE | 0 Participants |
| MLN1117 300 mg + Alisertib | Number of Participants With Dose Delays, Dose Reductions, and Dose Interruptions Due To AE in Part 1 and 2 | Dose reduction due to AE | 0 Participants |
| MLN1117 300 mg + Alisertib | Number of Participants With Dose Delays, Dose Reductions, and Dose Interruptions Due To AE in Part 1 and 2 | Dose delay due to AE | 0 Participants |
| MLN1117 600 mg + Alisertib | Number of Participants With Dose Delays, Dose Reductions, and Dose Interruptions Due To AE in Part 1 and 2 | Dose reduction due to AE | 1 Participants |
| MLN1117 600 mg + Alisertib | Number of Participants With Dose Delays, Dose Reductions, and Dose Interruptions Due To AE in Part 1 and 2 | Dose delay due to AE | 0 Participants |
| MLN1117 600 mg + Alisertib | Number of Participants With Dose Delays, Dose Reductions, and Dose Interruptions Due To AE in Part 1 and 2 | Dose interruption due to AE | 0 Participants |
| MLN1117 300 mg + Paclitaxel | Number of Participants With Dose Delays, Dose Reductions, and Dose Interruptions Due To AE in Part 1 and 2 | Dose interruption due to AE | 1 Participants |
| MLN1117 300 mg + Paclitaxel | Number of Participants With Dose Delays, Dose Reductions, and Dose Interruptions Due To AE in Part 1 and 2 | Dose delay due to AE | 0 Participants |
| MLN1117 300 mg + Paclitaxel | Number of Participants With Dose Delays, Dose Reductions, and Dose Interruptions Due To AE in Part 1 and 2 | Dose reduction due to AE | 1 Participants |
| MLN1117 600 mg + Paclitaxel | Number of Participants With Dose Delays, Dose Reductions, and Dose Interruptions Due To AE in Part 1 and 2 | Dose reduction due to AE | 0 Participants |
| MLN1117 600 mg + Paclitaxel | Number of Participants With Dose Delays, Dose Reductions, and Dose Interruptions Due To AE in Part 1 and 2 | Dose delay due to AE | 0 Participants |
| MLN1117 600 mg + Paclitaxel | Number of Participants With Dose Delays, Dose Reductions, and Dose Interruptions Due To AE in Part 1 and 2 | Dose interruption due to AE | 0 Participants |
| MLN1117 300 mg + TAK-659 | Number of Participants With Dose Delays, Dose Reductions, and Dose Interruptions Due To AE in Part 1 and 2 | Dose reduction due to AE | 4 Participants |
| MLN1117 300 mg + TAK-659 | Number of Participants With Dose Delays, Dose Reductions, and Dose Interruptions Due To AE in Part 1 and 2 | Dose delay due to AE | 1 Participants |
| MLN1117 300 mg + TAK-659 | Number of Participants With Dose Delays, Dose Reductions, and Dose Interruptions Due To AE in Part 1 and 2 | Dose interruption due to AE | 0 Participants |
| MLN1117 200 mg + Docetaxel | Number of Participants With Dose Delays, Dose Reductions, and Dose Interruptions Due To AE in Part 1 and 2 | Dose delay due to AE | 0 Participants |
| MLN1117 200 mg + Docetaxel | Number of Participants With Dose Delays, Dose Reductions, and Dose Interruptions Due To AE in Part 1 and 2 | Dose interruption due to AE | 0 Participants |
| MLN1117 200 mg + Docetaxel | Number of Participants With Dose Delays, Dose Reductions, and Dose Interruptions Due To AE in Part 1 and 2 | Dose reduction due to AE | 0 Participants |
| MLN1117 300 mg + Docetaxel | Number of Participants With Dose Delays, Dose Reductions, and Dose Interruptions Due To AE in Part 1 and 2 | Dose interruption due to AE | 0 Participants |
| MLN1117 300 mg + Docetaxel | Number of Participants With Dose Delays, Dose Reductions, and Dose Interruptions Due To AE in Part 1 and 2 | Dose reduction due to AE | 1 Participants |
| MLN1117 300 mg + Docetaxel | Number of Participants With Dose Delays, Dose Reductions, and Dose Interruptions Due To AE in Part 1 and 2 | Dose delay due to AE | 0 Participants |
Secondary
Overall Survival (OS) Based on RECIST Criteria V 1.1 Assessment
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)
Population: Study was terminated before the initiation of Part 2 of the study.
Secondary
Percentage of Participants With Disease Control Based on RECIST Criteria V 1.1 Assessment in Part 2
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)
Population: Study was terminated before the initiation of Part 2 of the study.
Secondary
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MLN1117 300 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 2: 6 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 3: 0.5 Hour Postdose | 3225.00 ng/mL | Standard Deviation 693.229 |
| MLN1117 300 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 2: 8 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 3: Predose | 2177.50 ng/mL | Standard Deviation 1453.717 |
| MLN1117 300 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 2: 24 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 1: Predose | NA ng/mL | — |
| MLN1117 300 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 17: 4 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 1: 2 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 17: 3 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 1: 3 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 17: 2 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 1: 4 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 17: 8 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 17: 1 Hour Postdose | NA ng/mL | — |
| MLN1117 300 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 1: 6 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 1: 0.5 Hour Postdose | NA ng/mL | — |
| MLN1117 300 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 17: 0.5 Hour Postdose | NA ng/mL | — |
| MLN1117 300 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 1: 8 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 17: Predose | NA ng/mL | — |
| MLN1117 300 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 1: 24 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 3: 24 Hours Postdose | 2217.33 ng/mL | Standard Deviation 1604.245 |
| MLN1117 300 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 2: Predose | NA ng/mL | — |
| MLN1117 300 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 3: 8 Hours Postdose | 4320.00 ng/mL | Standard Deviation 1862.078 |
| MLN1117 300 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 2: 0.5 Hour Postdose | NA ng/mL | — |
| MLN1117 300 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 3: 6 Hours Postdose | 4777.50 ng/mL | Standard Deviation 1753.024 |
| MLN1117 300 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 2: 1 Hour Postdose | NA ng/mL | — |
| MLN1117 300 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 3: 4 Hours Postdose | 4797.50 ng/mL | Standard Deviation 1240.225 |
| MLN1117 300 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 2: 2 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 17: 6 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 3: 3 Hours Postdose | 4815.00 ng/mL | Standard Deviation 810.535 |
| MLN1117 300 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 2: 3 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 1: 1 Hour Postdose | NA ng/mL | — |
| MLN1117 300 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 3: 2 Hours Postdose | 5007.50 ng/mL | Standard Deviation 1192.347 |
| MLN1117 300 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 2: 4 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 3: 1 Hour Postdose | 5010.00 ng/mL | Standard Deviation 1376.59 |
| MLN1117 600 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 17: 6 Hours Postdose | NA ng/mL | — |
| MLN1117 600 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 1: 4 Hours Postdose | NA ng/mL | — |
| MLN1117 600 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 3: 4 Hours Postdose | 4719.20 ng/mL | Standard Deviation 3100.983 |
| MLN1117 600 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 17: 1 Hour Postdose | NA ng/mL | — |
| MLN1117 600 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 3: 2 Hours Postdose | 6235.80 ng/mL | Standard Deviation 4139.804 |
| MLN1117 600 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 1: 6 Hours Postdose | NA ng/mL | — |
| MLN1117 600 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 2: 2 Hours Postdose | NA ng/mL | — |
| MLN1117 600 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 17: 0.5 Hour Postdose | NA ng/mL | — |
| MLN1117 600 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 3: 1 Hour Postdose | 5070.60 ng/mL | Standard Deviation 3278.807 |
| MLN1117 600 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 1: 8 Hours Postdose | NA ng/mL | — |
| MLN1117 600 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 1: 0.5 Hour Postdose | NA ng/mL | — |
| MLN1117 600 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 17: Predose | NA ng/mL | — |
| MLN1117 600 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 3: 3 Hours Postdose | 5650.00 ng/mL | Standard Deviation 3995.103 |
| MLN1117 600 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 1: 24 Hours Postdose | NA ng/mL | — |
| MLN1117 600 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 3: 24 Hours Postdose | 2357.42 ng/mL | Standard Deviation 1806.031 |
| MLN1117 600 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 2: 4 Hours Postdose | NA ng/mL | — |
| MLN1117 600 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 2: Predose | NA ng/mL | — |
| MLN1117 600 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 3: 8 Hours Postdose | 4354.80 ng/mL | Standard Deviation 2836.444 |
| MLN1117 600 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 2: 3 Hours Postdose | NA ng/mL | — |
| MLN1117 600 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 2: 6 Hours Postdose | NA ng/mL | — |
| MLN1117 600 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 3: 0.5 Hour Postdose | 4554.80 ng/mL | Standard Deviation 3431.547 |
| MLN1117 600 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 2: 0.5 Hour Postdose | NA ng/mL | — |
| MLN1117 600 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 2: 8 Hours Postdose | NA ng/mL | — |
| MLN1117 600 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 1: Predose | NA ng/mL | — |
| MLN1117 600 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 3: Predose | 3178.82 ng/mL | Standard Deviation 2696.065 |
| MLN1117 600 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 2: 24 Hours Postdose | NA ng/mL | — |
| MLN1117 600 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 3: 6 Hours Postdose | 4501.80 ng/mL | Standard Deviation 2904.73 |
| MLN1117 600 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 17: 4 Hours Postdose | NA ng/mL | — |
| MLN1117 600 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 1: 1 Hour Postdose | NA ng/mL | — |
| MLN1117 600 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 1: 2 Hours Postdose | NA ng/mL | — |
| MLN1117 600 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 17: 3 Hours Postdose | NA ng/mL | — |
| MLN1117 600 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 2: 1 Hour Postdose | NA ng/mL | — |
| MLN1117 600 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 1: 3 Hours Postdose | NA ng/mL | — |
| MLN1117 600 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 17: 8 Hours Postdose | NA ng/mL | — |
| MLN1117 600 mg + Alisertib | Plasma Concentration of MLN1117-1003 | Day 17: 2 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 2: 3 Hours Postdose | 3653.33 ng/mL | Standard Deviation 325.628 |
| MLN1117 300 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 3: 4 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 1: 4 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 2: 6 Hours Postdose | 2720.00 ng/mL | Standard Deviation 10 |
| MLN1117 300 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 17: 1 Hour Postdose | NA ng/mL | — |
| MLN1117 300 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 1: 1 Hour Postdose | NA ng/mL | — |
| MLN1117 300 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 3: 0.5 Hour Postdose | NA ng/mL | — |
| MLN1117 300 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 3: 1 Hour Postdose | NA ng/mL | — |
| MLN1117 300 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 2: 1 Hour Postdose | 3840.00 ng/mL | Standard Deviation 747.195 |
| MLN1117 300 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 1: 6 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 3: 2 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 17: 0.5 Hour Postdose | NA ng/mL | — |
| MLN1117 300 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 2: 0.5 Hour Postdose | 1762.00 ng/mL | Standard Deviation 1295.728 |
| MLN1117 300 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 2: 2 Hours Postdose | 4066.67 ng/mL | Standard Deviation 322.542 |
| MLN1117 300 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 17: 2 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 2: 8 Hours Postdose | 2536.67 ng/mL | Standard Deviation 87.369 |
| MLN1117 300 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 1: 8 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 1: 2 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 17: Predose | NA ng/mL | — |
| MLN1117 300 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 3: Predose | NA ng/mL | — |
| MLN1117 300 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 3: 3 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 17: 8 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 17: 6 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 1: 24 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 1: 0.5 Hour Postdose | NA ng/mL | — |
| MLN1117 300 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 3: 24 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 3: 6 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 17: 3 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 2: 4 Hours Postdose | 3206.67 ng/mL | Standard Deviation 256.97 |
| MLN1117 300 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 2: 24 Hours Postdose | 592.67 ng/mL | Standard Deviation 38.527 |
| MLN1117 300 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 2: Predose | 0.00 ng/mL | Standard Deviation 0 |
| MLN1117 300 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 1: Predose | NA ng/mL | — |
| MLN1117 300 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 3: 8 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 1: 3 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 17: 4 Hours Postdose | NA ng/mL | — |
| MLN1117 600 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 2: 24 Hours Postdose | 1279.83 ng/mL | Standard Deviation 1238.55 |
| MLN1117 600 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 1: Predose | NA ng/mL | — |
| MLN1117 600 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 1: 0.5 Hour Postdose | NA ng/mL | — |
| MLN1117 600 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 1: 1 Hour Postdose | NA ng/mL | — |
| MLN1117 600 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 1: 2 Hours Postdose | NA ng/mL | — |
| MLN1117 600 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 1: 3 Hours Postdose | NA ng/mL | — |
| MLN1117 600 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 1: 4 Hours Postdose | NA ng/mL | — |
| MLN1117 600 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 1: 6 Hours Postdose | NA ng/mL | — |
| MLN1117 600 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 1: 8 Hours Postdose | NA ng/mL | — |
| MLN1117 600 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 1: 24 Hours Postdose | NA ng/mL | — |
| MLN1117 600 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 2: Predose | 0.00 ng/mL | Standard Deviation 0 |
| MLN1117 600 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 2: 0.5 Hour Postdose | 1701.17 ng/mL | Standard Deviation 1407.015 |
| MLN1117 600 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 2: 1 Hour Postdose | 3261.83 ng/mL | Standard Deviation 2879.952 |
| MLN1117 600 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 2: 2 Hours Postdose | 3934.00 ng/mL | Standard Deviation 3419.86 |
| MLN1117 600 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 2: 3 Hours Postdose | 3753.50 ng/mL | Standard Deviation 3324.071 |
| MLN1117 600 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 2: 4 Hours Postdose | 3994.67 ng/mL | Standard Deviation 3191.5 |
| MLN1117 600 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 2: 6 Hours Postdose | 4311.67 ng/mL | Standard Deviation 2752.595 |
| MLN1117 600 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 2: 8 Hours Postdose | 3246.00 ng/mL | Standard Deviation 2026.285 |
| MLN1117 600 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 3: Predose | NA ng/mL | — |
| MLN1117 600 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 3: 0.5 Hour Postdose | NA ng/mL | — |
| MLN1117 600 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 3: 1 Hour Postdose | NA ng/mL | — |
| MLN1117 600 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 3: 2 Hours Postdose | NA ng/mL | — |
| MLN1117 600 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 3: 3 Hours Postdose | NA ng/mL | — |
| MLN1117 600 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 3: 4 Hours Postdose | NA ng/mL | — |
| MLN1117 600 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 3: 6 Hours Postdose | NA ng/mL | — |
| MLN1117 600 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 3: 8 Hours Postdose | NA ng/mL | — |
| MLN1117 600 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 3: 24 Hours Postdose | NA ng/mL | — |
| MLN1117 600 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 17: Predose | NA ng/mL | — |
| MLN1117 600 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 17: 0.5 Hour Postdose | NA ng/mL | — |
| MLN1117 600 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 17: 1 Hour Postdose | NA ng/mL | — |
| MLN1117 600 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 17: 2 Hours Postdose | NA ng/mL | — |
| MLN1117 600 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 17: 3 Hours Postdose | NA ng/mL | — |
| MLN1117 600 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 17: 4 Hours Postdose | NA ng/mL | — |
| MLN1117 600 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 17: 6 Hours Postdose | NA ng/mL | — |
| MLN1117 600 mg + Paclitaxel | Plasma Concentration of MLN1117-1003 | Day 17: 8 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + TAK-659 | Plasma Concentration of MLN1117-1003 | Day 1: 0.5 Hour Postdose | 675.04 ng/mL | Standard Deviation 816.641 |
| MLN1117 300 mg + TAK-659 | Plasma Concentration of MLN1117-1003 | Day 1: 3 Hours Postdose | 3315.29 ng/mL | Standard Deviation 1521.13 |
| MLN1117 300 mg + TAK-659 | Plasma Concentration of MLN1117-1003 | Day 1: Predose | 0.00 ng/mL | Standard Deviation 0 |
| MLN1117 300 mg + TAK-659 | Plasma Concentration of MLN1117-1003 | Day 17: 2 Hours Postdose | 5583.33 ng/mL | Standard Deviation 1146.575 |
| MLN1117 300 mg + TAK-659 | Plasma Concentration of MLN1117-1003 | Day 3: 4 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + TAK-659 | Plasma Concentration of MLN1117-1003 | Day 1: 2 Hours Postdose | 3054.14 ng/mL | Standard Deviation 1811.084 |
| MLN1117 300 mg + TAK-659 | Plasma Concentration of MLN1117-1003 | Day 2: 3 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + TAK-659 | Plasma Concentration of MLN1117-1003 | Day 17: 3 Hours Postdose | 5116.67 ng/mL | Standard Deviation 1608.426 |
| MLN1117 300 mg + TAK-659 | Plasma Concentration of MLN1117-1003 | Day 3: 1 Hour Postdose | NA ng/mL | — |
| MLN1117 300 mg + TAK-659 | Plasma Concentration of MLN1117-1003 | Day 1: 1 Hour Postdose | 2171.00 ng/mL | Standard Deviation 1840.041 |
| MLN1117 300 mg + TAK-659 | Plasma Concentration of MLN1117-1003 | Day 17: 8 Hours Postdose | 4330.00 ng/mL | Standard Deviation 2606.971 |
| MLN1117 300 mg + TAK-659 | Plasma Concentration of MLN1117-1003 | Day 2: 24 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + TAK-659 | Plasma Concentration of MLN1117-1003 | Day 2: 0.5 Hour Postdose | NA ng/mL | — |
| MLN1117 300 mg + TAK-659 | Plasma Concentration of MLN1117-1003 | Day 2: 8 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + TAK-659 | Plasma Concentration of MLN1117-1003 | Day 17: 4 Hours Postdose | 5066.67 ng/mL | Standard Deviation 2009.784 |
| MLN1117 300 mg + TAK-659 | Plasma Concentration of MLN1117-1003 | Day 3: Predose | NA ng/mL | — |
| MLN1117 300 mg + TAK-659 | Plasma Concentration of MLN1117-1003 | Day 3: 6 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + TAK-659 | Plasma Concentration of MLN1117-1003 | Day 2: 6 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + TAK-659 | Plasma Concentration of MLN1117-1003 | Day 3: 0.5 Hour Postdose | NA ng/mL | — |
| MLN1117 300 mg + TAK-659 | Plasma Concentration of MLN1117-1003 | Day 3: 2 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + TAK-659 | Plasma Concentration of MLN1117-1003 | Day 2: Predose | NA ng/mL | — |
| MLN1117 300 mg + TAK-659 | Plasma Concentration of MLN1117-1003 | Day 17: 6 Hours Postdose | 4293.33 ng/mL | Standard Deviation 1654.398 |
| MLN1117 300 mg + TAK-659 | Plasma Concentration of MLN1117-1003 | Day 3: 8 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + TAK-659 | Plasma Concentration of MLN1117-1003 | Day 2: 4 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + TAK-659 | Plasma Concentration of MLN1117-1003 | Day 1: 24 Hours Postdose | 1045.17 ng/mL | Standard Deviation 642.781 |
| MLN1117 300 mg + TAK-659 | Plasma Concentration of MLN1117-1003 | Day 3: 24 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + TAK-659 | Plasma Concentration of MLN1117-1003 | Day 2: 2 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + TAK-659 | Plasma Concentration of MLN1117-1003 | Day 1: 8 Hours Postdose | 2466.29 ng/mL | Standard Deviation 1112.35 |
| MLN1117 300 mg + TAK-659 | Plasma Concentration of MLN1117-1003 | Day 17: Predose | 978.33 ng/mL | Standard Deviation 1519.07 |
| MLN1117 300 mg + TAK-659 | Plasma Concentration of MLN1117-1003 | Day 3: 3 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + TAK-659 | Plasma Concentration of MLN1117-1003 | Day 1: 6 Hours Postdose | 2726.71 ng/mL | Standard Deviation 1259.976 |
| MLN1117 300 mg + TAK-659 | Plasma Concentration of MLN1117-1003 | Day 17: 0.5 Hour Postdose | 2893.67 ng/mL | Standard Deviation 1738.859 |
| MLN1117 300 mg + TAK-659 | Plasma Concentration of MLN1117-1003 | Day 1: 4 Hours Postdose | 3164.71 ng/mL | Standard Deviation 1522.096 |
| MLN1117 300 mg + TAK-659 | Plasma Concentration of MLN1117-1003 | Day 17: 1 Hour Postdose | 5596.67 ng/mL | Standard Deviation 387.599 |
| MLN1117 300 mg + TAK-659 | Plasma Concentration of MLN1117-1003 | Day 2: 1 Hour Postdose | NA ng/mL | — |
| MLN1117 200 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 3: 2 Hours Postdose | NA ng/mL | — |
| MLN1117 200 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 1: 3 Hours Postdose | NA ng/mL | — |
| MLN1117 200 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 2: Predose | 0.00 ng/mL | Standard Deviation 0 |
| MLN1117 200 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 1: 4 Hours Postdose | NA ng/mL | — |
| MLN1117 200 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 3: 3 Hours Postdose | NA ng/mL | — |
| MLN1117 200 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 17: 2 Hours Postdose | NA ng/mL | — |
| MLN1117 200 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 1: 6 Hours Postdose | NA ng/mL | — |
| MLN1117 200 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 3: 4 Hours Postdose | NA ng/mL | — |
| MLN1117 200 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 1: 2 Hours Postdose | NA ng/mL | — |
| MLN1117 200 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 3: 8 Hours Postdose | NA ng/mL | — |
| MLN1117 200 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 3: 1 Hour Postdose | NA ng/mL | — |
| MLN1117 200 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 17: 1 Hour Postdose | NA ng/mL | — |
| MLN1117 200 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 17: 3 Hours Postdose | NA ng/mL | — |
| MLN1117 200 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 1: 24 Hours Postdose | NA ng/mL | — |
| MLN1117 200 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 2: 0.5 Hour Postdose | 3240.00 ng/mL | Standard Deviation 1230.366 |
| MLN1117 200 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 1: 1 Hour Postdose | NA ng/mL | — |
| MLN1117 200 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 2: 4 Hours Postdose | 3725.00 ng/mL | Standard Deviation 3542.605 |
| MLN1117 200 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 17: 6 Hours Postdose | NA ng/mL | — |
| MLN1117 200 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 1: Predose | NA ng/mL | — |
| MLN1117 200 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 2: 24 Hours Postdose | 717.00 ng/mL | Standard Deviation 668.923 |
| MLN1117 200 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 3: 24 Hours Postdose | NA ng/mL | — |
| MLN1117 200 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 17: 8 Hours Postdose | NA ng/mL | — |
| MLN1117 200 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 2: 8 Hours Postdose | 3025.00 ng/mL | Standard Deviation 2807.214 |
| MLN1117 200 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 2: 2 Hours Postdose | 4615.00 ng/mL | Standard Deviation 4433.56 |
| MLN1117 200 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 17: 0.5 Hour Postdose | NA ng/mL | — |
| MLN1117 200 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 1: 8 Hours Postdose | NA ng/mL | — |
| MLN1117 200 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 3: Predose | NA ng/mL | — |
| MLN1117 200 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 2: 3 Hours Postdose | 4355.00 ng/mL | Standard Deviation 4362.849 |
| MLN1117 200 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 3: 6 Hours Postdose | NA ng/mL | — |
| MLN1117 200 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 2: 6 Hours Postdose | 3085.00 ng/mL | Standard Deviation 2920.351 |
| MLN1117 200 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 1: 0.5 Hour Postdose | NA ng/mL | — |
| MLN1117 200 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 17: 4 Hours Postdose | NA ng/mL | — |
| MLN1117 200 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 2: 1 Hour Postdose | 3165.00 ng/mL | Standard Deviation 1859.691 |
| MLN1117 200 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 3: 0.5 Hour Postdose | NA ng/mL | — |
| MLN1117 200 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 17: Predose | NA ng/mL | — |
| MLN1117 300 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 3: 0.5 Hour Postdose | NA ng/mL | — |
| MLN1117 300 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 17: 4 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 3: 1 Hour Postdose | NA ng/mL | — |
| MLN1117 300 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 2: 3 Hours Postdose | 1598.75 ng/mL | Standard Deviation 1269.397 |
| MLN1117 300 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 1: 0.5 Hour Postdose | NA ng/mL | — |
| MLN1117 300 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 3: 2 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 2: 2 Hours Postdose | 1456.23 ng/mL | Standard Deviation 1577.178 |
| MLN1117 300 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 3: 3 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 2: 1 Hour Postdose | 1554.00 ng/mL | Standard Deviation 2042.092 |
| MLN1117 300 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 3: 4 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 2: 0.5 Hour Postdose | 1333.05 ng/mL | Standard Deviation 1970.336 |
| MLN1117 300 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 3: 6 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 2: Predose | 0.00 ng/mL | Standard Deviation 0 |
| MLN1117 300 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 3: 8 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 1: 24 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 3: 24 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 1: 8 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 17: 6 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 17: Predose | NA ng/mL | — |
| MLN1117 300 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 1: 6 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 1: Predose | NA ng/mL | — |
| MLN1117 300 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 17: 0.5 Hour Postdose | NA ng/mL | — |
| MLN1117 300 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 1: 4 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 17: 1 Hour Postdose | NA ng/mL | — |
| MLN1117 300 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 1: 3 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 17: 2 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 1: 2 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 17: 8 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 17: 3 Hours Postdose | NA ng/mL | — |
| MLN1117 300 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 1: 1 Hour Postdose | NA ng/mL | — |
| MLN1117 300 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 2: 24 Hours Postdose | 420.80 ng/mL | Standard Deviation 477.731 |
| MLN1117 300 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 2: 8 Hours Postdose | 1443.25 ng/mL | Standard Deviation 992.241 |
| MLN1117 300 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 3: Predose | NA ng/mL | — |
| MLN1117 300 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 2: 6 Hours Postdose | 1417.75 ng/mL | Standard Deviation 907.208 |
| MLN1117 300 mg + Docetaxel | Plasma Concentration of MLN1117-1003 | Day 2: 4 Hours Postdose | 1475.75 ng/mL | Standard Deviation 1062.242 |
Secondary
Progression-Free Survival (PFS) Based on RECIST Criteria V 1.1 Assessment in Part 2
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)
Population: Study was terminated before the initiation of Part 2 of the study.
Secondary
Time to Disease Progression (TTP) Based on RECIST Criteria V 1.1 Assessment in Part 2
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)
Population: Study was terminated before the initiation of Part 2 of the study.