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

• ClinicalTrials.gov Identifier: NCT02915523
• Recruitment Status: Completed
• First Posted: September 27, 2016
• Last Update Posted: August 22, 2022
• Sponsor: Syndax Pharmaceuticals
• Collaborators: Merck KGaA, Darmstadt, Germany; Pfizer
• Information provided by (Responsible Party): Syndax Pharmaceuticals

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Epithelial Ovarian Cancer; Peritoneal Cancer; Fallopian Tube Cancer	Drug: entinostat; Drug: avelumab; Drug: Placebo	Phase 1; Phase 2

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 140 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: January 10, 2017
• Actual Primary Completion Date: February 21, 2019
• Actual Study Completion Date: April 21, 2021

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Entinostat plus Avelumab; 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; An orally available histone deacetylases inhibitor (HDACi).; Other Names: SNDX-275; MS-275; Drug: avelumab; 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.; Other Name: MSB0010718C
Placebo Comparator: Placebo plus Avelumab; 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; 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.; Other Name: MSB0010718C; Drug: Placebo; A pill containing no active drug ingredient.

Outcome Measures

Primary Outcome Measures :

1. Number of Participants taking 5 mg entinostat weekly in combination with avelumab with Adverse Events as a Measure of Safety and Tolerability [ Time Frame: 3 months ]
   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
2. Efficacy of entinostat in combination with avelumab at the RP2D versus avelumab plus placebo [ Time Frame: From date of first dose up to 24 months assessed every 6-8 weeks from screening through the end of study (approximately 24 months) ]
   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

Secondary Outcome Measures :

1. Progression-free survival [ Time Frame: From date of first dose through date of progression, expected to be 24 months ]
   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.
2. Overall Response Rate [Complete Response (CR) or Partial Response (PR)] [ Time Frame: From date of first dose through date of progression, expected to be approximately 12 months ]
   Assessed by RECIST 1.1 and immune response RECIST (irRECIST) every 6-8 weeks
3. Clinical Benefit Rate [CR or PR, or Stable Disease (SD) for at least 24 weeks] [ Time Frame: From date of first dose through date of progression, expected to be approximately 12 months ]
   Assessed by RECIST 1.1 and irRECIST
4. Overall Survival [ Time Frame: 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). ]
   Assessed by RECIST 1.1 and irRECIST
5. Duration of Response (in patients who experience best overall response of CR or PR) [ Time Frame: From date of first dose through date of progression, expected to be approximately 12 months ]
   Assessed by RECIST 1.1 and irRECIST
6. Incidence of treatment-emergent adverse events (TEAES), serious adverse events (SAEs), adverse events resulting in the permanent discontinuation of study drug, and deaths [ Time Frame: 24 months ]
   Evaluation of TEAEs & AEs captured in the EDC and of SAEs reported to Pharmacovigilance
7. Change from baseline in laboratory assessments [ Time Frame: 24 months ]
   Compare changes in laboratory assessments noted during treatment to baseline values prior to treatment
8. Time to Response (in patients who experience best overall response of CR or PR) [ Time Frame: Approximately 12 months ]
   Assessed by RECIST 1.1 and irRECIST
9. Cmax (maximum plasma concentration) of avelumab when given in combination with entinostat [ Time Frame: 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) ]
   Cmax of avelumab will be computed
10. Tmax (time of maximum plasma concentration) of avelumab when given in combination with entinostat [ Time Frame: 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 of Avelumab will be computed
11. 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 [ Time Frame: 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) ]
    AUC-0 will be computed
12. AUC0-inf (area under the plasma concentration-time curve from 0-time extrapolated to infinity) of avelumab when given in combination with entinostat [ Time Frame: 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) ]
    AUC-0 will be computed
13. t1/2 (elimination half-life and apparent plasma terminal phase elimination rate constant) of avelumab when given in combination with entinostat [ Time Frame: 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 will be computed

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, Florida

H. Lee Moffitt Cancer Center and Research

Tampa, Florida, United States, 33612

Florida Cancer Specialist East Region (SCRI Affiliate)

West Palm Beach, Florida, United States, 33401

United States, Illinois

University of Chicago

Chicago, Illinois, United States, 60637

United States, Maryland

Greater Baltimore Medical Center

Baltimore, Maryland, United States, 21204

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University

Baltimore, Maryland, United States, 21287

United States, Massachusetts

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114

Dana Farber Cancer Institute

Boston, Massachusetts, United States, 02215

United States, Missouri

HCA Midwest Health (SCRI Affiliate)

Kansas City, Missouri, United States, 64131

United States, New York

Memorial Sloan Kettering Cancer Center

New York, New York, United States, 10065

United States, Pennsylvania

University of Pennsylvania

Philadelphia, Pennsylvania, United States, 19107

United States, Tennessee

Sarah Cannon Research Institute

Nashville, Tennessee, United States, 37204

United States, Virginia

University of Virginia

Charlottesville, Virginia, United States, 22908

Sponsors and Collaborators

Syndax Pharmaceuticals

Merck KGaA, Darmstadt, Germany

Pfizer

Investigators

• Study Director: Michael Meyers, MD, PhD; Syndax Pharmaceuticals
• Principal Investigator: Ursula Matulonis, MD; Dana-Farber Cancer Institute

More Information

• Responsible Party: Syndax Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02915523
• Other Study ID Numbers: SNDX-275-0603
• First Posted: September 27, 2016
• Last Update Posted: August 22, 2022
• Last Verified: August 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: An independent data safety monitoring board (DSMB) will be established for the Phase 2 portion of this study to act in an advisory capacity to the Sponsor with respect to safeguarding the interests of trial patients and assessing the safety of the interventions administered during the trial.

Keywords provided by Syndax Pharmaceuticals:

Ovarian Cancer; Histone Deacetylase Inhibitors; Entinostat; Solid tumor; Avelumab; SNDX-275; Ovarian Neoplasms; Ovarian Diseases; Fallopian Tube Cancer; Peritoneal Cancer

Additional relevant MeSH terms:

Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Fallopian Tube Neoplasms; Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Endocrine System Diseases; Gonadal Disorders; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Fallopian Tube Diseases; Avelumab; Entinostat; Antineoplastic Agents, Immunological; Antineoplastic Agents; Histone Deacetylase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action