Testing A New Anti-cancer Drug Combination, Entinostat and ZEN003694, for Advanced and Refractory Solid Tumors

NCT05053971 | Recruiting Phase 1 FDA Drug

• 4 other identifiers: NCI-2021-09727200003325610499UM1CA186689
• Study Type: interventional
• Target: 49
• Locations: 1 country
• Sites: 3

Brief Summary

This phase I/II trial tests the safety, side effects, and best dose of entinostat and ZEN003694 in treating patients with solid tumors that have spread to other places in the body (advanced) or does not respond to treatment (refractory). Entinostat is in a class of drugs called histone deacetylase (HDAC) inhibitors. It may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. ZEN003694 is an inhibitor of a family of proteins called the bromodomain and extra-terminal (BET). It may prevent the growth of tumor cells that over produce BET protein. This trial aims to test the safety of combination therapy with entinostat and ZEN003694 in treating patients with advanced or refractory solid tumors.

Conditions

Locally Advanced Pancreatic Carcinoma; Stage III Pancreatic Cancer AJCC v8; Refractory Malignant Solid Neoplasm; Metastatic Pancreatic Carcinoma; Advanced Malignant Solid Neoplasm; Stage IV Pancreatic Cancer AJCC v8; Refractory Pancreatic Carcinoma; Stage II Pancreatic Cancer AJCC v8; Unresectable Pancreatic Carcinoma

Outcome Measures

Primary Outcomes (3)

• Maximum tolerated dose (MTD) (Phase Ib)

  The MTD is defined as the highest dose level at which \< 33% of the dose cohort (0 of 3 or 1 of 6) experience a dose-limiting toxicity (DLT) in the first cycle. Up to 3 additional patients (maximum enrollment 6) will be added at the MTD level to more fully characterize the safety of the drug combination. If \< 33% (2) patients in this expanded cohort experience a DLT, this will be declared the MTD, and thus the phase 2 dose. If 2 or more patients experience a DLT, this dose level will be adopted as the maximum administered dose (MAD) and drop to the dose level immediately below, for the MTD and the phase 2 dose.

  Up to 28 days

• Recommended phase 2 dose (RP2D) (Phase Ib)

  The RP2D is generally defined as =\<1 out of 6 at highest dose level below the maximally administered dose.

  Up to 28 days

• Objective response rate (ORR) (Phase II)

  Each patient will be assigned one of the following categories: 1) complete response, 2) partial response, 3) stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, insufficient data). All of the patients who met the eligibility criteria (with the possible exception of those who received no study medication) should be included in the main analysis of the response rate. Patients in response categories 4-9 should be considered to have a treatment failure (disease progression). Thus, an incorrect treatment schedule or drug administration does not result in exclusion from the analysis of the response rate. Precise definitions for categories 4-9 will be protocol specific.

  Up to 4 weeks post intervention

Secondary Outcomes (4)

• Response rate (RR) in patients with advanced/progressive pancreatic cancer (Phase II)

  Up to 4 weeks post intervention

• Duration of response

  Up to 4 weeks post intervention

• Overall survival

  Up to 4 weeks post intervention

• Progression free survival

  Up to 4 weeks post intervention

Other Outcomes (1)

• Non-sequencing biomarker analysis

  Up to 4 weeks post intervention

Study Arms (1)

Treatment (entinostat, ZEN003694)

EXPERIMENTAL

PHASE I RUN-IN PERIOD (DAILY DOSING) (NO LONGER USED PER AMENDMENT DATED JUNE 12, 2025): Patients receive ZEN003694 PO QD during days -14 to 1. Patients also undergo core needle biopsy within 30 days prior to starting therapy. PHASE I \& II COMBINATION TREATMENT (DAILY DOSING) (NO LONGER USED PER AMENDMENT DATED JUNE 12, 2025): Patients receive entinostat PO QW on days 1, 8, 15, and 22, and ZEN003694 PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo core needle biopsy on day 1 of cycle 1, and on day 1 of cycle 14. PHASE I and PHASE II (INTERMITTENT DOSING): Patients receive entinostat PO on days 1, 8, 15, and 22 of each cycle and ZEN003694 PO QD on days 1-5, 8-12, 15-19, and 22-26 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo CT throughout the study.

Drug: BET Bromodomain Inhibitor ZEN-3694; Procedure: Computed Tomography; Procedure: Core Biopsy; Drug: Entinostat

Interventions

Computed Tomography PROCEDURE

Undergo CT

Also known as: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, Diagnostic CAT Scan, Diagnostic CAT Scan Service Type, tomography

Treatment (entinostat, ZEN003694)

BET Bromodomain Inhibitor ZEN-3694 DRUG

Given PO

Also known as: BETi ZEN-3694, ZEN 3694, ZEN-3694, ZEN003694

Treatment (entinostat, ZEN003694)

Entinostat DRUG

Given PO

Also known as: HDAC inhibitor SNDX-275, MS 27-275, MS 275, MS-275, MS275, SNDX 275, SNDX-275, SNDX275

Treatment (entinostat, ZEN003694)

Core Biopsy PROCEDURE

Undergo core needle biopsy

Also known as: BIOPSY, CORE, CNB, Core Needle, Core Needle Biopsy, Needle Biopsy

Treatment (entinostat, ZEN003694)

Eligibility Criteria

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

You may qualify if:

• Patients must have a) advanced or refractory solid tumor and must meet standard requirements for treatment
• For patients in Phase 2: Patients must have locally advanced, unresectable OR metastatic pancreatic cancer refractory to standard therapy
• For patients with solid tumors, they must have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
• For patients with solid tumors, they must have received at least one standard of care regimen for metastatic disease
• Age \>= 18 years. Because no dosing or adverse event data are currently available on the use of ZEN003694, alone or in combination with entinostat, in patients \< 18 years of age, children are excluded from this study
• Eastern Cooperative Oncology Group (ECOG) performance status =\< 1 (Karnofsky \>= 70%)
• Hemoglobin \>= 9.0 g/dL (measured within 14 days prior to administration of study treatment)
• Absolute neutrophil count (ANC) \>= 1,500/mcL (measured within 14 days prior to administration of study treatment)
• Platelets \>= 100,000/mcL (measured within 14 days prior to administration of study treatment)
• Total bilirubin =\< 1.5 x institutional upper limit of normal (ULN) (measured within 14 days prior to administration of study treatment)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) =\< 2.5 x institutional ULN (measured within 14 days prior to administration of study treatment)
• Glomerular filtration rate (GFR) \>= 60 mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal (measured within 14 days prior to administration of study treatment)
• Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) test \< 1.5 x ULN (measured within 14 days prior to administration of study treatment)
• Albumin \> 2.5 g/dL (measured within 14 days prior to administration of study treatment)
• Patients with treated brain metastases are eligible if follow-up brain imaging at least 4 weeks after central nervous system (CNS)-directed therapy shows no evidence of progression

You may not qualify if:

• Patients who have had any anti-cancer therapy within 30 days (or 5 half-lives, whichever is shorter) prior to the first dose of the investigational products
• Patients who have received radiation therapy within 21 days prior to the first dose of the investigational products
• Patients who have a diagnosis of NK cell lymphoma
• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities \> grade 1) with the exception of alopecia, or stable chronic grade 2 toxicities that do not overlap with presumed toxicities of entinostat or ZEN003694
• Patients who are receiving any other investigational agents
• Patients with known untreated or symptomatic brain or leptomeningeal metastases are excluded. Patients with previously treated CNS metastasis may be included provided that they have stable CNS disease for at least 4 weeks (confirmed by imaging) without symptoms and are off corticosteroids (above physiologic dose) for that indication
• Patients with significant malabsorption or nausea and vomiting that would interfere with oral therapies
• Patients with bleeding diathesis or clinically significant bleeding within the prior 6 months
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to entinostat (e.g. medications that have a benzamide structure (tiapride, remoxipride, clebopride) or ZEN003694
• Patients receiving any medications or substances that are strong inhibitors or strong inducers of CYP3A4 or substrates of CYP1A2 with narrow therapeutic windows are ineligible. Strong inhibitors or inducers of CYP3A4 and substrates of CYP1A2 must be discontinued at least 7 days prior to the first dose of ZEN003694. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
• Patients with uncontrolled intercurrent illness
• Pregnant women are excluded from this study because entinostat is an HDACi and ZEN003694 is a BETi with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with entinostat or ZEN003694, breastfeeding should be discontinued throughout the treatment period and for at least 28 days following the last dose of study treatment if the mother is treated with entinostat or ZEN003694
• Patients with any of the following cardiac criteria:
• Patients with a corrected QT interval calculated by the Fridericia formula (QTcF) \> 450 msec by electrocardiogram (ECG).
• Concomitant use of any agent known to cause corrected QT interval (QTc) prolongation.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (3)

Yale University

New Haven, Connecticut, 06520, United States

RECRUITING

UF Health Cancer Institute - Gainesville

Gainesville, Florida, 32610, United States

RECRUITING

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, 73104, United States

RECRUITING

Related Publications (1)

• Tost J, Ak-Aksoy S, Campa D, Corradi C, Farinella R, Ibanez-Costa A, Dubrot J, Earl J, Melian EB, Kataki A, Kolnikova G, Madjarov G, Chaushevska M, Strnadel J, Tanic M, Tomas M, Dubovan P, Urbanova M, Buocikova V, Smolkova B. Leveraging epigenetic alterations in pancreatic ductal adenocarcinoma for clinical applications. Semin Cancer Biol. 2025 Feb;109:101-124. doi: 10.1016/j.semcancer.2025.01.003. Epub 2025 Jan 23.

  PMID: 39863139 DERIVED

MeSH Terms

Conditions

Pancreatic Neoplasms

Interventions

Biopsy, Needle; Biopsy, Large-Core Needle; entinostat

Condition Hierarchy (Ancestors)

Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Biopsy; Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Specimen Handling; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Punctures; Investigative Techniques

Study Officials

• Patricia M LoRusso

  Yale University Cancer Center LAO

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 22, 2021
• First Posted: September 23, 2021
• Study Start: November 16, 2022
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): July 1, 2026
• Last Updated: April 13, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will share

Locations

US (3)