Dose Escalation, Multi-arm Study of MLN4924 Plus Docetaxel, Gemcitabine, or Combination of Carboplatin and Paclitaxel in Participants With Solid Tumors

Study Overview
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Brief Summary
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The purpose of this study is to establish the maximum tolerated dose (MTD) and assess the safety and tolerability of MLN4924 (pevonedistat) in combination with docetaxel, paclitaxel and carboplatin, and gemcitabine in participants with solid tumors.

Official Title
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A Phase 1b, Open-Label, Dose Escalation, Multi-arm Study of MLN4924 Plus Docetaxel, Gemcitabine, or Combination of Carboplatin and Paclitaxel in Patients With Solid Tumors

Conditions
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Solid Tumors

Intervention / Treatment
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* Drug: MLN4924
* Drug: Paclitaxel
* Drug: Gemcitabine
* Drug: Docetaxel
* Drug: Carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years of age or older Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 Have a histologically or cytologically confirmed metastatic or locally advanced and incurable solid tumor that is felt to be appropriate for treatment with 1 of the 3 chemotherapy regimens in this study, or have progressed despite standard therapy, or for whom conventional therapy is not considered effective. The tumor must be radiographically or clinically evaluable and/or measurable Recovered (that is, <=Grade 1 toxicity) from the effects of prior antineoplastic therapy Female participants who are post menopausal, surgically sterile, or agree to practice 2 effective methods of contraception or agree to practice true abstinence Male participants who agree to practice effective barrier contraception or agree to practice true abstinence Voluntary written consent must be given before performance of any study-related procedure Suitable venous access for the study-required blood sampling Adequate clinical laboratory values during the screening period as specified in the protocol Participants who are willing to refrain from donating blood for at least 90 days after their final dose of MLN4924 and (for male participants) willing to refrain from donating semen for at least 4 months after their final dose of MLN4924 Availability of fixed tumor specimen (block or slides) for exploratory biomarker analysis. If no slides or block are available, fresh tumor biopsies should be obtained and used for these assessments Exclusion Criteria: Major surgery within 14 days before the first dose of study drug Female participants who are lactating or pregnant Active uncontrolled infection or severe infectious disease Receiving antibiotic therapy within 14 days before the first dose of study treatment Life-threatening illness unrelated to cancer Known hypersensitivity to study-assigned chemotherapy Prior treatment with MLN4924; however, prior treatment with docetaxel, paclitaxel,carboplatin, and gemcitabine is allowed History of severe hypersensitivity reactions to docetaxel (polysorbate 80-based formulations) for participants to be enrolled in Arm 1 (MLN4924 + docetaxel), history of hypersensitivity to carboplatin for participants to be enrolled in Arm 2 (MLN4924 + paclitaxel + carboplatin), or history of severe hypersensitivity to paclitaxel (cremophor-based formulations) for participants to be enrolled in Arm 2 Persistent diarrhea (greater than Grade 2) lasting >3 days within 2 weeks before the first dose of study treatment Systemic antineoplastic therapy within 21 days before the first dose of study drug Radiotherapy within 14 days preceding the first dose of study treatment Prior treatment with radiation therapy involving greater than or equal to (>=) 25% of the hematopoietically active bone marrow Treatment with cytochrome P450 3A (CYP3A) inducers within 14 days before the first dose of MLN4924. Treatment with CYP3A inhibitors within 14 days before the first dose of MLN4924; however, voriconazole and fluconazole need only be stopped for 3 days before MLN4924. Participants must have no history of amiodarone use in the 6 months before the first dose of MLN4924 14. Clinically uncontrolled central nervous system (CNS) involvement 15. Any serious medical or psychiatric illness 16. Treatment with any investigational products 21 days prior to treatment 17. Unwilling or unable to refrain from using statins 24 hours before, the day of, and 24 hours after each MLN4924 administration 18. Known human immunodeficiency virus (HIV) positive or hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection 19. Known hepatic cirrhosis 20. Known cardiac/cardiopulmonary disease 21. Left ventricular ejection fraction 23. with a cardiac pacer whose heart rate is set at a fixed rate and participants on concomitant medication that may limit increase in heart rate in response to hypotension 24 History of severe intolerance to cytotoxic agent(s) given in the assigned arm

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MLN4924 and Docetaxel (Arm 1)<br> | Drug: MLN4924<br>* MLN4924 (intravenously [IV]) in participants in a 21-day cycle: MLN4924 on Days 1,3,5 of each cycle<br>* Other names: Pevonedistat;Drug: Docetaxel<br>* Docetaxel (IV) in participants in a 21-day cycle: - Docetaxel on Day 1 of each cycle<br>|
| Experimental: MLN4924 + Paclitaxel + Carboplatin (Arm 2)<br> | Drug: MLN4924<br>* MLN4924 (intravenously [IV]) in participants in a 21-day cycle: MLN4924 on Days 1,3,5 of each cycle<br>* Other names: Pevonedistat;Drug: Paclitaxel<br>* Paclitaxel (IV) in a 21-day cycle: Paclitaxel on Day 1 of each cycle<br>Drug: Carboplatin<br>* Carboplatin (IV) in participants in a 21-day cycle: - Carboplatin on Day 1 of each cycle<br>|
| Experimental: MLN4924 + Gemcitabine (Arm 3)<br> | Drug: MLN4924<br>* MLN4924 (intravenously [IV]) in participants in a 21-day cycle: MLN4924 on Days 1,3,5 of each cycle<br>* Other names: Pevonedistat;Drug: Gemcitabine<br>* Gemcitabine (IV) in participants in a 28-day cycle: -Gemcitabine on Days 1,8,15 of each cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experience at Least 1 Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) |  | Baseline up to 30 days after the last dose of study drug (up to 5 years) | 
| Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings |  | Baseline up to 30 days after the last dose of study drug (up to 5 years) | 
| Number of Participants With TEAEs Related to Clinically Significant Vital Sign Findings |  | Baseline up to 30 days after the last dose of study drug (up to 5 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Objective Response | Percentage of participants with objective response based on assessment of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CR: complete disappearance of all target lesions and non-target disease, with exception of nodal disease; all nodes, both target and non-target, must decrease to normal (short axis less than [<] 10 millimeter [mm]); no new lesions. PR: greater than or equal to (>=) 30 percent (%) decrease under baseline of sum of diameters of all target lesions; short axis was used in sum for target nodes, while longest diameter was used in sum for all other target lesions; no unequivocal progression of non-target disease; no new lesions. | Screening, Cycle 2 Days 15 (Arm 1, 2a, and 2) and 22 (Arm 3) then every other Cycle thereafter up to 30 days after the last dose of study drug (up to 5 years) (Cycle Length = 21 days [Arm 1, 2a, and 2] and 28 days [Arm 3]) | 
| Duration of Response | Duration of response: time from the date of first documented response per the investigator response assessment (CR or PR) to the date of PD or the date of last disease assessment if the participant discontinued the study before PD using RECIST 1.1 CR: complete disappearance of all target lesions and non-target disease, with exception of nodal disease; all nodes, both target and non-target, must decrease to normal (short axis <10 mm); no new lesions. PR: >=30% decrease under baseline of sum of diameters of all target lesions; short axis was used in sum for target nodes, while longest diameter was used in sum for all other target lesions; no unequivocal progression of non-target disease; no new lesions. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in sum of diameters of target lesions, taking as reference smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. | From the date of first documented response (CR or PR) to the date of first documented PD or the date of last disease assessment if the participants discontinued the study before PD (up to 5 years) | 
| Dose-escalation Phase: Plasma Concentrations-time Data of MLN4924 |  | Cycle 1 Day 1 pre-dose and at multiple time points (up to 20 hours) post-dose (Cycle Length=21 days [Arm 1 and 2] and 28 days [Arm 3]) | 
| MTD Expansion Phase: Plasma Concentrations-time Data of MLN4924 | The number of participants analyzed includes only those participants who had data available for this measure. | Cycle 1 Days 1 and 5 pre-dose and at multiple time points (up to 20 hours) post-dose (Cycle Length=21 days [Arm 1 and 2]) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MLN4924, Solid Tumors