MLN1117 in Combination With Docetaxel, Paclitaxel, and Other Investigational Anticancer Agents to Treat Participants With Gastric and Gastroesophageal Adenocarcinoma
Condition: Advanced and Metastatic Gastric or Gastroesophageal Adenocarcinoma
MeSH terms: Adenocarcinoma
Intervention: MLN1117; TAK-659; Alisertib; Paclitaxel; Docetaxel
Intervention description: MLN1117 Tablets; TAK-659 Tablets; Alisertib Tablets; Paclitaxel intravenous infusion; Docetaxel intravenous infusion
Intervention MeSH terms: Paclitaxel; Docetaxel; Serabelisib
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 32.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Drug Therapy

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).
    

Eligibility criteria:

        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.