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

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.

• MLN1117 (Drug), also known as TAK-117: MLN1117 Tablets
• TAK-659 (Drug): TAK-659 Tablets
• Alisertib (Drug), also known as MLN8237: Alisertib Tablets
• Paclitaxel (Drug): Paclitaxel intravenous infusion
• Docetaxel (Drug): Docetaxel intravenous infusion

Primary outcomes

• 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 outcomes

• 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.
• 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.
• 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.
• 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]

Sex: All, ages: 18 Years to any

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 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.
13. 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.
14. 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.

Participant flow

Outcome results

• Number of Participants Who Experienced Cycle 1 Dose Limiting Toxicity (DLT) in Part 1 (Primary), Number, participants: MLN1117 300 mg + Alisertib 0; MLN1117 600 mg + Alisertib 1; MLN1117 300 mg + Paclitaxel 0; MLN1117 600 mg + Paclitaxel 0; MLN1117 300 mg + TAK-659 1; MLN1117 200 mg + Docetaxel 0; MLN1117 300 mg + Docetaxel 1
• Number of Participants With at Least 1 Treatment-Emergent Adverse Event (TEAE) in Part 1 (Primary), Number, participants: MLN1117 300 mg + Alisertib 4; MLN1117 600 mg + Alisertib 6; MLN1117 300 mg + Paclitaxel 3; MLN1117 600 mg + Paclitaxel 6; MLN1117 300 mg + TAK-659 7; MLN1117 200 mg + Docetaxel 2; MLN1117 300 mg + Docetaxel 4
• Number of Participants With at Least 1 ≥ Grade 3 TEAE in Part 1 (Primary), Number, participants: MLN1117 300 mg + Alisertib 4; MLN1117 600 mg + Alisertib 4; MLN1117 300 mg + Paclitaxel 2; MLN1117 600 mg + Paclitaxel 2; MLN1117 300 mg + TAK-659 6; MLN1117 200 mg + Docetaxel 2; MLN1117 300 mg + Docetaxel 4
• Number of Participants With at Least 1 Treatment-Emergent Serious Adverse Event (SAE) in Part 1 (Primary), Number, participants: MLN1117 300 mg + Alisertib 2; MLN1117 600 mg + Alisertib 3; MLN1117 300 mg + Paclitaxel 1; MLN1117 600 mg + Paclitaxel 2; MLN1117 300 mg + TAK-659 5; MLN1117 200 mg + Docetaxel 2; MLN1117 300 mg + Docetaxel 4
• Number of Participants With at Least 1 Dose Modification Due to AE in Part 1 (Primary), Number, participants: MLN1117 300 mg + Alisertib 0; MLN1117 600 mg + Alisertib 1; MLN1117 300 mg + Paclitaxel 1; MLN1117 600 mg + Paclitaxel 0; MLN1117 300 mg + TAK-659 4; MLN1117 200 mg + Docetaxel 0; MLN1117 300 mg + Docetaxel 1
• Overall Response Rate in Part 2 (Primary)
• Number of Participants With at Least 1 TEAE and Serious TEAE in Part 1 and 2 (Secondary), Number, participants: MLN1117 300 mg + Alisertib 4; MLN1117 600 mg + Alisertib 6; MLN1117 300 mg + Paclitaxel 3; MLN1117 600 mg + Paclitaxel 6; MLN1117 300 mg + TAK-659 7; MLN1117 200 mg + Docetaxel 2; MLN1117 300 mg + Docetaxel 4; Part 2
• Number of Participants With Dose Delays, Dose Reductions, and Dose Interruptions Due To AE in Part 1 and 2 (Secondary), Count of participants, Participants: MLN1117 300 mg + Alisertib 0; MLN1117 600 mg + Alisertib 0; MLN1117 300 mg + Paclitaxel 0; MLN1117 600 mg + Paclitaxel 0; MLN1117 300 mg + TAK-659 1; MLN1117 200 mg + Docetaxel 0; MLN1117 300 mg + Docetaxel 0; Part 2
• Progression-Free Survival (PFS) Based on RECIST Criteria V 1.1 Assessment in Part 2 (Secondary)
• Percentage of Participants With Disease Control Based on RECIST Criteria V 1.1 Assessment in Part 2 (Secondary)
• Duration of Response (DOR) Based on RECIST Criteria V 1.1 Assessment in Part 2 (Secondary)
• Time to Disease Progression (TTP) Based on RECIST Criteria V 1.1 Assessment in Part 2 (Secondary)
• Overall Survival (OS) Based on RECIST Criteria V 1.1 Assessment (Secondary)
• Plasma Concentration of MLN1117-1003 (Secondary), Mean, ng/mL: MLN1117 300 mg + Alisertib NA +/- NA; MLN1117 600 mg + Alisertib NA +/- NA; MLN1117 300 mg + Paclitaxel NA +/- NA; MLN1117 600 mg + Paclitaxel NA +/- NA; MLN1117 300 mg + TAK-659 0.00 +/- 0.000; MLN1117 200 mg + Docetaxel NA +/- NA; MLN1117 300 mg + Docetaxel 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.

Serious adverse events by term

Other adverse events by term

100 more terms not shown.

Limitations and 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.

• Study Protocol and Statistical Analysis Plan (PDF, 2016-01-25)

• Medical Director, Study director, Takeda

NIH grants: 2015