Continuation Study of Entinostat in Combination With Pembrolizumab in Patients With Advanced Solid Tumors

A Phase 1, Randomized, Open-Label, Continuation Study of Entinostat in Combination With Pembrolizumab in Patients With Advanced Solid Tumors (SNDX-275-0141, MK3475-460/KEYNOTE-460)

The objectives of this study are to explore different dosing levels and schedules of entinostat in combination with pembrolizumab in patients with advanced solid tumors, in terms of safety, tolerability, pharmacokinetics (PK), impact on immune correlatives, and efficacy

Study Overview

• Status: Completed
• Conditions: Neoplasms; Neoplasms by Histologic Type; Lung Diseases; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Endocrine Gland Neoplasms; Breast Diseases; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Bronchial Neoplasms; Solid Tumors; Renal Neoplasm
• Intervention / Treatment: Drug: Entinostat; Drug: Pembrolizumab

Detailed Description

This is a Phase 1, open-label, single center, randomized study to assess the safety and tolerability of 3 different dose regimens of entinostat in combination with pembrolizumab in patients with advanced solid tumors who previously completed Study SNDX-275-0140 (NCT02897778). Up to 30 patients will be randomized in a 1:1:1 fashion to one of three arms. In the event that greater than or equal to 2 out of the first 6 patients randomized experience a dose-limiting toxicity, the next patient randomized to that Arm will receive treatment at a reduced starting dose as outlined in the protocol.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • San Antonio, Texas, United States, 78229
      • The START Center for Cancer Care

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Completed Study SNDX-275-0140 (NCT02897778)
2. Any AE or toxicity experienced in Study SNDX-275-0140 (NCT02897778) is resolved to less than or equal to Grade 1
3. Continues to meet inclusion criteria for Study SNDX-275-0140 (NCT02897778) at the time of entry into this study

Exclusion Criteria:

1. Completed Study SNDX-275-0140 (NCT02897778) more than 30 days prior to Cycle 1 Day 1 of this study
2. Continues to meet exclusion criteria for Study SNDX-275-0140 (NCT02897778) at the time of entry into this study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: ENT 1mg daily with pembro every 3 weeks; Entinostat daily in combination with pembrolizumab every three weeks	Drug: Entinostat; HDAC (histone deacetylase) inhibitor; Other Names: MS-275; SNDX-275; Drug: Pembrolizumab; A selective humanized monoclonal antibody (mAb); Other Names: Keytruda; MK-3475; SCH-900475
Active Comparator: ENT 5mg weekly with pembro every 3 weeks; Entinostat once weekly in combination with pembrolizumab every three weeks	Drug: Entinostat; HDAC (histone deacetylase) inhibitor; Other Names: MS-275; SNDX-275; Drug: Pembrolizumab; A selective humanized monoclonal antibody (mAb); Other Names: Keytruda; MK-3475; SCH-900475
Active Comparator: ENT 10mg bi-weekly with pembro every 3 weeks; Entinostat once every other week in combination with pembrolizumab every three weeks	Drug: Entinostat; HDAC (histone deacetylase) inhibitor; Other Names: MS-275; SNDX-275; Drug: Pembrolizumab; A selective humanized monoclonal antibody (mAb); Other Names: Keytruda; MK-3475; SCH-900475

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse events (AEs) resulting in the permanent discontinuation of study drug, and deaths occurring within the reporting period required for the study	Each treatment cycle is 21 days. All events will be collected from informed consent through 90 days post-last dose or through 30 days after initiation of new anti-cancer therapy
Changes from baseline in laboratory results	Baseline through 90 day safety follow-up visit
Changes from baseline in vital signs	Baseline through 90 day safety follow-up visit
Changes from baseline in ECG results	Baseline through 90 day safety follow-up visit

Secondary Outcome Measures

Outcome Measure	Time Frame
AUC0-t (area under the curve to last observed concentration time) of entinostat when given in combination with pembrolizumab	Pre-dose through Cycle 3 Day 1
AUC0-inf (area under the curve extrapolated to infinity) of entinostat when given in combination with pembrolizumab	Pre-dose through Cycle 3 Day 1
Cmax (maximum plasma concentration) of entinostat when given in combination with pembrolizumab	Pre-dose through Cycle 3 Day 1
Tmax (time to maximum plasma concentration) of entinostat when given in combination with pembrolizumab	Pre-dose through Cycle 3 Day 1
T1/2 (elimination half life) of entinostat when given in combination with pembrolizumab	Pre-dose through Cycle 3 Day 1
Vd (clearance and volume of distribution) of entinostat when given in combination with pembrolizumab	Pre-dose through Cycle 3 Day 1

Other Outcome Measures

Outcome Measure	Time Frame
Ratio of effector T cells to regulatory T cells in blood pre-therapy and post-therapy	Pre-dose through Cycle 3 Day 1
Changes in the number of circulating immune related cells	Pre-dose through Cycle 3 Day 1
Changes in protein lysine acetylation in peripheral blood cells pre-therapy and post-therapy	Pre-dose through Cycle 3 Day 1
Best overall tumor response	Baseline up to 2 years

Collaborators and Investigators

• Sponsor: Syndax Pharmaceuticals
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Study Director: Michael Meyers, MD, PhD, Syndax Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): September 20, 2016
• Primary Completion (Actual): July 17, 2019
• Study Completion (Actual): February 9, 2021

Study Registration Dates

• First Submitted: September 13, 2016
• First Submitted That Met QC Criteria: September 16, 2016
• First Posted (Estimate): September 21, 2016

Study Record Updates

• Last Update Posted (Actual): January 25, 2022
• Last Update Submitted That Met QC Criteria: January 24, 2022
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Keywords: solid tumor; pembrolizumab; entinostat; Histone Deacetylase Inhibitor
• Additional Relevant MeSH Terms: Digestive System Diseases; Skin Diseases; Respiratory Tract Diseases; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Endocrine System Diseases; Gastrointestinal Diseases; Bronchial Diseases; Carcinoma, Bronchogenic; Neoplasms; Kidney Neoplasms; Lung Diseases; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Gastrointestinal Neoplasms; Digestive System Neoplasms; Breast Diseases; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Endocrine Gland Neoplasms; Thoracic Neoplasms; Bronchial Neoplasms; Respiratory Tract Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Histone Deacetylase Inhibitors; Pembrolizumab; Entinostat
• Other Study ID Numbers: SNDX-275-0141

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: Data will be reviewed throughout the study by the sponsor, clinical research organization assisting with SAE management, and routine monitoring to safeguard the interests of the trial patients and to assess the safety of the interventions administered during the trial.