Clinical trial NCT02915523: Study of Avelumab With or Without Entinostat in Participants With Advanced Epithelial Ovarian Cancer
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Epithelial Ovarian Cancer
Peritoneal Cancer
Fallopian Tube Cancer
Keywords: Ovarian Cancer
Histone Deacetylase Inhibitors
Entinostat
Solid tumor
Avelumab
SNDX-275
Ovarian Neoplasms
Ovarian Diseases
Fallopian Tube Cancer
Peritoneal Cancer
Lead sponsor: Syndax Pharmaceuticals
Sponsor class: INDUSTRY
Collaborators: name: Merck KGaA, Darmstadt, Germany
name: Pfizer
First posted: 2016-09-27
Enrollment: 140
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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 participants with refractory or recurrent epithelial ovarian cancer.

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 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.

Eligibility 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
* 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

Primary outcomes:
measure: 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)
timeFrame: From date of randomization to PD or death due to any cause (maximum exposure: 24 cycles [each cycle = 14 days])
measure: Phase 1b: Number of Participants With at Least One Dose Limiting Toxicity (DLT) Adverse Event (AE)
timeFrame: Day 1 through Day 28 (Cycles 1 and 2)
Secondary outcomes:
measure: Phase 1b: Recommended Phase 2 Dose (RP2D)
timeFrame: Day 1 through Day 28 (Cycles 1 and 2)
measure: Phase 2: PFS, as Determined by the Local Investigator Using Immune Response RECIST (irRECIST)
timeFrame: From date of randomization to PD or death due to any cause (maximum exposure: 24 cycles [each cycle = 14 days])
measure: Phase 2: Objective Response Rate (ORR), as Assessed Using RECIST 1.1
timeFrame: From date of randomization to date of progression (maximum exposure: 24 cycles [each cycle = 14 days])
measure: Phase 2: ORR, as Assessed Using irRECIST
timeFrame: From date of randomization to date of progression (maximum exposure: 24 cycles [each cycle = 14 days])
measure: Phase 2: Clinical Benefit Rate (CBR), as Assessed Using RECIST 1.1
timeFrame: From date of randomization to date of progression (maximum exposure: 24 cycles [each cycle = 14 days])
measure: Phase 2: CBR, as Assessed Using irRECIST
timeFrame: From date of randomization to date of progression (maximum exposure: 24 cycle [each cycle = 14 days])
measure: Phase 2: Overall Survival
timeFrame: From date of randomization to the date of death (maximum exposure: 24 cycles [each cycle = 14 days])
measure: Phase 2: Duration of Response
timeFrame: From start date of CR or PR to date of progression (maximum exposure: 24 cycles [each cycle = 14 days])
measure: Phase 2: Time to Response
timeFrame: From the date of randomization to date of PR or CR (maximum exposure: 24 cycles [each cycle = 14 days])
measure: 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
timeFrame: From first dose of study drug up to 30 days after end of treatment (maximum exposure: 24 cycles [each cycle = 14 days])
measure: Phase 2: Number of Participants With TEAEs, SAEs, AEs Resulting in the Permanent Discontinuation of Study Drug, and Death
timeFrame: From first dose of study drug up to 30 days after end of treatment (maximum exposure: 24 cycles [each cycle = 14 days])
measure: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Avelumab When Given in Combination With Entinostat
timeFrame: Pre-dose and post-infusion on Day 1 of Cycle 1 the 30-day follow-up (maximum exposure: 24 cycles [each cycle = 14 days])
Other outcomes:
Locations:
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center and Research
state: Florida
city: West Palm Beach
country: United States
facility: Florida Cancer Specialist East Region (SCRI Affiliate)
state: Florida
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Baltimore
country: United States
facility: Greater Baltimore Medical Center
state: Maryland
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Kansas City
country: United States
facility: HCA Midwest Health (SCRI Affiliate)
state: Missouri
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
Study officials:
affiliation: Syndax Pharmaceuticals
name: Michael Meyers, MD, PhD
role: STUDY_DIRECTOR
affiliation: Dana-Farber Cancer Institute
name: Ursula Matulonis, MD
role: PRINCIPAL_INVESTIGATOR
References: