An Open-Label Study of the Safety, Tolerability, and Pharmacokinetic/Pharmacodynamic Profile of M4344 (Formerly VX-803) as a Single Agent and in Combination With Cytotoxic Chemotherapy in Participants With Advanced Solid Tumors

Overview

The purpose of this study is to evaluate the safety and tolerability of multiple ascending doses of single-agent M4344 administered twice-weekly (BIW), twice daily (BID) or once daily dose schedule in participants with advanced solid tumors. This investigation is a three part study examining M4344 alone and in combination with carboplatin, and cisplatin to determine the safety and maximum tolerated dose.

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Non-Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: June 11, 2021

Interventions

  • Drug: M4344
    • Dose escalation of M4344 administered as a single agent.
  • Drug: Carboplatin
    • Carboplatin will be administered in combination with escalated dose of M4344.

Arms, Groups and Cohorts

  • Experimental: Part A: M4344 BIW
    • Dose escalation of M4344 administered BIW as a single agent.
  • Experimental: Part A2: M4344 BID or once daily
    • Dose escalation of M4344 administered BID or once daily as a single agent.
  • Experimental: Part B1: M4344 + Carboplatin
    • Dose escalation of M4344 in combination with carboplatin.
  • Experimental: Part C1: M4344
    • An expanded cohort study to confirm the potential effect of M4344 in participants whose tumor carry a loss-of-function mutation in the gene ARID1A.
  • Experimental: Part C2: M4344
    • An expanded cohort study to confirm the potential effect of M4344 in participants whose tumor carry a loss-of-function mutation in the genes ATRX and/or DAXX.
  • Experimental: Part C3: M4344
    • An expanded cohort study to confirm the potential effect of M4344 in participants whose tumor carry a loss-of-function mutation in the gene ataxia telangiectasia mutated (ATM).

Clinical Trial Outcome Measures

Primary Measures

  • Parts A, A2, B1, C1, C2, C3: Number of Participants with Treatment Emergent Adverse Events and Serious Adverse Events
    • Time Frame: From baseline until 14 Days after discontinuation of study treatment (assessed up to 6 years)
  • Parts A, A2, B1, C1, C2, C3: Number of Participants with Clinically Significant Changes in Clinical Laboratory Values (Serum Chemistry and Hematology), Vital Signs, and Electrocardiogram (ECG) Assessments
    • Time Frame: From baseline until 14 Days after discontinuation of study treatment (assessed up to 6 years)
    • Number of participants with clinically significant changes in clinical laboratory values (serum chemistry and hematology), vital signs, and ECG assessments were assessed.
  • Part A, A2: Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 (RP2D) of Single-Agent M4344 Administered BIW or BID or Once Daily
    • Time Frame: Evaluation for dose-limiting toxicity will be during Cycle 1 (each cycle is of 21 days) for each participant
  • Part B1: Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 (RP2D) of M4344 Administered in Combination with Carboplatin
    • Time Frame: Evaluation for dose-limiting toxicity will be during Cycle 1 (each cycle is of 21 days) for each participant
  • Part C1, C2, C3: Proportion of Participants With Objective Response according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Assessed by the Investigator
    • Time Frame: Baseline until disease progression or start of new anti-cancer treatment line (approximately up to 6 years)

Secondary Measures

  • Part A: Area Under the Concentration Curve (AUC) of M4344
    • Time Frame: Cycle 1, Day 1 up to Cycle 1, Day 15 (each cycle is of 21 days)
  • Part A: Maximum Observed Plasma Concentration (Cmax) of M4344
    • Time Frame: Cycle 1, Day 1 up to Cycle 1, Day 15 (each cycle is of 21 days)
  • Part A: Time to Reach Maximum Plasma Concentration (tmax) of M4344
    • Time Frame: Cycle 1, Day 1 up to Cycle 1, Day 15 (each cycle is of 21 days)
  • Part A2: Area Under the Concentration Curve (AUC) of M4344 and Metabolites
    • Time Frame: Cycle 1, Day 1 up to Cycle 1, Day 15 (each cycle is of 21 days)
  • Part A2: Maximum Observed Plasma Concentration (Cmax) of M4344 and Metabolites
    • Time Frame: Cycle 1, Day 1 up to Cycle 1, Day 15 (each cycle is of 21 days)
  • Part A2: Time to Reach Maximum Plasma Concentration (tmax) of M4344 and Metabolites
    • Time Frame: Cycle 1, Day 1 up to Cycle 1, Day 15 (each cycle is of 21 days)
  • Parts A, A2, B1: Objective Tumor Response (OR) and Disease Stabilization (SD) as Evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
    • Time Frame: Every 2 Cycles (each cycle is of 21 days) until tumor progression (approximately up to 6 years)
  • Part B1: Area Under the Concentration Curve (AUC) of M4344
    • Time Frame: Cycle 1, Day 2 up to Cycle 1, Day 9 (each cycle is of 21 days)
  • Part B1: Maximum Observed Plasma Concentration (Cmax) of M4344
    • Time Frame: Cycle 1, Day 2 up to Cycle 1, Day 9 (each cycle is of 21 days)
  • Part B1: Time to Reach Maximum Plasma Concentration (tmax) of M4344
    • Time Frame: Cycle 1, Day 2 up to Cycle 1, Day 9 (each cycle is of 21 days)
  • Part C1, C2, C3: Confirmed Best Overall Response (BOR) According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) as Assessed by Investigator
    • Time Frame: Baseline, until disease progression or start of new anti-cancer treatment line (approximately up to 6 years)
  • Part C1, C2, C3: Duration of Response Assessed from Complete Response (CR) or Partial Response (PR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
    • Time Frame: Baseline until PD, death, or last adequate tumor assessment (approximately up to 6 years)
  • Part C1, C2, C3: Progression Free Survival (PFS) as Evaluated by RECIST Version 1.1
    • Time Frame: Baseline until tumor progression (approximately up to 6 years)
  • Part C1, C2, C3: Overall Survival (OS)
    • Time Frame: Assessed every 3 months for up to 1 year or more or until study closure, whichever comes first (approximately up to 6 years)
  • Part C1, C2, C3: Area Under the Concentration Curve (AUC) of M4344 and Metabolites
    • Time Frame: Cycle 1, Day 1 up to Cycle 12, Day 1 (each cycle is of 21 days)
  • Part C1, C2, C3: Maximum Observed Plasma Concentration (Cmax) of M4344 and Metabolites
    • Time Frame: Cycle 1, Day 1 up to Cycle 12, Day 1 (each cycle is of 21 days)
  • Part C1, C2, C3: Time to Reach Maximum Plasma Concentration (tmax) of M4344 and Metabolites
    • Time Frame: Cycle 1, Day 1 up to Cycle 12, Day 1 (each cycle is of 21 days)
  • Time-Matched Change from Baseline in Plasma PK Concentrations
    • Time Frame: Pre-dose on Day 1 till safety follow-up (approximately up to 6 years)
  • Time-Matched Change from Baseline in Digital Electrocardiogram (ECG) Measures
    • Time Frame: Pre-dose on Day 1 till safety follow-up (approximately up to 6 years)

Participating in This Clinical Trial

Inclusion Criteria

  • Part A and A2: Participants with one histologically or cytologically confirmed malignant advanced solid tumor, for which no standard therapy is available which may convey clinical benefit
  • Part B1: Participants with one histologically or cytologically confirmed malignant advanced solid tumor, for which no standard therapy is available which may convey clinical benefit and/or participants must have progressed after at least 1 prior chemotherapy regimen in the metastatic setting, and for which carboplatin would be considered standard of care.
  • Parts C1, C2, and C3: Participants with 1 histologically or cytologically confirmed malignant advanced solid tumors for which no recommended standard therapy is available (that is, participants who have exhausted all standard of care options according to National Comprehensive Cancer Network [NCCN] Guidance) which may convey clinical benefit, and whose tumor has at least 1 of the following biomarkers as determined by a central trial assay or by an assay with appropriate regulatory status: – C1: loss-of-function mutations in the gene ARID1A – C2: loss-of-function mutations in the genes ATRX and/or DAXX – C3: loss-of-function mutation in the gene ataxia telangiectasia mutated (ATM) – This mandatory biomarker assessment must be conducted during prescreening on a fresh tumor biopsy (or a biopsy obtained after the end of the previous treatment regimen). If this is not possible for medical reason(s), available archival tumor material can be used (historical data should not be used to confirm biomarker status)
  • Measurable disease according to RECIST criteria (Version 1.1)
  • WHO performance status of 0 or 1
  • Life expectancy of greater than or equal to (>=)12 weeks
  • Hematological and biochemical indices within acceptable ranges at Screening
  • Other protocol defined inclusion criteria could apply

Exclusion Criteria

  • Radiotherapy, unless brief course for palliative therapy, endocrine therapy, target-specific therapy, immunotherapy, or chemotherapy during the 4 weeks (6 weeks for nitrosoureas and Mitomycin-C, and 4 weeks for investigational medicinal products) or 4 drug half-lives before first dose of study drug, whichever is greater
  • Part B1: More than 6 cycles of prior therapy with carboplatin
  • Ongoing toxic manifestations of previous treatments. Exceptions to this are alopecia or certain Grade 1 toxicities, which in the opinion of the investigator should not exclude the participant

a. Part B1: Any known history of Grade 4 thrombocytopenia with any prior chemotherapy regimen (not applicable for Parts C1, C2, and C3)

  • Brain metastases unless asymptomatic, treated, stable, and not requiring steroids for at least 4 weeks before first dose of study drug
  • Female participants who are already pregnant or lactating, or plan to become pregnant within 6 months of the last dose of study drug are excluded. Female participants of childbearing potential must adhere to contraception guidelines. Female participants will be considered to be of nonchildbearing potential if they have undergone surgical hysterectomy or bilateral oophorectomy or have been amenorrheic for over 2 years with a screening serum follicle-stimulating hormone (FSH) level within the laboratory's reference range for postmenopausal females.
  • Male participants with partners of childbearing potential must agree to adhere to contraception guidelines. Men with pregnant or lactating partners or partners who plan to become pregnant during the study or within 6 months of the last dose of study drug are excluded.
  • Major surgery less than or equal to (<=) 4 weeks before first dose of study drug or incomplete recovery from a prior major surgical procedure
  • Serious co-morbid medical conditions, including clinically-significant cardiac disease
  • Other protocol defined exclusion criteria could apply

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • EMD Serono Research & Development Institute, Inc.
  • Collaborator
    • Merck KGaA, Darmstadt, Germany
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Medical Responsible, Study Director, EMD Serono Research & Development Institute, Inc., a subsidiary of Merck KGaA, Darmstadt, Germany
  • Overall Contact(s)
    • US Medical Information, 888-275-7376, service@emdgroup.com

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