Phase Ib/II Study of Carboplatin + M6620 + Avelumab in PARPi-resistant Ovarian Cancer

Overview

The study is to evaluate the efficacy and safety of avelumab in combination with M6620 + carboplatin in participants with PARPi-resistant, recurrent, platinum sensitive ovarian, primary peritoneal, or fallopian tube cancer.

Full Title of Study: “A Phase Ib Safety Run-in and Randomized Phase II, Open-label Study to Evaluate the Efficacy, Safety, Tolerability, and Pharmacokinetics of M6620 in Combination With Avelumab and Carboplatin in Comparison to Standard of Care Therapy in Participants With PARPi-resistant Recurrent Ovarian, Primary Peritoneal, or Fallopian Tube Cancer”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: November 6, 2019

Interventions

  • Drug: M6620
    • Part A: Participants will be administered M6620 90 milligram per square meter (mg/m^2) intravenously (IV) on Day 2 of every 3 weeks (Q3W) cycle for a maximum of 6 cycles in combination treatment with carboplatin and avelumab on Day 1. The M6620 dose may be de-escalated to 60 mg/m^2, or 40 mg/m^2. Part B: Participants will be administered M6620 at a dose as confirmed by the safety monitoring committee after the safety run-in (Part A).
  • Drug: Avelumab
    • Part A and B: Participants will be administered IV infusion of avelumab 1600 mg on Day 1 of each Q3W cycle for maximum of 6 cycles in combination treatment with carboplatin and M6620 followed by avelumab 800 mg IV on Day 1 of every two weeks (Q2W) cycle as maintenance monotherapy after the last dose of carboplatin and M6620 until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death.
  • Drug: Carboplatin
    • Part A and B (Experimental): Participants will be administered carboplatin area under the concentration-time curve 5 on Day 1 of each Q3W cycle for a maximum of 6 cycles in combination treatment with avelumab and M6620. Part B (SoC): Participants will be administered carboplatin intravenously (IV) area under the concentration-time curve (AUC) 5 (+ paclitaxel) or AUC 4 (+ gemcitabine) as a standard of care (SoC) treatment on Day 1 of each Q3W or every 4 weeks (Q4W) cycle for a maximum of 6 cycles, with or without bevacizumab.
  • Drug: Paclitaxel
    • Part B: Participants will be administered Paclitaxel 175 mg/m^2 IV on Day 1 Q3W in combination with carboplatin for 6 cycles, with or without bevacizumab.
  • Drug: Gemcitabine
    • Part B: Participants will be administered Gemcitabine 1000 mg/m^2 IV on Day 1 and 8 of each Q3W cycle in combination with carboplatin for a maximum of 6 cycles.
  • Drug: Bevacizumab
    • Part B: Participants will be administered bevacizumab 15 milligram per kilogram (mg/kg) IV on Day 1 of each Q3W cycle in combination with carboplatin/paclitaxel or carboplatin/gemcitabine followed by bevacizumab monotherapy until disease progression.
  • Drug: Pegylated Liposomal Doxorubicin (PLD)
    • Participants will be administered PLD 30 mg/m^2 Q4W in combination with carboplatin for a maximum of 6 cycles with or without bevacizumab.

Arms, Groups and Cohorts

  • Experimental: Carboplatin + M6620 + Avelumab (Part A, Part B)
    • Part A: Participants will receive avelumab and carboplatin followed by M6620 as a safety run in cohort (non-randomized); Part B participants will be randomized to receive avelumab and carboplatin followed by M6620 (dose-expansion phase II).
  • Active Comparator: Standard of care (SoC) treatment (Part B)
    • Part B participants will be randomized to receive standard of care chemotherapy (Investigator choice of 2 options).

Clinical Trial Outcome Measures

Primary Measures

  • Part A: Occurrence of Dose-limiting Toxicities (DLTs) During the DLT Observation Period
    • Time Frame: Up to 3 weeks
  • Part B: Progression Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors version (RECIST) v1.1
    • Time Frame: Up to 3 years

Secondary Measures

  • Part A: Occurrence of Treatment-emergent Adverse Events (TEAEs) and Treatment-related Adverse Events (AEs) According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE)
    • Time Frame: Up to 3 years
  • Part A and B: Number of Participants With Confirmed Best Overall Response (BOR)
    • Time Frame: Up to 3 years
  • Part A and B: Progression-free survival (PFS)
    • Time Frame: Up to 3 years
  • Part A and B: Duration of response (DOR)
    • Time Frame: Up to 3 years
  • Part A and B: Time to progression (TTP)
    • Time Frame: Up to 3 years
  • Part A and B: Time to first subsequent therapy (TFST)
    • Time Frame: Up to 3 years
  • Part A and B: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-t) of M6620 and Avelumab
    • Time Frame: Pre-dose, 0, 1, 2, 3 and 6 hours post-dose on Day 2 Cycle 1; post-dose 47 hours on Day 4 Cycle 1; pre-dose and at 0 hour on Day 2 Cycle 2 (each Cycle is 21 days)
  • Part A and B: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M6620 and Avelumab
    • Time Frame: Pre-dose, 0, 1, 2, 3 and 6 hours post-dose on Day 2 Cycle 1; post-dose 47 hours on Day 4 Cycle 1; pre-dose and at 0 hour on Day 2 Cycle 2 (each Cycle is 21 days)
  • Part A and B: Area Under the Concentration-time Curve (AUC) of M6620 and Avelumab Over the Dosing Interval From Time Zero to Tau hour
    • Time Frame: Pre-dose, 0, 1, 2, 3 and 6 hours post-dose on Day 2 Cycle 1; post-dose 47 hours on Day 4 Cycle 1; pre-dose and at 0 hour on Day 2 Cycle 2 (each Cycle is 21 days)
  • Part A and B: Terminal Rate Constant (λz) of M6620 and Avelumab
    • Time Frame: Pre-dose, 0, 1, 2, 3 and 6 hours post-dose on Day 2 Cycle 1; post-dose 47 hours on Day 4 Cycle 1; pre-dose and at 0 hour on Day 2 Cycle 2 (each Cycle is 21 days)
  • Part A and B : Maximum Observed Drug Concentration (Cmax) of M6620 and Avelumab
    • Time Frame: Pre-dose, 0, 1, 2, 3 and 6 hours post-dose on Day 2 Cycle 1; post-dose 47 hours on Day 4 Cycle 1; pre-dose and at 0 hour on Day 2 Cycle 2 (each Cycle is 21 days)
  • Part A: Minimum Observed Drug Concentration (Cmin) of M6620 and Avelumab
    • Time Frame: Pre-dose, 0, 1, 2, 3 and 6 hours post-dose on Day 2 Cycle 1; post-dose 47 hours on Day 4 Cycle 1; pre-dose and at 0 hour on Day 2 Cycle 2 (each Cycle is 21 days)
  • Part A and B: Time to Reach the Maximum Plasma Concentration (tmax) of M6620 and Avelumab
    • Time Frame: Pre-dose, 0, 1, 2, 3 and 6 hours post-dose on Day 2 Cycle 1; post-dose 47 hours on Day 4 Cycle 1; pre-dose and at 0 hour on Day 2 Cycle 2 (each Cycle is 21 days)
  • Part A and B: Apparent Terminal Half-life (t1/2) of M6620 and Avelumab
    • Time Frame: Pre-dose, 0, 1, 2, 3 and 6 hours post-dose on Day 2 Cycle 1; post-dose 47 hours on Day 4 Cycle 1; pre-dose and at 0 hour on Day 2 Cycle 2 (each Cycle is 21 days)
  • Part B: Occurrence of TEAEs and Treatment-related AEs and Immune-related Adverse Events (irAEs) According to NCI-CTCAE
    • Time Frame: Up to 3 years

Participating in This Clinical Trial

Inclusion Criteria

  • Female participants with recurrent epithelial ovarian cancer who have disease progression following maintenance treatment with a PARPi as defined below:

1. Participant must have histologically diagnosed epithelial ovarian, primary peritoneal, or fallopian tube cancer, with nonmucinous histology

2. Participants must have completed at least 2 previous courses of platinum containing therapy (for example, carboplatin or cisplatin) and had documented response (complete response [CR] or partial response [PR]) to the last platinum-based treatment prior to treatment with a PARPi

3. Participant has received the last dose of platinum-containing treatment at least 6 months prior to study enrollment

4. Participant has documented disease progression (radiological) after at least 4 months of maintenance treatment with PARPi following a response to platinum-based chemotherapy.

  • Confirmed breast cancer gene (BRCA) 1/2 mutation status or agree to its testing on samples collected in the study.
  • Available formalin-fixed, paraffin-embedded (FFPE) tumor biopsies.
  • Part A: Optional 2 paired on-treatment biopsies on Day 2 of Cycle 1 (first biopsy) and Day 2 of Cycle 1 or Cycle 2 (second biopsy) respectively, before and after M6620 administration, if assessed as feasible at low risk by the interventional radiologist.
  • Part B: Histological tissue specimen (tissue block or 8 to 10 unstained slides) must be available. An archival tumor biopsy is acceptable if obtained after the last progression on PARPi treatment and is less than 4 months old. Otherwise, participants must be willing to undergo mandatory biopsy during the Screening Period to obtain sufficient tissue for histological assessment. Participants need to have an attempted biopsy. However, participants who have measurable disease documented by a radiologist as not feasible or safe to be biopsied are eligible to enter the study
  • Measurable disease according to RECIST v1.1.
  • Other protocol defined inclusion criteria could apply

Exclusion Criteria

  • Treatment with a nonpermitted drug/intervention as listed below:

1. Concurrent anticancer treatment (e.g., cytoreductive therapy, radiotherapy, immune therapy, cytokine therapy, monoclonal antibody, or targeted small molecule therapy) or any study intervention within 4 weeks prior to start of study intervention, or not recovered from AEs related to such therapies

2. History of prior dose reductions or dose interruptions while receiving cisplatin or carboplatin due to toxicity from the platinum or intolerance to either agent, unless discussed with and approved by the Sponsor Medical Monitor

3. Prior treatment with a PD-1/PD-L1 targeting agent

  • Current use of the following medications at the time of enrollment:

1. Immunotherapy or immunosuppressive drugs at the time of enrollment (for example (e.g.,) chemotherapy or systemic corticosteroids) EXCEPT for (a) intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra articular injection), (b) systemic corticosteroids at physiologic doses less than or equals to (≤) 10 milligram per day (mg/day) of prednisone or equivalent, (c) steroids as premedication for hypersensitivity reactions (e.g., computed tomography [CT] scan premedication)

2. Growth factors EXCEPT where indicated for treatment of study intervention related myelosuppression and for prophylaxis of repeat myelosuppression after initial occurrence

3. Herbal remedies with immunostimulating properties (e.g., mistletoe extract) or known to potentially interfere with major organ function (e.g., hypericin)

4. Other DNA damage repair inhibitors (except PARPi) (e.g., inhibitors of ATR, ataxia telangiectasia mutated [ATM] kinase, DNA-dependent protein kinase [DNA-PK], or Wee kinases).

  • Other protocol defined exclusion criteria could apply

Gender Eligibility: Female

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, Merck KGaA, Darmstadt, Germany

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