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Completed

NCT Number: NCT02915523

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

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.

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Key information

Conditions

Epithelial Ovarian Cancer Adnexal Diseases Carcinoma Carcinoma, Ovarian Epithelial Endocrine Gland Neoplasms Endocrine System Diseases Fallopian Tube Cancer Fallopian Tube Diseases Fallopian Tube Neoplasms Female Urogenital Diseases Female Urogenital Diseases and Pregnancy Complications Genital Diseases Genital Diseases, Female Genital Neoplasms, Female Gonadal Disorders Neoplasms Neoplasms by Histologic Type Neoplasms by Site Neoplasms, Glandular and Epithelial Ovarian Diseases Ovarian Neoplasms Peritoneal Cancer Urogenital Diseases Urogenital Neoplasms

Age range

18 year and older

Sex eligibility

Female

Study type

Interventional

Phase

Phase 1 / Phase 2

Primary location

H. Lee Moffitt Cancer Center and Research, Tampa, Florida, United States

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Entinostat

Drug

An orally available histone deacetylases inhibitor (HDACi).

Other names: SNDX-275, MS-275

Avelumab

Drug

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: MSB0010718C

Placebo

Drug

A pill containing no active drug ingredient.

Primary outcomes

  1. 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)

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

    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.

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

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

    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.

Secondary outcomes

  1. Phase 1b: Recommended Phase 2 Dose (RP2D)

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

    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.

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

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

    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.

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

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

    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.

  4. Phase 2: ORR, as Assessed Using irRECIST

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

    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%.

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

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

    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.

  6. Phase 2: CBR, as Assessed Using irRECIST

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

    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).

  7. Phase 2: Overall Survival

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

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

  8. Phase 2: Duration of Response

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

    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.

  9. Phase 2: Time to Response

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

    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.

  10. 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

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

    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'.

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

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

    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'.

  12. 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])

Sponsors and collaborators

Lead sponsor

Syndax Pharmaceuticals

Industry

Collaborators

  • Merck KGaA, Darmstadt, Germany
  • Pfizer

Registry information

Official study 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

Important dates

Study start
2016
Primary completion
2019
Study completion
2021
First posted
Sep 27, 2016
Registry last updated
Jan 10, 2024

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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