Study of Avelumab With or Without Entinostat in Participants With Advanced Epithelial Ovarian Cancer

Syndax Pharmaceuticals140 enrolled

Overview

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 participants with refractory or recurrent epithelial ovarian cancer.

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 participants with advanced epithelial ovarian cancer in a randomized, double-blind, placebo-controlled setting. In Phase 2, participants will be randomized in a 2:1 ratio to receive avelumab plus entinostat or avelumab plus placebo, respectively. All participants will be assessed at Screening and at specified times during the conduct of the study using standard clinical and laboratory assessments. Participants will be assessed for response through radiological assessments. Participants 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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

140

Conditions

Epithelial Ovarian Cancer

Interventions

entinostatDRUG

An orally available histone deacetylases inhibitor (HDACi).

avelumabDRUG

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.

PlaceboDRUG

A pill containing no active drug ingredient.

Eligibility

Sex: FEMALEMin age: 18 Years

Medical Language ↔ Plain English

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 * Participant must have acceptable, applicable laboratory requirements * Participants 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 participant risk

Locations (12)

H. Lee Moffitt Cancer Center and Research

Tampa, Florida, United States

Florida Cancer Specialist East Region (SCRI Affiliate)

West Palm Beach, Florida, United States

University of Chicago

Chicago, Illinois, United States

Greater Baltimore Medical Center

Baltimore, Maryland, United States

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University

Baltimore, Maryland, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Dana Farber Cancer Institute

Boston, Massachusetts, United States

HCA Midwest Health (SCRI Affiliate)

Kansas City, Missouri, United States

Memorial Sloan Kettering Cancer Center

New York, New York, United States

University of Pennsylvania

Philadelphia, Pennsylvania, United States

...and 2 more locations

Outcomes

Primary Outcomes

Phase 2: Progression Free Survival (PFS), as Determined by the Local Investigator Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

PFS was defined as the number of months from randomization to progressive disease (PD) or death due to any cause, whichever occurred first. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeters (mm); the appearance of one or more new lesions; and unequivocal progression of existing non-target lesions.

Time frame: From date of randomization to PD or death due to any cause (maximum exposure: 24 cycles [each cycle = 14 days])

Phase 1b: Number of Participants With at Least One Dose Limiting Toxicity (DLT) Adverse Event (AE)

A DLT was defined as the occurrence of any protocol-specified event within the first 2 cycles of treatment (from Cycle 1 Day 1 through the end of Cycle 2) of entinostat in combination with avelumab that were considered by the investigator to be at least possibly related to study drug.

Time frame: Day 1 through Day 28 (Cycles 1 and 2)

Secondary Outcomes

Phase 1b: Recommended Phase 2 Dose (RP2D)

The RP2D was determined in discussion with the Sponsor, Medical Monitor, and Dose Determination Phase Investigators. Additionally, observations related to immune correlates, and any cumulative toxicity observed after multiple cycles might be included in the rationale supporting the RP2D. The RP2D could be equal to or less than the preliminary maximum tolerated dose (MTD). The MTD was defined as the highest dose level at which \<33% of 6 participants experienced DLT.

Time frame: Day 1 through Day 28 (Cycles 1 and 2)

Phase 2: PFS, as Determined by the Local Investigator Using Immune Response RECIST (irRECIST)

PFS was defined as the number of months from randomization to PD or death due to any cause, whichever occurred first. PD: Sum of the diameters (longest for non-nodal lesions, shortest for nodal lesions) of target and new measurable lesions increases ≥20% (compared to nadir), confirmed by a repeat, consecutive observation at least 4 weeks from the date first documented.

Time frame: From date of randomization to PD or death due to any cause (maximum exposure: 24 cycles [each cycle = 14 days])

Phase 2: Objective Response Rate (ORR), as Assessed Using RECIST 1.1

The ORR was defined as the percentage of participants with confirmed complete response (CR) or partial response (PR). CR: Disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Disappearance of all non-target lesions and normalisation of tumour marker level. All lymph nodes must be non-pathological in size (\<10 mm short axis). PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Time frame: From date of randomization to date of progression (maximum exposure: 24 cycles [each cycle = 14 days])

Phase 2: ORR, as Assessed Using irRECIST

The ORR was defined as the percentage of participants with confirmed CR or PR. CR: Complete disappearance of all lesions (whether measurable or not) and no new lesions. All measurable lymph nodes also must have a reduction in short axis to \<10 mm. PR: Sum of the diameters (longest for non-nodal lesions, shortest for nodal lesions) of target and new measurable lesions decreases ≥30%.

Time frame: From date of randomization to date of progression (maximum exposure: 24 cycles [each cycle = 14 days])

Phase 2: Clinical Benefit Rate (CBR), as Assessed Using RECIST 1.1

The CBR was defined as the percentage of participants with a confirmed CR, PR, or stable disease (SD) lasting for at least 6 months. CR: Disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Disappearance of all non-target lesions and normalisation of tumour marker level. All lymph nodes must be non-pathological in size (\<10 mm short axis). PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

Time frame: From date of randomization to date of progression (maximum exposure: 24 cycles [each cycle = 14 days])

Phase 2: CBR, as Assessed Using irRECIST

The CBR was defined as the percentage of participants with a confirmed CR, PR, or SD lasting for at least 6 months. CR: Complete disappearance of all lesions (whether measurable or not) and no new lesions. All measurable lymph nodes also must have a reduction in short axis to \<10 mm. PR: Sum of the diameters (longest for non-nodal lesions, shortest for nodal lesions) of target and new measurable lesions decreases ≥30%. SD: Sum of the diameters (longest for nonnodal lesions, shortest for nodal lesions) of target and new measurable lesions neither CR, PR, (compared to baseline) or PD (compared to nadir).

Time frame: From date of randomization to date of progression (maximum exposure: 24 cycle [each cycle = 14 days])

Phase 2: Overall Survival

Overall survival was defined as the number of months from randomization to the date of death (due to any cause).

Time frame: From date of randomization to the date of death (maximum exposure: 24 cycles [each cycle = 14 days])

Phase 2: Duration of Response

Duration of response was defined as the number of months from the start date of PR or CR (whichever response occurred first) and subsequently confirmed, to the first date that recurrent or progressive disease was documented. CR: Disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Disappearance of all non-target lesions and normalisation of tumour marker level. All lymph nodes must be non-pathological in size (\<10 mm short axis). PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study .In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm; the appearance of one or more new lesions; and unequivocal progression of existing non-target lesions.

Time frame: From start date of CR or PR to date of progression (maximum exposure: 24 cycles [each cycle = 14 days])

Phase 2: Time to Response

Time to response was defined as the number of months from the randomization date to the first date the participant achieved a PR or CR (whichever response occurred first and was subsequently confirmed). CR: Disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Disappearance of all non-target lesions and normalisation of tumour marker level. All lymph nodes must be non-pathological in size (\<10 mm short axis). PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Time frame: From the date of randomization to date of PR or CR (maximum exposure: 24 cycles [each cycle = 14 days])

Phase 1b: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), AEs Resulting in the Permanent Discontinuation of Study Drug, and Death

An adverse event (AE) was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. SAEs included death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized the participant and required medical intervention to prevent 1 of the outcomes listed in this definition. TEAEs were defined as AEs that started on or after the first administration of study drug and within 30 days of the last administration of any study treatment. A summary of serious and non-serious AEs regardless of causality is located in 'Reported Adverse Events module'.

Time frame: From first dose of study drug up to 30 days after end of treatment (maximum exposure: 24 cycles [each cycle = 14 days])

Phase 2: Number of Participants With TEAEs, SAEs, AEs Resulting in the Permanent Discontinuation of Study Drug, and Death

An AE was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. SAEs included death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized the participant and required medical intervention to prevent 1 of the outcomes listed in this definition. TEAEs were defined as AEs that started on or after the first administration of study drug and within 30 days of the last administration of any study treatment. A summary of serious and non-serious AEs regardless of causality is located in 'Reported Adverse Events module'.

Time frame: From first dose of study drug up to 30 days after end of treatment (maximum exposure: 24 cycles [each cycle = 14 days])

Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Avelumab When Given in Combination With Entinostat

Time frame: Pre-dose and post-infusion on Day 1 of Cycle 1 the 30-day follow-up (maximum exposure: 24 cycles [each cycle = 14 days])