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

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

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) of BET bromodomain inhibitor ZEN-3694 (ZEN003694) and entinostat in combination in patients with advanced and refractory solid tumors and lymphomas based on dose limiting toxicities (DLTs) of the combination of ZEN003694 and entinostat. (Phase I) II. To determine the overall response rate (ORR) of ZEN003694 and entinostat in advanced/progressive pancreatic cancer. (Phase II) SECONDARY OBJECTIVES: I. To describe the safety profile of ZEN003694 and entinostat in advanced and refractory solid tumors and lymphomas. (Phase I) II. To determine the progression-free survival (PFS), duration of response (DOR), and overall survival (OS) of ZEN003694 and entinostat in this patient population. (Phase I) III. To describe the safety profile of ZEN003694 and entinostat in advanced/progressive pancreatic cancer. (Phase II) IV. To determine the progression-free survival (PFS), duration of response (DOR), and overall survival (OS) of ZEN003694 and entinostat in this patient population. (Phase II) V. To assess the effect of ZEN003694 and entinostat therapy on apoptosis, as measured by an apoptosis multiplex immunoassay. (Phase I & II) EXPLORATORY OBJECTIVES: I. To assess the effect of ZEN003694 and entinostat therapy on c-MYC and YAP1 as measured by apoptosis immunofluorescence assay. II. To assess the effect of ZEN003694 and entinostat therapy on c-MYC and YAP1 as measured by ribonucleic acid (RNA) and protein expression. III. To assess the effect of ZEN003694 and entinostat therapy on tumor burden and gene expression patterns as measured by whole exome sequencing (WES) and RNA sequencing (RNASeq) on circulating tumor deoxyribonucleic acid (DNA) (ctDNA) specimens. OUTLINE: This is a phase I, dose-escalation study of ZEN003694 in combination with entinostat followed by a phase II study. PHASE I RUN-IN PERIOD: Patients receive ZEN003694 orally (PO) once daily (QD) during days -14 to 1. Patients also undergo core needle biopsy within 30 days prior to starting therapy. PHASE II RUN-IN PERIOD: Patients receive ZEN003694 PO QD or entinostat PO once per week (QW) during days -14 to 1 based on the order to which they are enrolled to the study (e.g. every other patient starts by taking ZEN003694 alone for 14 days). Patients also undergo core needle biopsy within 30 days prior to starting therapy. PHASE I & II COMBINATION TREATMENT: 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. After completion of study treatment, patients are followed for 30 days.

Official Title
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Phase Ib/II Study of ZEN003694 and Entinostat in Advanced and Refractory Solid Tumors and Lymphomas

Conditions
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Advanced Lymphoma, Advanced Malignant Solid Neoplasm, Advanced Pancreatic Carcinoma, B-Cell Non-Hodgkin Lymphoma, Metastatic Pancreatic Carcinoma, Refractory B-Cell Non-Hodgkin Lymphoma, Refractory Lymphoma, Refractory Malignant Solid Neoplasm, Refractory Pancreatic Carcinoma, Refractory T-Cell Non-Hodgkin Lymphoma, Stage II Pancreatic Cancer AJCC v8, Stage III Pancreatic Cancer AJCC v8, Stage IV Pancreatic Cancer AJCC v8, Unresectable Pancreatic Carcinoma

Intervention / Treatment
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* Drug: BET Bromodomain Inhibitor ZEN-3694
* Procedure: Core Biopsy
* Drug: Entinostat


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have a) advanced or refractory solid tumor or b) lymphoma (all B cell lymphomas and T cell lymphomas other than natural killer [NK]-cell lymphoma) 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 lymphoma, they must have measurable disease based on Response Evaluation Criteria in Lymphoma (RECIL) criteria, or Lugano Classification criteria For patients with solid tumors, they must have received at least one standard of care regimen for metastatic disease. For patients with lymphoma, they should have received at least two previous therapies with at least one combination chemotherapy regimen for metastatic disease Patients with lymphoma must have exhausted or refused potential curative therapy prior to enrolling 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 =< 2 (Karnofsky >= 60%) 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) Serum creatinine clearance > 50 mL/min (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) Troponin =< 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 Patients must have tumors determined to be easily accessible for biopsy and must be willing to have serial biopsies. Tumor biopsies will be performed on the most accessible biopsiable site of disease. All possible precautions to avoid complications will be taken, including discussions in multidisciplinary meetings, if needed. If a biopsy cannot be performed safely (e.g. there is no safely accessible biopsiable tumour tissue) or biopsy does not yield sufficient tissue for analysis, participation is still allowed 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 with lymphoma must not have indolent or asymptomatic disease Patients who have had any anti-cancer therapy within 14 days (or 5 half-lives, whichever is longer) 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: Patients are assigned to ZEN003694 or entinostat in the Phase II Run-In period based on the order to which they are enrolled to the study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (entinostat, ZEN003694)<br>PHASE I RUN-IN PERIOD: Patients receive ZEN003694 PO QD during days -14 to 1. Patients also undergo core needle biopsy within 30 days prior to starting therapy. PHASE II RUN-IN PERIOD: Patients receive ZEN003694 PO QD or entinostat PO QW during days -14 to 1 based on the order to which they are enrolled to the study (e.g. every other patient starts by taking ZEN003694 alone for 14 days). Patients also undergo core needle biopsy within 30 days prior to starting therapy. PHASE I & II COMBINATION TREATMENT: 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. | Drug: BET Bromodomain Inhibitor ZEN-3694<br>* Given PO<br>* Other names: ZEN003694;Procedure: Core Biopsy<br>* Undergo core needle biopsy<br>* Other names: Needle Biopsy;Drug: Entinostat<br>* Given PO<br>* Other names: SNDX-275;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate (RR) in patients with advanced/progressive pancreatic cancer (Phase II) | The exact two-sided 95% confidence intervals (CIs) for the RR will be reported. | Up to 4 weeks post intervention | 
| Duration of response | The 95% CIs for the duration of response will be reported. | Up to 4 weeks post intervention | 
| Overall survival | Will be estimated using the Kaplan-Meier method with the 95% CIs. The CI based on Greenwood's variance will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. In addition, the 95% CIs for the duration of response will be reported. | Up to 4 weeks post intervention | 
| Progression free survival | Will be estimated using the Kaplan-Meier method with the 95% CIs. The CI based on Greenwood's variance will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. In addition, the 95% CIs for the duration of response will be reported. | Up to 4 weeks post intervention |