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

Primary Purpose

Ovarian Cancer

Status

Completed

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

M6620

Avelumab

Carboplatin

About this trial

This is an interventional treatment trial for Ovarian Cancer focused on measuring Avelumab, Carboplatin, Primary Peritoneal Cancer, Fallopian Tube Cancer, Platinum sensitive ovarian cancer, Deoxy ribonucleic acid (DNA)-damage response inhibition

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Part A: Carboplatin + M6620 + Avelumab

Arm Description

Outcomes

Primary Outcome Measures

Part A: Number of Participants With Dose Limiting Toxicities (DLTs)

DLT: any death not clearly due to underlying disease/extraneous causes/Grade(Gr) >=3 nonhematologic/Gr>=4 hematologic toxicity that was probably/definitely related to any of study interventions, individually/combination that occurred during DLT observation period, except for any of following: Gr3 infusion-related reaction; Transient (<=6hr) Gr3 flu-like symptoms/fever, controlled with medical management; Transient (<=72hr) Gr3 fatigue, local reactions, headache, nausea/emesis; Gr3 diarrhea, skin toxicity, liver function test increase; Single laboratory values out of normal range and controlled with medical management; Tumor flare phenomenon: local pain, irritation/rash, localized at sites of known/suspected tumor; Neutropenia (Gr3/4) for <7 days not associated with any infection; Gr3 thrombocytopenia for <7 days without clinically significant bleeding and not requiring platelet transfusion; Symptomatic thyroid dysfunction manageable with treatment.

Secondary Outcome Measures

Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs

An adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A serious AE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs were defined as events that started or worsened after first dose of study intervention until 30 days after last dose. TEAEs included both serious and non-serious AEs. Treatment-related TEAE: reasonably related to the study intervention. The AE could medically (pharmacologically/clinically) be attributed to the study intervention under study in this clinical study protocol.

Part A: Number of Participants With Confirmed Best Overall Response (BOR)

Confirmed BOR according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and as assessed by an Investigator was defined as best response of any of the complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from the date of randomization until disease progression/ recurrence (taking the smallest measurement recorded since the start of treatment as reference). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. SD: Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions and unequivocal progression of non-target lesions. Number of participants with BOR in each category (CR, PR, SD, PD) were reported.

Part A: Progression-Free Survival (PFS)

PFS according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and as assessed by an Investigator was defined as the time from date of randomization until date of the first observation of progressive disease (PD) or death due to any cause within 12 weeks of the last tumor assessment in the absence of documented PD, whichever occurs first. PD was defined as at least a 20% increase in the sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions and unequivocal progression of non-target lesions. Participant wise data reported for this outcome measure.

Part A: Duration of Response (DoR)

DoR according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and as assessed by an Investigator was defined as the time from first documentation of objective response (Complete Response [CR] or Partial Response [PR]) to the date of first documentation of objective progression of disease (PD) or death due to any cause whichever occurs first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions and unequivocal progression of non-target lesions. If a participant has not an event (PD or death), DoR was censored at the date of last adequate tumor assessment.

Part A: Time to Progression (TTP)

TTP according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and assessed by an Investigator was defined as the time from first dose of study intervention until progression disease (PD). PD was defined as at least a 20% increase in the sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions and unequivocal progression of non-target lesions. Participant wise data reported for this outcome measure.

Part A: Time to First Subsequent Therapy (TFST)

The TFST was defined as the time from the date of randomization to the start date of the first subsequent anti-cancer therapy or death.

Part A: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-t) of M6620 and Avelumab

Area under the plasma concentration vs time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was to be calculated according to the mixed log-linear trapezoidal rule.

Part A: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M6620 and Avelumab

AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLOQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.

Part A: Area Under the Plasma Concentration-Time Curve During a Dosing Interval (AUCtau)

AUCtau was defined as area under the plasma concentration-time curve from time zero to the end of the dosing interval (tau). AUCtau was calculated using the mixed log linear trapezoidal rule.

Part A: Terminal Rate Constant (Lambda z) of M6620 and Avelumab

Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.

Part A: Maximum Observed Plasma Concentration (Cmax) of M6620 and Avelumab

Cmax was obtained directly from the concentration versus time curve.

Part A: Minimum Observed Plasma Concentration (Cmin) of M6620 and Avelumab

Cmin was minimum observed plasma concentration obtained directly from the concentration versus time curve.

Part A: Time to Reach the Maximum Plasma Concentration (Tmax) of M6620 and Avelumab

Tmax was obtained directly from the concentration versus time curve.

Part A: Apparent Terminal Half-life (t1/2) of M6620 and Avelumab

t1/2 was the time measured for the concentration to decrease by one half. t1/2 was calculated by natural log 2 divided by Lambda z.

Full Information

NCT ID

NCT03704467

First Posted

October 3, 2018

Last Updated

October 21, 2020

Sponsor

EMD Serono Research & Development Institute, Inc.

Collaborators

Merck KGaA, Darmstadt, Germany

1. Study Identification

Unique Protocol Identification Number

NCT03704467

Brief Title

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

2. Study Status

Record Verification Date

October 2020

Overall Recruitment Status

Completed

Study Start Date

March 4, 2019 (Actual)

Primary Completion Date

November 6, 2019 (Actual)

Study Completion Date

November 6, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

EMD Serono Research & Development Institute, Inc.

Collaborators

Merck KGaA, Darmstadt, Germany

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Ovarian Cancer

Keywords

Avelumab, Carboplatin, Primary Peritoneal Cancer, Fallopian Tube Cancer, Platinum sensitive ovarian cancer, Deoxy ribonucleic acid (DNA)-damage response inhibition

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

3 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Part A: Carboplatin + M6620 + Avelumab

Arm Type

Experimental

Intervention Type

Drug

Intervention Name(s)

M6620

Intervention Description

Participants received 90 milligrams per square meter (mg/m^2) of M6620, 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.

Intervention Type

Drug

Intervention Name(s)

Avelumab

Intervention Description

Participants received 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. Thereafter, avelumab 800 mg intravenously on Day 1 of every two weeks as a maintenance mono-therapy until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death.

Intervention Type

Drug

Intervention Name(s)

Carboplatin

Intervention Description

Participants received 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.

Primary Outcome Measure Information:

Title

Part A: Number of Participants With Dose Limiting Toxicities (DLTs)

Description

Time Frame

Up to 3 weeks

Secondary Outcome Measure Information:

Title

Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs

Description

Time Frame

Time from first dose of study treatment up to 230 days

Title

Part A: Number of Participants With Confirmed Best Overall Response (BOR)

Description

Time Frame

Time from first dose of study treatment up to 230 days

Title

Part A: Progression-Free Survival (PFS)

Description

Time Frame

Time from first dose of study treatment up to 230 days

Title

Part A: Duration of Response (DoR)

Description

Time Frame

Time from first dose of study treatment up to 230 days

Title

Part A: Time to Progression (TTP)

Description

Time Frame

Time from first dose of study treatment up to 230 days

Title

Part A: Time to First Subsequent Therapy (TFST)

Description

The TFST was defined as the time from the date of randomization to the start date of the first subsequent anti-cancer therapy or death.

Time Frame

From date of randomization to the earliest date of first subsequent therapy or death, assessed up to 230 days

Title

Part A: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-t) of M6620 and Avelumab

Description

Time Frame