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

NCT02551055 | Terminated Phase 1 Results FDA Drug

• 4 other identifiers: C032-6001 (MLN1117-1003)2015-001032-38U1111-1166-8653REec-2016-2039
• Study Type: interventional
• Target: 32
• Locations: 2 countries
• Sites: 6

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).

Conditions

Advanced and Metastatic Gastric or Gastroesophageal Adenocarcinoma

Keywords

Drug Therapy

Outcome Measures

Primary Outcomes (6)

• 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.

  Up to Cycle 1 (28 days for MLN1117+TAK-659, MLN1117+Alisertib, MLN1117+Paclitaxel or 21 days for MLN1117+Docetaxel)

• 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.

  From first dose of study drug through 30 days after the last dose of study drug (approximately up to 366 days)

• 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.

  From first dose of study drug through 30 days after the last dose of study drug (approximately up to 366 days)

• 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.

  From first dose of study drug through 30 days after the last dose of study drug (approximately up to 366 days)

• 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).

  From first dose of study drug through 30 days after the last dose of study drug (approximately up to 366 days)

• 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.

  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)

Secondary Outcomes (8)

• 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)

• 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)

• 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)

• 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)

• 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)

Study Arms (7)

MLN1117 300 mg + Alisertib

EXPERIMENTAL

MLN1117 300 mg, tablets, orally, once daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15, 16, 17; 22, 23, and 24) and 4 days off per week and alisertib 40 mg, tablets, orally, twice daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15,16, and 17) and 4 days off per week on Weeks 1-3, and 1 week off in 28-day treatment cycles until PD or unacceptable toxicity.

Drug: MLN1117; Drug: Alisertib

MLN1117 600 mg + Alisertib

EXPERIMENTAL

MLN1117 600 mg, tablets, orally, once daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15, 16, 17; 22, 23, and 24) and 4 days off per week and alisertib 40 mg, tablets, orally, twice daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15,16, and 17) and 4 days off per week on Weeks 1-3, and 1 week off in 28-day treatment cycles until PD or unacceptable toxicity.

Drug: MLN1117; Drug: Alisertib

MLN1117 300 mg + Paclitaxel

EXPERIMENTAL

MLN1117 300 mg, tablets, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, 18; 23, 24, and 25) and 4 days off per week and paclitaxel 80 mg/m\^2, infusion, intravenously, once weekly on (Days 1, 8, and 15) and 1 week off, in 28-day treatment cycles until PD or unacceptable toxicity.

Drug: MLN1117; Drug: Paclitaxel

MLN1117 600 mg + Paclitaxel

EXPERIMENTAL

MLN1117 600 mg, tablets, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, 18; 23, 24, and 25) and 4 days off per week and paclitaxel 80 mg/m\^2, infusion, intravenously, once weekly on (Days 1, 8, and 15) and 1 week off, in 28-day treatment cycles until PD or unacceptable toxicity.

Drug: MLN1117; Drug: Paclitaxel

MLN1117 300 mg + TAK-659

EXPERIMENTAL

MLN1117 300 mg, tablets, orally, once daily for 3 days on (Days 1, 2, 3; 8, 9, 10; 15, 16, 17; and 22, 23, and 24) and 4 days off per week and TAK-659 100 mg (as determined in study C34001 \[NCT02000934\]), tablets, orally, once daily, in 28-day treatment cycles until progressive disease (PD) or unacceptable toxicity.

Drug: MLN1117; Drug: TAK-659; Drug: Docetaxel

MLN1117 200 mg + Docetaxel

EXPERIMENTAL

MLN1117 200 mg, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, and 18) and 4 days off per week and docetaxel 75 mg/m\^2, infusion, intravenously, on Day 1 once every 3 weeks in 21-day treatment cycles until PD or unacceptable toxicity.

Drug: MLN1117; Drug: Docetaxel

MLN1117 300 mg + Docetaxel

EXPERIMENTAL

MLN1117 300 mg, orally, once daily for 3 days on (Days 2, 3, 4; 9, 10, 11; 16, 17, and 18) and 4 days off per week and docetaxel 75 mg/m\^2, infusion, intravenously, on Day 1 once every 3 weeks in 21-day treatment cycles until PD or unacceptable toxicity.

Drug: MLN1117

Interventions

MLN1117 DRUG

MLN1117 Tablets

Also known as: TAK-117

MLN1117 200 mg + Docetaxel; MLN1117 300 mg + Alisertib; MLN1117 300 mg + Docetaxel; MLN1117 300 mg + Paclitaxel; MLN1117 300 mg + TAK-659; MLN1117 600 mg + Alisertib; MLN1117 600 mg + Paclitaxel

TAK-659 DRUG

TAK-659 Tablets

MLN1117 300 mg + TAK-659

Alisertib DRUG

Alisertib Tablets

Also known as: MLN8237

MLN1117 300 mg + Alisertib; MLN1117 600 mg + Alisertib

Paclitaxel DRUG

Paclitaxel intravenous infusion

MLN1117 300 mg + Paclitaxel; MLN1117 600 mg + Paclitaxel

Docetaxel DRUG

Docetaxel intravenous infusion

MLN1117 200 mg + Docetaxel; MLN1117 300 mg + TAK-659

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Part 1 and Part 2
• Is male or female aged 18 years or older at the time of consent.
• Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 14 days before enrollment.
• 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.
• 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.)

You may not qualify if:

• Part 1 and Part 2
• Has radiotherapy within 14 days before enrollment.
• 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.
• 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.
• 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.
• Has signs of peripheral neuropathy ≥ National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade 2.
• Has symptomatic brain metastases or brain metastases with a stable neurologic status for \<2 weeks after completion of the definitive therapy and steroids.
• Has systemic infection requiring intravenous (IV) antibiotic therapy or other serious infection within 14 days before the first dose of study drug.
• 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.
• 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.
• 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.
• 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.
• 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

Sponsors & Collaborators

• Millennium Pharmaceuticals, Inc.: lead

Study Sites (6)

Unknown Facility

Lake Success, New York, United States

Location

Unknown Facility

New York, New York, United States

Location

Unknown Facility

Philadelphia, Pennsylvania, United States

Location

Unknown Facility

Dallas, Texas, United States

Location

Unknown Facility

Houston, Texas, United States

Location

Unknown Facility

Barcelona, Spain

Location

MeSH Terms

Interventions

serabelisib; TAK-659; MLN 8237; Paclitaxel; Docetaxel

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes

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.

Results Point of Contact

• Title: Medical Director
• Organization: Takeda

trialdisclosures@takeda.com

+1-877-825-3327

Study Officials

• Medical Director

  Takeda

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 2, 2015
• First Posted: September 16, 2015
• Study Start: October 15, 2015
• Primary Completion: February 17, 2017
• Study Completion: February 17, 2017
• Last Updated: September 20, 2019
• Results First Posted: September 20, 2019

Record last verified: 2019-08

Locations

ES (1); US (5)