A Clinical Trial of Entinostat in Combination With Nivolumab for Patients With Previously Treated Unresectable or Metastatic Cholangiocarcinoma and Pancreatic Adenocarcinoma

Study Overview
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Brief Summary
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The proposed study is an open-label, two-arm study of entinostat plus nivolumab in patients with unresectable or metastatic cholangiocarcinoma (CCA) or pancreatic ductal adenocarcinoma (PDAC).

Official Title
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A Phase 2 Clinical Trial of Entinostat in Combination With Nivolumab for Patients With Previously Treated Unresectable or Metastatic Cholangiocarcinoma and Pancreatic Adenocarcinoma

Conditions
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Metastatic Cholangiocarcinoma, Cholangiocarcinoma, Pancreatic Cancer, Metastatic Pancreatic Cancer, Unresectable Pancreatic Cancer, Unresectable Cholangiocarcinoma

Intervention / Treatment
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* Drug: Entinostat
* Drug: Nivolumab
* Drug: Entinostat
* Drug: Nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years. Have histologically or cytologically proven cholangiocarcinoma or adenocarcinoma of the pancreas that is metastatic or unresectable. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 Life expectancy of greater than 12 weeks. Patients must have adequate organ and marrow function defined by study-specified laboratory tests. Woman of child bearing potential must have a negative pregnancy test. Must have progressive measurable disease. Must have an accessible non-bone tumor that can be biopsied. Must use acceptable form of birth control while on study. Willing to provide tissue and blood samples. Ability to understand and willingness to sign a written informed consent document. Exclusion Criteria: Chemotherapy, radiotherapy, investigational therapy, or surgery less than 3 weeks prior to trial registration Prior treatment with epigenetic therapy (such as entinostat, panobinostat, vorinostat, romidepsin, 5-azacitidine, or decitabine) Prior treatment with immunotherapy agents (including, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA4, etc.). Hypersensitivity reaction to any monoclonal antibody. History of any autoimmune disease: inflammatory bowel disease, (including ulcerative colitis and Crohn's Disease), rheumatoid arthritis, systemic progressive sclerosis (scleroderma), systemic lupus erythematosus (SLE) autoimmune vasculitis (e.g., Wegener's Granulomatosis), central nervous system (CNS) or motor neuropathy considered to be of autoimmune origin (e.g., Guillain-Barre Syndrome, Myasthenia Gravis, Multiple Sclerosis). Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (precipitating event). Have significant and/or malignant pleural effusion Has a pulse oximetry < 92% on room air. Known history or evidence of brain metastases. Conditions, including alcohol or drug dependence, intercurrent illness, or lack of sufficient peripheral venous access, that would affect the patient's ability to comply with study visits and procedures. Are pregnant or breastfeeding. Infection with HIV or hepatitis B or C. Patients on immunosuppressive agents. Requiring concurrent administration of valproic acid. Patients with diverticulitis, intra-abdominal abscess, or GI obstruction Any contraindication to oral agents. Another active malignancy ≤ 3 years prior to registration with the exception of non-melanotic skin cancer or carcinoma-in-situ of any type. Unwilling or unable to follow the study schedule for any reason. Evidence of ascites on imaging.

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A - Cholangiocarcinoma<br> | Drug: Entinostat<br>* Entinostat (5mg) will be administered starting with 2 lead-in doses at 14 and 7 days before the first dose of nivolumab in combination with entinostat. After the lead-in dose, entinostat will be administered once a week (days 1, 8, 15, and 21 of each treatment cycle).<br>* Other names: SNDX-275;Drug: Nivolumab<br>* After both lead-in doses of entinostat, nivolumab (240 mg) will be administered every 2 weeks (day 1 and day 15 of a cycle).<br>* Other names: OPDIVO, BMS-936558, MDX1106, ONO-4538;|
| Experimental: ARM B - Pancreatic Cancer<br> | Drug: Entinostat<br>* Entinostat (5mg) will be administered starting with 2 lead-in doses at 14 and 7 days before the first dose of nivolumab in combination with entinostat. After the lead-in dose, entinostat will be administered once a week (days 1, 8, 15, and 21 of each treatment cycle).<br>* Other names: SNDX-275;Drug: Nivolumab<br>* After both lead-in doses of entinostat, nivolumab (240 mg) will be administered every 2 weeks (day 1 and day 15 of a cycle).<br>* Other names: OPDIVO, BMS-936558, MDX1106, ONO-4538;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) Using Response Evaluation Criteria for Solid Tumors (RECIST 1.1) | Objective Response Rate (ORR) is defined as the number of patients achieving a complete response (CR) or partial response (PR) based on RECIST 1.1 criteria. CR = disappearance of all target lesions, PR is =>30% decrease in sum of diameters of target lesions. | 27 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Experiencing a Grade 3 or Above Treatment-related Adverse Event (AE) | When calculating the incidence of AEs, each AE (as defined by NCI CTCAE v4.03) will be counted only once for a given subject. | 29 months | 
| Overall Survival (OS) | OS is defined as the duration of time from start of study treatment to time of death (OS will be censored on the date the subject was last known to be alive for subjects without documentation of death at the time of analysis). Estimation based on the Kaplan-Meier curve. | 38 months | 
| Overall Survival (OS) at 6 Months | OS is defined as the proportion of subjects who are alive at 6 months. Estimation based on the Kaplan-Meier curve. | 6 months | 
| Overall Survival (OS) at 12 Months | OS is defined as the proportion of subjects who are alive at 12 months. Estimation based on the Kaplan-Meier curve. | 12 months | 
| Overall Survival (OS) at 24 Months | OS is defined as the proportion of subjects who are alive at 24 months. Estimation based on the Kaplan-Meier curve. | 24 months | 
| Overall Survival (OS) at 36 Months | OS is defined as the proportion of subjects who are alive at 36 months. Estimation based on the Kaplan-Meier curve. | 36 months | 
| Duration of Response (DOR) | Duration of response (DOR) will be calculated for subjects who achieve a best overall response of CR or PR. DOR is defined as the number of months from the start date of PR or CR (whichever response is recorded first) and subsequently confirmed to the first date that recurrent or progressive disease or death is documented. Per RECIST 1.1 criteria, CR = disappearance of all target lesions, Partial Response (PR) is =>30% decrease in sum of diameters of target lesions, Progressive Disease (PD) is >20% increase in sum of diameters of target lesions. | 27 months | 
| Progression Free Survival (PFS) at 6 Months | PFS is defined as the proportion of patients without disease progression (PD or relapse from CR) or death due to any cause at 6 months. Disease progression will be assessed using RECIST (version 1.1). Per RECIST 1.1 criteria, CR = disappearance of all target lesions, Partial Response (PR) is =>30% decrease in sum of diameters of target lesions, Progressive Disease (PD) is >20% increase in sum of diameters of target lesions, Stable Disease (SD) is <30% decrease or <20% increase in sum of diameters of target lesions.Estimation based on the Kaplan-Meier curve. | 6 months | 
| Progression Free Survival (PFS) at 12 Months | PFS is defined as the proportion of patients without disease progression (PD or relapse from CR) or death due to any cause at 12 months. Disease progression will be assessed using RECIST (version 1.1). Per RECIST 1.1 criteria, CR = disappearance of all target lesions, Partial Response (PR) is =>30% decrease in sum of diameters of target lesions, Progressive Disease (PD) is >20% increase in sum of diameters of target lesions, Stable Disease (SD) is <30% decrease or <20% increase in sum of diameters of target lesions.Estimation based on the Kaplan-Meier curve. | 12 months | 
| Progression Free Survival (PFS) at 24 Months | PFS is defined as the proportion of patients without disease progression (PD or relapse from CR) or death due to any cause at 24 months. Disease progression will be assessed using RECIST (version 1.1). Per RECIST 1.1 criteria, CR = disappearance of all target lesions, Partial Response (PR) is =>30% decrease in sum of diameters of target lesions, Progressive Disease (PD) is >20% increase in sum of diameters of target lesions, Stable Disease (SD) is <30% decrease or <20% increase in sum of diameters of target lesions.Estimation based on the Kaplan-Meier curve. | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immunotherapy, Nivolumab, Entinostat, Pancreatic Adenocarcinoma, Cholangiocarcinoma, Unresectable, Metastatic, PD-1, Antibody