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

Primary Purpose

Epithelial Ovarian Cancer, Peritoneal Cancer, Fallopian Tube Cancer

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
entinostat
avelumab
Placebo
Sponsored by
Syndax Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Epithelial Ovarian Cancer focused on measuring Ovarian Cancer, Histone Deacetylase Inhibitors, Entinostat, Solid tumor, Avelumab, SNDX-275, Ovarian Neoplasms, Ovarian Diseases, Fallopian Tube Cancer, Peritoneal Cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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

Sites / Locations

  • H. Lee Moffitt Cancer Center and Research
  • Florida Cancer Specialist East Region (SCRI Affiliate)
  • University of Chicago
  • Greater Baltimore Medical Center
  • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University
  • Massachusetts General Hospital
  • Dana Farber Cancer Institute
  • HCA Midwest Health (SCRI Affiliate)
  • Memorial Sloan Kettering Cancer Center
  • University of Pennsylvania
  • Sarah Cannon Research Institute
  • University of Virginia

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Entinostat plus Avelumab

Placebo plus Avelumab

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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
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

Secondary Outcome Measures

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.
Overall Response Rate [Complete Response (CR) or Partial Response (PR)]
Assessed by RECIST 1.1 and immune response RECIST (irRECIST) every 6-8 weeks
Clinical Benefit Rate [CR or PR, or Stable Disease (SD) for at least 24 weeks]
Assessed by RECIST 1.1 and irRECIST
Overall Survival
Assessed by RECIST 1.1 and irRECIST
Duration of Response (in patients who experience best overall response of CR or PR)
Assessed by RECIST 1.1 and irRECIST
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
Change from baseline in laboratory assessments
Compare changes in laboratory assessments noted during treatment to baseline values prior to treatment
Time to Response (in patients who experience best overall response of CR or PR)
Assessed by RECIST 1.1 and irRECIST
Cmax (maximum plasma concentration) of avelumab when given in combination with entinostat
Cmax of avelumab will be computed
Tmax (time of maximum plasma concentration) of avelumab when given in combination with entinostat
Tmax of Avelumab will be computed
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
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
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

Full Information

First Posted
September 14, 2016
Last Updated
August 17, 2022
Sponsor
Syndax Pharmaceuticals
Collaborators
Merck KGaA, Darmstadt, Germany, Pfizer
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1. Study Identification

Unique Protocol Identification Number
NCT02915523
Brief Title
Phase 1b/2 Study of Avelumab With or Without Entinostat in Patients 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

2. Study Status

Record Verification Date
August 2022
Overall Recruitment Status
Completed
Study Start Date
January 10, 2017 (Actual)
Primary Completion Date
February 21, 2019 (Actual)
Study Completion Date
April 21, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Syndax Pharmaceuticals
Collaborators
Merck KGaA, Darmstadt, Germany, Pfizer

4. Oversight

Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
140 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Entinostat plus Avelumab
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Placebo plus Avelumab
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
entinostat
Other Intervention Name(s)
SNDX-275, MS-275
Intervention Description
An orally available histone deacetylases inhibitor (HDACi).
Intervention Type
Drug
Intervention Name(s)
avelumab
Other Intervention Name(s)
MSB0010718C
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
A pill containing no active drug ingredient.
Primary Outcome Measure Information:
Title
Number of Participants taking 5 mg entinostat weekly in combination with avelumab with Adverse Events as a Measure of Safety and Tolerability
Description
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
Time Frame
3 months
Title
Efficacy of entinostat in combination with avelumab at the RP2D versus avelumab plus placebo
Description
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
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)
Secondary Outcome Measure Information:
Title
Progression-free survival
Description
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.
Time Frame
From date of first dose through date of progression, expected to be 24 months
Title
Overall Response Rate [Complete Response (CR) or Partial Response (PR)]
Description
Assessed by RECIST 1.1 and immune response RECIST (irRECIST) every 6-8 weeks
Time Frame
From date of first dose through date of progression, expected to be approximately 12 months
Title
Clinical Benefit Rate [CR or PR, or Stable Disease (SD) for at least 24 weeks]
Description
Assessed by RECIST 1.1 and irRECIST
Time Frame
From date of first dose through date of progression, expected to be approximately 12 months
Title
Overall Survival
Description
Assessed by RECIST 1.1 and irRECIST
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).
Title
Duration of Response (in patients who experience best overall response of CR or PR)
Description
Assessed by RECIST 1.1 and irRECIST
Time Frame
From date of first dose through date of progression, expected to be approximately 12 months
Title
Incidence of treatment-emergent adverse events (TEAES), serious adverse events (SAEs), adverse events resulting in the permanent discontinuation of study drug, and deaths
Description
Evaluation of TEAEs & AEs captured in the EDC and of SAEs reported to Pharmacovigilance
Time Frame
24 months
Title
Change from baseline in laboratory assessments
Description
Compare changes in laboratory assessments noted during treatment to baseline values prior to treatment
Time Frame
24 months
Title
Time to Response (in patients who experience best overall response of CR or PR)
Description
Assessed by RECIST 1.1 and irRECIST
Time Frame
Approximately 12 months
Title
Cmax (maximum plasma concentration) of avelumab when given in combination with entinostat
Description
Cmax of avelumab will be computed
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)
Title
Tmax (time of maximum plasma concentration) of avelumab when given in combination with entinostat
Description
Tmax of Avelumab will be computed
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)
Title
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
Description
AUC-0 will be computed
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)
Title
AUC0-inf (area under the plasma concentration-time curve from 0-time extrapolated to infinity) of avelumab when given in combination with entinostat
Description
AUC-0 will be computed
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)
Title
t1/2 (elimination half-life and apparent plasma terminal phase elimination rate constant) of avelumab when given in combination with entinostat
Description
T1/2 will be computed
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)

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Michael Meyers, MD, PhD
Organizational Affiliation
Syndax Pharmaceuticals
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Ursula Matulonis, MD
Organizational Affiliation
Dana-Farber Cancer Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
H. Lee Moffitt Cancer Center and Research
City
Tampa
State/Province
Florida
ZIP/Postal Code
33612
Country
United States
Facility Name
Florida Cancer Specialist East Region (SCRI Affiliate)
City
West Palm Beach
State/Province
Florida
ZIP/Postal Code
33401
Country
United States
Facility Name
University of Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
Facility Name
Greater Baltimore Medical Center
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21204
Country
United States
Facility Name
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Dana Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
HCA Midwest Health (SCRI Affiliate)
City
Kansas City
State/Province
Missouri
ZIP/Postal Code
64131
Country
United States
Facility Name
Memorial Sloan Kettering Cancer Center
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
University of Pennsylvania
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19107
Country
United States
Facility Name
Sarah Cannon Research Institute
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37204
Country
United States
Facility Name
University of Virginia
City
Charlottesville
State/Province
Virginia
ZIP/Postal Code
22908
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing 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.

Learn more about this trial

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

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