Ph1b/2 Dose-Escalation Study of Entinostat With Pembrolizumab in Non-small Cell Lung Cancer (NSCLC) With Expansion Cohorts in NSCLC, Melanoma, and Colorectal Cancer (CRC)

NCT02437136 | Completed Phase 1 Results

• 2 other identifiers: SNDX-275-0601KN 142
• Study Type: interventional
• Target: 191
• Locations: 1 country
• Sites: 11

Brief Summary

The purpose of this study is to determine the safety and tolerability of entinostat used in combination with pembrolizumab in participants with NSCLC. Additionally, the purpose of the study is to assess how effective entinostat and pembrolizumab are in combination in participants with NSCLC, Melanoma, and Mismatch-Repair Proficient CRC.

Conditions

Non-Small Cell Lung Cancer; Melanoma; Mismatch Repair-Proficient Colorectal Cancer

Outcome Measures

Primary Outcomes (1)

• Phase 2: Objective Response Rate (ORR), as Assessed Using Immune Response RECIST (irRECIST)

  The ORR was defined as the percentage of participants with confirmed complete response (CR) or partial response (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 millimeters (mm). PR: Sum of the diameters (longest for non-nodal lesions, shortest for nodal lesions) of target and new measurable lesions decreases ≥30%. For purposes of analysis, 1 month was considered to be 30.4375 days.

  From date of randomization to date of progression (up to 765 days)

Secondary Outcomes (14)

• Phase 2: Clinical Benefit Rate (CBR), as Assessed Using irRECIST

  6 months

• Phase 2: CBR, as Assessed Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

  6 months

• Phase 2: Progression Free Survival (PFS), as Assessed Using irRECIST

  6 months

• Phase 2: PFS, as Assessed Using RECIST 1.1

  6 months

• Phase 2: PFS Duration, as Determined by the Local Investigator Using irRECIST

  From date of randomization to PD or death due to any cause (up to 765 days)

Study Arms (7)

Phase 1b (Dose Escalation): Entinostat 3 mg Weekly + Pembrolizumab

EXPERIMENTAL

Participants with NSCLC will receive entinostat 3 mg administered orally weekly (Days 1, 8, and 15 of each 21-day cycle) along with pembrolizumab 200 mg via intravenous (IV) infusion once every 3 weeks (Day 1 of each 21-day cycle).

Drug: entinostat; Drug: pembrolizumab

Phase 1b (Dose Escalation): Entinostat 5 mg Weekly + Pembrolizumab

EXPERIMENTAL

Participants with NSCLC will receive entinostat 5 mg administered orally weekly (Days 1, 8, and 15 of each 21-day cycle) along with pembrolizumab 200 mg via IV infusion once every 3 weeks (Day 1 of each 21-day cycle).

Drug: entinostat; Drug: pembrolizumab

Phase 1b (Dose Confirmation): Entinostat 5 mg Weekly + Pembrolizumab

EXPERIMENTAL

Participants with NSCLC will receive entinostat 5 mg administered orally weekly (Days 1, 8, and 15 of each 21-day cycle) along with pembrolizumab 200 mg via IV infusion once every 3 weeks (Day 1 of each 21-day cycle).

Drug: entinostat; Drug: pembrolizumab

Phase 2, Cohort 1: Entinostat 5 mg Weekly + Pembrolizumab

EXPERIMENTAL

Participants with NSCLC with squamous cell or adenocarcinoma histology who had not been treated with a programmed cell death receptor-1 (PD-1)- or programmed cell death ligand-1 (PD-L1)-blocking antibody, will receive entinostat 5 mg administered orally weekly (Days 1, 8, and 15 of each 21-day cycle) along with pembrolizumab 200 mg via IV infusion once every 3 weeks (Day 1 of each 21-day cycle).

Drug: entinostat; Drug: pembrolizumab

Phase 2, Cohort 2: Entinostat 5 mg Weekly + Pembrolizumab

EXPERIMENTAL

Participants with NSCLC (any histology) who has previously been treated with and unequivocally progressed on either a PD-1- or PD-L1-blocking antibody, will receive entinostat 5 mg administered orally weekly (Days 1, 8, and 15 of each 21-day cycle) along with pembrolizumab 200 mg via IV infusion once every 3 weeks (Day 1 of each 21-day cycle).

Drug: entinostat; Drug: pembrolizumab

Phase 2, Cohort 3: Entinostat 5 mg Weekly + Pembrolizumab

EXPERIMENTAL

Participants with melanoma who has previously been treated with and unequivocally progressed on either a PD-1- or PD-L1-blocking antibody, will receive entinostat 5 mg administered orally weekly (Days 1, 8, and 15 of each 21-day cycle) along with pembrolizumab 200 mg via IV infusion once every 3 weeks (Day 1 of each 21-day cycle).

Drug: entinostat; Drug: pembrolizumab

Phase 2, Cohort 4: Entinostat 5 mg Weekly + Pembrolizumab

EXPERIMENTAL

Participants with CRC (mismatch repair-proficient) who had not been previously treated with a PD-1- or PD-L1-blocking antibody, received entinostat 5 mg administered orally weekly (Days 1, 8, and 15 of each 21-day cycle) along with pembrolizumab 200 mg via IV infusion once every 3 weeks (Day 1 of each 21-day cycle).

Drug: entinostat; Drug: pembrolizumab

Interventions

entinostat DRUG

An orally available histone deacetylases inhibitor (HDACs)

Also known as: SNDX-275, MS-275

Phase 1b (Dose Confirmation): Entinostat 5 mg Weekly + Pembrolizumab; Phase 1b (Dose Escalation): Entinostat 3 mg Weekly + Pembrolizumab; Phase 1b (Dose Escalation): Entinostat 5 mg Weekly + Pembrolizumab; Phase 2, Cohort 1: Entinostat 5 mg Weekly + Pembrolizumab; Phase 2, Cohort 2: Entinostat 5 mg Weekly + Pembrolizumab; Phase 2, Cohort 3: Entinostat 5 mg Weekly + Pembrolizumab; Phase 2, Cohort 4: Entinostat 5 mg Weekly + Pembrolizumab

pembrolizumab DRUG

A selective humanized monoclonal antibody (mAb)

Also known as: Keytruda, MK-3475, SCH 900475

Phase 1b (Dose Confirmation): Entinostat 5 mg Weekly + Pembrolizumab; Phase 1b (Dose Escalation): Entinostat 3 mg Weekly + Pembrolizumab; Phase 1b (Dose Escalation): Entinostat 5 mg Weekly + Pembrolizumab; Phase 2, Cohort 1: Entinostat 5 mg Weekly + Pembrolizumab; Phase 2, Cohort 2: Entinostat 5 mg Weekly + Pembrolizumab; Phase 2, Cohort 3: Entinostat 5 mg Weekly + Pembrolizumab; Phase 2, Cohort 4: Entinostat 5 mg Weekly + Pembrolizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants with NSCLC:
• Has histologically- or pathologically-confirmed recurrent/metastatic NSCLC.
• If has adenocarcinoma, required to have previously been tested for anaplastic lymphoma kinase (ALK) rearrangements and epidermal growth factor receptor (EGFR) mutations, with results available for collection in this study, and, if positive, has been treated with prior epidermal growth factor receptor (EGFR) or ALK therapy.
• Received at least 1 chemotherapeutic regimen in the advanced/metastatic setting and experienced documented, unequivocal progressive disease by either RECIST 1.1 or clinical assessment. Additional requirements related to prior treatments applied and may have been dependent on mutational status.
• Participants with NSCLC enrolled in Cohort 1 of the Expansion Phase should not have been previously treated with a PD-1/PD-L1-blocking antibody.
• Participants in Expansion Phase, Cohorts 2 (NSCLC) and 3 (Melanoma):
• Previously treated with a PD-1/PD-L1-blocking antibody and experienced documented, unequivocal radiographic progression of disease by irRECIST, or similar criteria during or within 12 weeks after last dose of such treatment. Participants must have received at least 6 weeks of PD-1/PD-L1 therapy for Cohort 2 and at least 8 weeks of PD-1/PD-L1 therapy for Cohort 3.
• Participants with Melanoma:
• In addition to having been previously treated with a PD-1/PD-L1-blocking antibody, has a histologically- or cytologically-confirmed diagnosis of unresectable or metastatic melanoma and experienced unequivocal progressive disease during treatment with a Serine/threonine-protein kinase B-Raf (BRAF) inhibitor if BRAF V600 mutation-positive. Treatment with BRAF inhibitor may occur after treatment with the checkpoint inhibitor.
• Participants in Expansion Phase, Cohort 4 (CRC):
• Received at least 1 chemotherapeutic regimen in the advanced/metastatic setting and experienced documented, unequivocal progressive disease by either RECIST 1.1 or clinical assessment. Must have documented mismatch repair-proficient colon cancer as determined by either immunohistochemistry for mismatch repair proteins or polymerase chain reaction (PCR)-based functional microsatellite instability. Participants with CRC enrolled in Cohort 4 should not have been previously treated with a PD-1/PD-L1-blocking antibody (that is, pembrolizumab, nivolumab, MEDI4736, or GNE PDL1 \[MPDL3280A\]).
• All Participants:
• Aged 18 years or older on the day written informed consent is given.
• If has brain metastases, must have stable neurologic status following local therapy for at least 4 weeks without the use of steroids or on stable or decreasing dose of ≤10 milligrams (mg) daily prednisone (or equivalent), and must be without neurologic dysfunction that would confound the evaluation of neurologic and other AEs.
• Evidence of locally recurrent or metastatic disease based on imaging studies within 28 days before the first study drug dose:

You may not qualify if:

• Participants meeting any of the following criteria are not eligible for study participation:
• Diagnosis of immunodeficiency or receiving systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor.
• Active autoimmune disease that has required systemic treatment in past 2 years (that is, with disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (for example, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.
• History of interstitial lung disease (ILD).
• Allergy to benzamide or inactive components of entinostat.
• History of allergies to any active or inactive ingredients of pembrolizumab or severe hypersensitivity (≥Grade 3) to pembrolizumab.
• History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating Investigator, including, but not limited to:
• Myocardial infarction or arterial thromboembolic events within 6 months prior to baseline or severe or unstable angina, New York Heart Association (NYHA) Class III or IV disease, or a QTc interval \> 470 milliseconds (msec).
• Uncontrolled heart failure or hypertension, uncontrolled diabetes mellitus, or uncontrolled systemic infection.
• Another known additional malignancy that is progressing or requires active treatment (excluding adequately treated basal cell carcinoma, squamous cell of the skin, cervical intraepithelial neoplasia \[CIN\]/cervical carcinoma in situ or melanoma in situ, or ductal carinoma in situ of the breast). Prior history of other cancer is allowed, as long as there is no active disease within the prior 5 years.
• Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
• Active infection requiring systemic therapy.
• Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
• Note: Participants with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging \[using the identical imaging modality for each assessment, either MRI or CT scan\] for at least 4 weeks prior to the first dose of study drug and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 2 weeks prior to the first dose of study drug or are on stable or decreasing dose of ≤10 mg daily prednisone (or equivalent). This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
• Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.

Sponsors & Collaborators

• Syndax Pharmaceuticals: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (11)

Yale University

New Haven, Connecticut, 06519, United States

Location

Emory University

Atlanta, Georgia, 30322, United States

Location

University of Maryland, Marlene and Stewart Greenbaum Cancer Center

Baltimore, Maryland, 21201, United States

Location

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, 21231, United States

Location

Dana Farber Cancer Institution

Boston, Massachusetts, 02215, United States

Location

Roswell Park Cancer Institute

Buffalo, New York, 14263, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

The University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, 27599, United States

Location

St Luke's University Health Network

Easton, Pennsylvania, 18045, United States

Location

Sarah Cannon Research Institute

Nashville, Tennessee, 37203, United States

Location

Vanderbilt University Medical Center

Nashville, Tennessee, 37230, United States

Location

Related Publications (2)

• Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989 Mar;10(1):1-10. doi: 10.1016/0197-2456(89)90015-9.

  PMID: 2702835 BACKGROUND

• Hellmann MD, Janne PA, Opyrchal M, Hafez N, Raez LE, Gabrilovich DI, Wang F, Trepel JB, Lee MJ, Yuno A, Lee S, Brouwer S, Sankoh S, Wang L, Tamang D, Schmidt EV, Meyers ML, Ramalingam SS, Shum E, Ordentlich P. Entinostat plus Pembrolizumab in Patients with Metastatic NSCLC Previously Treated with Anti-PD-(L)1 Therapy. Clin Cancer Res. 2021 Feb 15;27(4):1019-1028. doi: 10.1158/1078-0432.CCR-20-3305. Epub 2020 Nov 17.

  PMID: 33203644 DERIVED

Related Links

• CTCAE v. 4.03

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Melanoma

Interventions

entinostat; pembrolizumab

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Skin Diseases; Skin and Connective Tissue Diseases

Results Point of Contact

• Title: Kate Madigan, MD, Chief Medical Officer
• Organization: Syndax Pharmaceuticals, Inc.

kmadigan@syndax.com

858-888-3798

Study Officials

• Pasi A Janne, MD, PhD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 27, 2015
• First Posted: May 7, 2015
• Study Start: August 26, 2015
• Primary Completion: September 29, 2022
• Study Completion: September 29, 2022
• Last Updated: March 20, 2025
• Results First Posted: March 20, 2025

Record last verified: 2025-03

Locations

US (11)