Phase 1b/2 Study of Avelumab With or Without Entinostat in Patients With Advanced Epithelial Ovarian Cancer

Study Overview
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Brief Summary
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The purpose of this study is to determine the biologically active dose of entinostat, when given in combination with avelumab, that is safe and warrants further investigation. Additionally, this study will evaluate the effectiveness of entinostat in combination with avelumab at the determined dose in terms of progression free survival compared to avelumab plus placebo in patients with refractory or recurrent epithelial ovarian cancer.

Detailed Description
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The study is comprised of 2 phases: an open-label Safety Lead-in (Phase 1b) followed by an Expansion Phase (Phase 2). The Expansion Phase will evaluate the efficacy and safety of entinostat with avelumab when administered at the Recommended Phase 2 Dose (RP2D) versus avelumab alone in patients with advanced epithelial ovarian cancer in a randomized, double-blind, placebo-controlled setting. In Phase 2, patients will be randomized in a 2:1 ratio to receive avelumab plus entinostat or avelumab plus placebo, respectively. All patients will be assessed at Screening and at specified times during the conduct of the study using standard clinical and laboratory assessments. Patients will be assessed for response through radiological assessments. Patients will continue receiving their appropriate cycles of study treatment until tumor progression or adverse events (AEs) occur which necessitate discontinuing therapy as determined by the Investigator.

Official Title
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A Randomized, Placebo-controlled, Double-blind, Multicenter Phase 1b/2 Study of Avelumab With or Without Entinostat in Patients With Advanced Epithelial Ovarian Cancer Which Has Progressed or Recurred After First-line Platinum-based Chemotherapy and at Least Two Subsequent Lines of Treatment With a Safety Lead-in

Conditions
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Peritoneal Cancer, Epithelial Ovarian Cancer, Fallopian Tube Cancer

Intervention / Treatment
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* Drug: entinostat
* Drug: avelumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed epithelial ovarian, fallopian tube, or peritoneal cancer Recurrent or progressive disease on or after initial platinum-based chemotherapy Evidence of measurable disease based on imaging studies within 28 days before the first dose of study drug Previously received at least 3, but no more than 6, lines of therapy including at least 1 course of platinum-based therapy Patient must have acceptable, applicable laboratory requirements Patients may have a history of brain metastasis provided certain protocol criteria are met Experienced resolution of toxic effect(s) of the most recent prior anti-cancer therapy to Grade ≤1 (except alopecia or neuropathy) Able to understand and give written informed consent and comply with study procedures. Exclusion Criteria: Non-epithelial ovarian carcinomas or ovarian tumors with low malignant potential (i.e., borderline tumors) Another known malignancy that is progressing or requires active treatment (excluding adequately treated basal cell carcinoma or cervical intraepithelial neoplasia/cervical carcinoma in situ or melanoma in situ). Prior history of other cancer is allowed, as long as there is no active disease within the prior 5 years. Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to enrollment. Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent Previously treated with a histone deacetylase inhibitor (i.e., vorinostat, belinostat, romidepsin, panobinostat), PD-1/PD-L1-blocking antibody (i.e., atezolizumab, nivolumab, pembrolizumab), or a cytotoxic T-lymphocyte associated protein-4 (CTLA-4) agent Currently enrolled in (or completed) another investigational drug study within 30 days prior to study drug administration A medical condition that precludes adequate study treatment or increases patient risk

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Entinostat plus Avelumab<br>Avelumab is administered intravenously (IV) on Day 1 of each 14-day cycle in combination with Entinostat administration on D1 and D8 of each cycle at the Maximum tolerated Dose (MTD)/RP2D as determined in the Phase Ib (Dose Determination) part of the study. | Drug: entinostat<br>* An orally available histone deacetylases inhibitor (HDACi).<br>* Other names: MS-275;Drug: avelumab<br>* A fully human antibody of the immunoglobulin (Ig) G1 isotype that targets and blocks Programmed death-ligand 1 (PD-L1), the ligand for Programmed cell death protein 1 (PD-1) receptor.<br>* Other names: MSB0010718C;|
| Placebo Comparator: Placebo plus Avelumab<br>Avelumab is administered intravenously (IV) on Day 1 of each 14-day cycle in combination with placebo administered on D1 and D8 of each cycle. | Drug: avelumab<br>* A fully human antibody of the immunoglobulin (Ig) G1 isotype that targets and blocks Programmed death-ligand 1 (PD-L1), the ligand for Programmed cell death protein 1 (PD-1) receptor.<br>* Other names: MSB0010718C;Drug: Placebo<br>* A pill containing no active drug ingredient.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants taking 5 mg entinostat weekly in combination with avelumab with Adverse Events as a Measure of Safety and Tolerability | Phase 1 Dose Determination - Up to 18 patients will be enrolled in this phase of the study which employs a rolling 6 phase 1 design, where six patients must be treated in a dose level and have safety assessed in order to determine the dose-limiting toxicity (DLT) and the MTD and/or RP2D based on entinostat in combination with avelumab | 3 months | 
| Efficacy of entinostat in combination with avelumab at the RP2D versus avelumab plus placebo | An evaluation of the efficacy of entinostat in combination with avelumab at the RP2D versus avelumab plus placebo, as determined by the duration of Progression-free Survival (PFS) by RECIST1.1 | From date of first dose up to 24 months assessed every 6-8 weeks from screening through the end of study (approximately 24 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival | Assessed by immune response RECIST (irRECIST). PFS is defined as the number of months from the date of the first dose of study drug to the earliest of documented PD or death due to any cause without prior progression. | From date of first dose through date of progression, expected to be 24 months | 
| Overall Response Rate [Complete Response (CR) or Partial Response (PR)] | Assessed by RECIST 1.1 and immune response RECIST (irRECIST) every 6-8 weeks | From date of first dose through date of progression, expected to be approximately 12 months | 
| Clinical Benefit Rate [CR or PR, or Stable Disease (SD) for at least 24 weeks] | Assessed by RECIST 1.1 and irRECIST | From date of first dose through date of progression, expected to be approximately 12 months | 
| Overall Survival | Assessed by RECIST 1.1 and irRECIST | Approximately 36 months from date of first dose. Overall survival is defined as the number of months from date of first dose to the date of death (due to any cause). | 
| Duration of Response (in patients who experience best overall response of CR or PR) | Assessed by RECIST 1.1 and irRECIST | From date of first dose through date of progression, expected to be approximately 12 months | 
| Incidence of treatment-emergent adverse events (TEAES), serious adverse events (SAEs), adverse events resulting in the permanent discontinuation of study drug, and deaths | Evaluation of TEAEs & AEs captured in the EDC and of SAEs reported to Pharmacovigilance | 24 months | 
| Change from baseline in laboratory assessments | Compare changes in laboratory assessments noted during treatment to baseline values prior to treatment | 24 months | 
| Time to Response (in patients who experience best overall response of CR or PR) | Assessed by RECIST 1.1 and irRECIST | Approximately 12 months | 
| Cmax (maximum plasma concentration) of avelumab when given in combination with entinostat | Cmax of avelumab will be computed | Pre-dose and post-infusion on Day 1 of Cycles 1 thru 6, then cycles 8, 10, 12, 16, 20, 28, 32, 36, 48, and at the 90-day follow-up (UP TO 24 MONTHS) | 
| Tmax (time of maximum plasma concentration) of avelumab when given in combination with entinostat | Tmax of Avelumab will be computed | Pre-dose and post-infusion on Day 1 of Cycles 1 thru 6, then cycles 8, 10, 12, 16, 20, 28, 32, 36, 48, and at the 90-day follow-up (UP TO 24 MONTHS) | 
| Area under the plasma concentration-time curve from time zero to the last measurable concentration (AUC0-t) of avelumab when given in combination with entinostat | AUC-0 will be computed | Pre-dose and post-infusion on Day 1 of Cycles 1 thru 6, then cycles 8, 10, 12, 16, 20, 28, 32, 36, 48, and at the 90-day follow-up (UP TO 24 MONTHS) | 
| AUC0-inf (area under the plasma concentration-time curve from 0-time extrapolated to infinity) of avelumab when given in combination with entinostat | AUC-0 will be computed | Pre-dose and post-infusion on Day 1 of Cycles 1 thru 6, then cycles 8, 10, 12, 16, 20, 28, 32, 36, 48, and at the 90-day follow-up (UP TO 24 MONTHS) | 
| t1/2 (elimination half-life and apparent plasma terminal phase elimination rate constant) of avelumab when given in combination with entinostat | T1/2 will be computed | Pre-dose and post-infusion on Day 1 of Cycles 1 thru 6, then cycles 8, 10, 12, 16, 20, 28, 32, 36, 48, and at the 90-day follow-up (UP TO 24 MONTHS) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fallopian Tube Cancer, Peritoneal Cancer, Ovarian Cancer, Histone Deacetylase Inhibitors, Entinostat, Solid tumor, Avelumab, SNDX-275, Ovarian Neoplasms, Ovarian Diseases