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

Ovarian Cancer Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03704467
• Other study ID #: MS201943_0029
• Secondary ID: 2018-001534-17
• Status: Completed
• Phase: Phase 1
• Start date: March 4, 2019
• Est. completion date: November 6, 2019

Study information

• Verified date: October 2020
• Source: EMD Serono
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 3
• Est. completion date: November 6, 2019
• Est. primary completion date: November 6, 2019
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Carcinoma, Ovarian Epithelial
• Ovarian Cancer
• Ovarian Neoplasms

Intervention

Drug:
• M6620
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.
• Avelumab
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.
• Carboplatin
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.

Locations

Country	Name	City	State
Belgium	UZ Leuven	Leuven
Belgium	CHU Sart Tilman	Liège
Belgium	GZA Ziekenhuizen - Campus Sint-Augustinus	Wilrijk
United Kingdom	Royal Marsden Hospital	London
United Kingdom	Royal Marsden Hospital	Sutton	Surrey
United Kingdom	Royal Cornwall Hospital	Truro	Cornwall
United States	Mary Crowley Cancer Research Centers	Dallas	Texas
United States	Marin Cancer Care, Inc.	Greenbrae	California
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Mount Sinai - PRIME	New York	New York
United States	Peggy & Charles Stephenson Oklahoma Cancer Ctr	Oklahoma City	Oklahoma
United States	Covenant Health Care	Saginaw	Michigan
United States	The Stamford Hospital	Stamford	Connecticut

Sponsors (2)

Lead Sponsor	Collaborator
EMD Serono Research & Development Institute, Inc.	Merck KGaA, Darmstadt, Germany

Countries where clinical trial is conducted

United States,  Belgium,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	Up to 3 weeks
Secondary	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.	Time from first dose of study treatment up to 230 days
Secondary	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.	Time from first dose of study treatment up to 230 days
Secondary	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.	Time from first dose of study treatment up to 230 days
Secondary	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.	Time from first dose of study treatment up to 230 days
Secondary	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.	Time from first dose of study treatment up to 230 days
Secondary	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.	From date of randomization to the earliest date of first subsequent therapy or death, assessed up to 230 days
Secondary	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.	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)
Secondary	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.	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)
Secondary	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.	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)
Secondary	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.	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)
Secondary	Part A: Maximum Observed Plasma Concentration (Cmax) of M6620 and Avelumab	Cmax was obtained directly from the concentration versus time curve.	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)
Secondary	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.	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)
Secondary	Part A: Time to Reach the Maximum Plasma Concentration (Tmax) of M6620 and Avelumab	Tmax was obtained directly from the concentration versus time curve.	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)
Secondary	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.	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)

External Links

•   Trial Awareness and Transparency website
•   US Medical Information website, Medical Resources