Recruiting

Phase 1

Phase 2

Entinostat & ZEN003694Testing A New Anti-cancer Drug Combination, Entinostat and ZEN003694, for Advanced and Refractory Solid Tumors

Sponsor:

National Cancer Institute (NCI)

Code:

NCT05053971

Conditions

Advanced Malignant Solid Neoplasm

Locally Advanced Pancreatic Carcinoma

Metastatic Pancreatic Carcinoma

Refractory Malignant Solid Neoplasm

Refractory Pancreatic Carcinoma

Eligibility Criteria

Sex: All

Age: 18+

Healthy Volunteers: Not accepted

Interventions

BET Bromodomain Inhibitor ZEN-3694

Computed Tomography

Core Biopsy

Entinostat

Study Details

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

Advanced Malignant Solid Neoplasm

Locally Advanced Pancreatic Carcinoma

Metastatic Pancreatic Carcinoma

Refractory Malignant Solid Neoplasm

Refractory Pancreatic Carcinoma

Study ID

NCT05053971

Start date

Nov 16, 2022

Status verified date

Jul, 2026

Completion date

Jul 1, 2027

Anticipated

Primary completion date

Jul 1, 2027

Anticipated

Eligibility Criteria

Sex: All

Age: 18+

Healthy Volunteers: Not accepted

Inclusion Criteria:

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
Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
Patients should be New York Heart Association Functional Classification of class 2B or better
Patients must be able to swallow and retain orally administered medication
Women of childbearing potential must have a negative pregnancy test within 7 days of starting treatment
The effects of entinostat and ZEN003694 on the developing human fetus are unknown. For this reason and because histone deacetylase inhibitor (HDACi) and BET inhibitor (BETi) agents are known to be teratogenic, women of child-bearing potential and their male partner must agree to use contraception from the time of the screening pregnancy test, continuing for the duration of study participation, and for 3 months after completing the study treatment
Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity who have a legally-authorized representative (LAR) and/or family member available will also be eligible
Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load

Exclusion Criteria:

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.
Clinically significant conduction abnormalities or arrhythmias.
Presence of a cardiac pacemaker or defibrillator with a paced ventricular rhythm limiting ECG analysis.
History or evidence of current >= Class II congestive heart failure as defined by New York Heart Association (NYHA).
History of acute coronary syndromes (including unstable angina and myocardial infarction), coronary angioplasty, or stenting within the past 6 months. Subjects with a history of stent placement requiring ongoing antithrombotic therapy (e.g. clopidogrel, prasugrel) will not be permitted to enroll. Clinically significant cardiomegaly, ventricular hypertrophy, or cardiomyopathy
Use of oral Factor Xa inhibitors (i.e., rivaroxaban, apixaban, betrixaban, edoxaban otamixaban, letaxaban, eribaxaban) and Factor IIa inhibitors (i.e., dabigatran). Low molecular weight heparin is allowed
Patients with radiation to > 25% of the bone marrow
Patients who have had a bone-targeted radionuclide within 6 weeks of the first dose of ZEN003694
Patients who have previously received ZEN003694 or who have been treated with an HDAC inhibitor or investigational BET inhibitor
Major surgery other than diagnostic surgery, dental surgery or stenting within 4 weeks prior to the first dose of ZEN003694

Study Design

Enrollment

49 participants

Anticipated

Intervention Model

Sequential

Primary purpose

Treatment

Interventions and Outcome Measures

Arms

experimental: Treatment (entinostat, ZEN003694)

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.

Interventions

BET Bromodomain Inhibitor ZEN-3694

Given PO

Computed Tomography

Undergo CT

Core Biopsy

Undergo core needle biopsy

Entinostat

Given PO

Primary outcome measure

Maximum tolerated dose (MTD) (Phase Ib) [ Time Frame: Up to 28 days ]
Recommended phase 2 dose (RP2D) (Phase Ib) [ Time Frame: Up to 28 days ]
Objective response rate (ORR) (Phase II) [ Time Frame: Up to 4 weeks post intervention ]

Central Contacts and Locations

Locations

Yale University

Recruiting

New Haven, Connecticut, United States, 06520

Contacts

Site Public Contact

203-785-5702 canceranswers@yale.edu

Principal Investigator:

Patricia M. LoRusso

UF Health Cancer Institute - Gainesville

Recruiting

Gainesville, Florida, United States, 32610

Contacts

Site Public Contact

352-273-8010 cancer-center@ufl.edu

Principal Investigator:

Thomas J. George

University of Oklahoma Health Sciences Center

Recruiting

Oklahoma City, Oklahoma, United States, 73104

Contacts

Site Public Contact

405-271-8777 ou-clinical-trials@ouhsc.edu

Principal Investigator:

Abdul Rafeh Naqash

More Information

Sponsor

National Cancer Institute (NCI)

Last update posted

Jul 15, 2026

Last verified

Jul, 2026

Trial information was received from ClinicalTrials.gov and was last updated on 2026-09-10. This information was provided to ClinicalTrials.gov by National Cancer Institute (NCI) on 2026-07-15.