Clinical trial NCT03704467: Phase Ib/II Study of Carboplatin + M6620 + Avelumab in PARPi-resistant Ovarian Cancer
Official title: 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: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Ovarian Cancer
Keywords: Avelumab
Carboplatin
Primary Peritoneal Cancer
Fallopian Tube Cancer
Platinum sensitive ovarian cancer
Deoxy ribonucleic acid (DNA)-damage response inhibition
Lead sponsor: EMD Serono
Sponsor class: INDUSTRY
Collaborators: name: Merck KGaA, Darmstadt, Germany
First posted: 2018-10-12
Enrollment: 3
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The study was 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.

Detailed description: The study was intended to be a phase Ib/II trial, but after completing Phase 1b and confirming the safe combination dose, the sponsor decided not to conduct Phase II.

Eligibility criteria: 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 Response Evaluation Criteria in Solid Tumors version 1.1 (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

Primary outcomes:
measure: Part A: Number of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: Up to 3 weeks
Secondary outcomes:
measure: Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs
timeFrame: Time from first dose of study treatment up to 230 days
measure: Part A: Number of Participants With Confirmed Best Overall Response (BOR)
timeFrame: Time from first dose of study treatment up to 230 days
measure: Part A: Progression-Free Survival (PFS)
timeFrame: Time from first dose of study treatment up to 230 days
measure: Part A: Duration of Response (DoR)
timeFrame: Time from first dose of study treatment up to 230 days
measure: Part A: Time to Progression (TTP)
timeFrame: Time from first dose of study treatment up to 230 days
measure: Part A: Time to First Subsequent Therapy (TFST)
timeFrame: From date of randomization to the earliest date of first subsequent therapy or death, assessed up to 230 days
measure: Part A: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-t) of M6620 and Avelumab
timeFrame: 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)
measure: Part A: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M6620 and Avelumab
timeFrame: 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)
measure: Part A: Area Under the Plasma Concentration-Time Curve During a Dosing Interval (AUCtau)
timeFrame: 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)
measure: Part A: Terminal Rate Constant (Lambda z) of M6620 and Avelumab
timeFrame: 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)
measure: Part A: Maximum Observed Plasma Concentration (Cmax) of M6620 and Avelumab
timeFrame: 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)
measure: Part A: Minimum Observed Plasma Concentration (Cmin) of M6620 and Avelumab
timeFrame: 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)
measure: Part A: Time to Reach the Maximum Plasma Concentration (Tmax) of M6620 and Avelumab
timeFrame: 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)
measure: Part A: Apparent Terminal Half-life (t1/2) of M6620 and Avelumab
timeFrame: 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)
Other outcomes:
Locations:
city: Greenbrae
country: United States
facility: Marin Cancer Care, Inc.
state: California
city: Stamford
country: United States
facility: The Stamford Hospital
state: Connecticut
city: Saginaw
country: United States
facility: Covenant Health Care
state: Michigan
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: New York
country: United States
facility: Mount Sinai - PRIME
state: New York
city: Oklahoma City
country: United States
facility: Peggy & Charles Stephenson Oklahoma Cancer Ctr
state: Oklahoma
city: Dallas
country: United States
facility: Mary Crowley Cancer Research Centers
state: Texas
city: Leuven
country: Belgium
facility: UZ Leuven
city: Liège
country: Belgium
facility: CHU Sart Tilman
city: Wilrijk
country: Belgium
facility: GZA Ziekenhuizen - Campus Sint-Augustinus
city: Truro
country: United Kingdom
facility: Royal Cornwall Hospital
state: Cornwall
city: Sutton
country: United Kingdom
facility: Royal Marsden Hospital
state: Surrey
city: London
country: United Kingdom
facility: Royal Marsden Hospital
Study officials:
affiliation: Merck KGaA, Darmstadt, Germany
name: Medical Responsible
role: STUDY_DIRECTOR
References: