Phase 1b/2 Study of Avelumab With or Without Entinostat in Patients With Advanced Epithelial Ovarian Cancer
Study Details
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 |
|---|---|---|
|
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
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:
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 Names:
|
| 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 Names:
Drug: Placebo
A pill containing no active drug ingredient.
|
Outcome Measures
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 [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
- Efficacy of entinostat in combination with avelumab at the RP2D versus avelumab plus placebo [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
- Progression-free survival [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.
- Overall Response Rate [Complete Response (CR) or Partial Response (PR)] [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
- Clinical Benefit Rate [CR or PR, or Stable Disease (SD) for at least 24 weeks] [From date of first dose through date of progression, expected to be approximately 12 months]
Assessed by RECIST 1.1 and irRECIST
- Overall Survival [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
- Duration of Response (in patients who experience best overall response of CR or PR) [From date of first dose through date of progression, expected to be approximately 12 months]
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 [24 months]
Evaluation of TEAEs & AEs captured in the EDC and of SAEs reported to Pharmacovigilance
- Change from baseline in laboratory assessments [24 months]
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) [Approximately 12 months]
Assessed by RECIST 1.1 and irRECIST
- Cmax (maximum plasma concentration) of avelumab when given in combination with entinostat [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
- Tmax (time of maximum plasma concentration) of avelumab when given in combination with entinostat [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
- 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 [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
- AUC0-inf (area under the plasma concentration-time curve from 0-time extrapolated to infinity) of avelumab when given in combination with entinostat [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
- t1/2 (elimination half-life and apparent plasma terminal phase elimination rate constant) of avelumab when given in combination with entinostat [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
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
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Patient must have acceptable, applicable laboratory requirements
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Patients may have a history of brain metastasis provided certain protocol criteria are met
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Experienced resolution of toxic effect(s) of the most recent prior anti-cancer therapy to Grade ≤1 (except alopecia or neuropathy)
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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.
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Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to enrollment.
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Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent
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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
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A medical condition that precludes adequate study treatment or increases patient risk
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | H. Lee Moffitt Cancer Center and Research | Tampa | Florida | United States | 33612 |
| 2 | Florida Cancer Specialist East Region (SCRI Affiliate) | West Palm Beach | Florida | United States | 33401 |
| 3 | University of Chicago | Chicago | Illinois | United States | 60637 |
| 4 | Greater Baltimore Medical Center | Baltimore | Maryland | United States | 21204 |
| 5 | Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University | Baltimore | Maryland | United States | 21287 |
| 6 | Massachusetts General Hospital | Boston | Massachusetts | United States | 02114 |
| 7 | Dana Farber Cancer Institute | Boston | Massachusetts | United States | 02215 |
| 8 | HCA Midwest Health (SCRI Affiliate) | Kansas City | Missouri | United States | 64131 |
| 9 | Memorial Sloan Kettering Cancer Center | New York | New York | United States | 10065 |
| 10 | University of Pennsylvania | Philadelphia | Pennsylvania | United States | 19107 |
| 11 | Sarah Cannon Research Institute | Nashville | Tennessee | United States | 37204 |
| 12 | 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, Inc.
- Principal Investigator: Ursula Matulonis, MD, Dana-Farber Cancer Institute
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- SNDX-275-0603