A Study to Evaluate the Effects of Rifampin on Pharmacokinetics (PK) of Pevonedistat in Participants With Advanced Solid Tumors

Study Overview
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Brief Summary
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The purpose of this study is to assess the effect of multiple-dose administration of rifampin on the single dose PK of pevonedistat in adult participants with advanced solid tumors.

Detailed Description
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The study will enroll approximately 20 participants. The study will be conducted in two Parts: Part A and optional Part B. Part A will have a drug-drug interaction (DDI) assessment. In Part A, participants will be assigned to: • Pevonedistat 50 mg/m^2 + Rifampin Eligible participants from Part A will continue treatment in optional Part B with pevonedistat in combination with SoC chemotherapy, docetaxel or carboplatin plus paclitaxel. The investigator will decide which SoC combination partner a participant will receive. Pevonedistat 25 mg/m^2 + Docetaxel Pevonedistat 20 mg/m^2 + Carboplatin + Paclitaxel This multi-center trial will be conducted in the United States. The overall time to participate in this study is 18 months. Participants will make a final visit to the clinic 30 days after receiving their last dose of study drug or before the start of subsequent therapy.

Official Title
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A Phase 1 Study to Evaluate the Effects of Rifampin on Pharmacokinetics of Pevonedistat in Patients With Advanced Solid Tumors

Conditions
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Advanced Solid Neoplasm

Intervention / Treatment
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* Drug: Pevonedistat
* Drug: Rifampin
* Drug: Docetaxel
* Drug: Carboplatin
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult participants who have a histologically or cytologically confirmed metastatic or locally advanced solid tumor that is appropriate for treatment with either docetaxel or carboplatin + paclitaxel in Part B of this study, or have progressed despite standard therapy, or for whom conventional therapy is not considered effective. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Expected survival of at least 3 months from the date of enrollment in the study. Recovered (that is, less than or equal to (<=) Grade 1 toxicity) from the effects of prior antineoplastic therapy. Adequate organ functions (kidney, liver, cardiac, bone marrow). Suitable venous access for the study-required blood sampling (including PK sampling). Exclusion Criteria: Prior treatment with radiation therapy involving greater than or equal to (>=) 25% of the hematopoietically active bone marrow. Life-threatening illness or serious (acute or chronic) medical or psychiatric illness unrelated to cancer. Active, uncontrolled infection or severe infectious disease. Known human immunodeficiency virus (HIV) seropositive or known hepatitis B or hepatitis C infection. With significant heart or pulmonary disease. Requiring chronic treatment with breast cancer resistance protein (BCRP) inhibitors. Criteria for Continuation into Optional Part B: To be eligible for Part B, participants must have completed Part A and be reassessed to determine if they meet the continuation criteria for Part B.

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: Part A: Pevonedistat 50 mg/m^2 + Rifampin 600 mg<br>Pevonedistat 50 milligram per square meter (mg/m^2), intravenous infusion, once on Day 1 and 10 along with rifampin 600 milligram (mg), capsule, orally, once daily from Day 3 up to Day 11 in Part A. After completion of Part A, participants had opportunity to continue into optional Part B. | Drug: Pevonedistat<br>* Pevonedistat intravenous infusion.<br>* Other names: MLN4924, TAK-924;Drug: Rifampin<br>* Rifampin capsules.<br>|
| Experimental: Part B: Pevonedistat<br>Pevonedistat 25 mg/m^2 intravenously in combination with docetaxel 75 mg/m^2 or at 20 mg/m^2 in combination with carboplatin +paclitaxel 175 mg/m^2; pevonedistat was given in combination on Day 1 and as a single agent on Days 3 and 5 of each 21-day cycle. Participants were treated for up to 12 cycles or symptomatic deterioration or PD, treatment was discontinued for another reason, or until the study is stopped in Part B. The choice of combination partner (docetaxel or carboplatin + paclitaxel) was based on investigator discretion. If the sponsor and investigator determine that a participant would derive clinical benefit from continued treatment, the participant may remain on the current combination therapy or receive pevonedistat as a single agent beyond 12 cycles. | Drug: Pevonedistat<br>* Pevonedistat intravenous infusion.<br>* Other names: MLN4924, TAK-924;Drug: Docetaxel<br>* Docetaxel intravenous infusion.<br>Drug: Carboplatin<br>* Carboplatin intravenous infusion.<br>Drug: Paclitaxel<br>* Paclitaxel intravenous infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Ratio of Maximum Observed Plasma Concentration (Cmax) for Pevonedistat Without Rifampin (Day 1) and With Rifampin (Day 10) | The Least square (LS) means ratio of Day 10 over Day 1 were calculated from a mixed-model analysis of variance model. | Days 1 and 10 pre-dose and at multiple time points (up to 48 hours) post-dose | 
| Part A: Ratio of Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) for Pevonedistat Without Rifampin (Day 1) and With Rifampin (Day 10) | The LS means ratio of Day 10 over Day 1 were calculated from a mixed-model analysis of variance model. | Days 1 and 10 pre-dose and at multiple time points (up to 48 hours) post-dose | 
| Part A: Ratio of Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC∞) for Pevonedistat Without Rifampin (Day 1) and With Rifampin (Day 10) | The LS means ratio of Day 10 over Day 1 were calculated from a mixed-model analysis of variance model. | Days 1 and 10 pre-dose and at multiple time points (up to 48 hours) post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Total Clearance After Intravenous Administration (CL) for Pevonedistat Without Rifampin (Day 1) and With Rifampin (Day 10) |  | Days 1 and 10 pre-dose and at multiple time points (up to 48 hours) post-dose | 
| Part A: Volume of Distribution at Steady State After Intravenous Administration (Vss) for Pevonedistat Without Rifampin (Day 1) and With Rifampin (Day 10) |  | Days 1 and 10 pre-dose and at multiple time points (up to 48 hours) post-dose | 
| Part A: Terminal Disposition Phase Half-life (T1/2z) for Pevonedistat Without Rifampin (Day 1) and With Rifampin (Day 10) |  | Days 1 and 10 pre-dose and at multiple time points (up to 48 hours) post-dose | 
| Part B: Number of Participants With Best Overall Response as Per Investigator's Assessment | Best overall response was defined as participants with best response among complete response (CR) or partial response (PR) or stable disease (SD), or progressive disease (PD). It was assessed by investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CR: disappearance of all target lesions. Any pathological lymph nodes (whether target and non-target) must have reduction in short axis to less than (<) 10 millimeter (mm). PR: at least 30 percent (%) decrease in sum of diameter of target lesions, taking as reference baseline sum of diameter. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference smallest sum of diameter. PD: at least 20% increase in sum of diameter of target lesions, taking as reference, smallest sum on study. | Up to Cycle 17 (end of treatment) (Cycle length =21 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug therapy