Cholangiocarcinoma, Metastatic Cholangiocarcinoma, Metastatic Pancreatic Cancer, Pancreatic Cancer, Unresectable Cholangiocarcinoma, Unresectable Pancreatic Cancer
Conditions
Keywords
Immunotherapy, Nivolumab, Entinostat, Pancreatic Adenocarcinoma, Cholangiocarcinoma, Unresectable, Metastatic, PD-1, Antibody
Brief summary
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).
Interventions
DRUGEntinostat
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).
DRUGNivolumab
After both lead-in doses of entinostat, nivolumab (240 mg) will be administered every 2 weeks (day 1 and day 15 of a cycle).
Sponsors
Syndax Pharmaceuticals
Bristol-Myers Squibb
National Cancer Institute (NCI)
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥18 years. 2. Have histologically or cytologically proven cholangiocarcinoma or adenocarcinoma of the pancreas that is metastatic or unresectable. 3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 4. Life expectancy of greater than 12 weeks. 5. Patients must have adequate organ and marrow function defined by study-specified laboratory tests. 6. Woman of child bearing potential must have a negative pregnancy test. 7. Must have progressive measurable disease. 8. Must have an accessible non-bone tumor that can be biopsied. 9. Must use acceptable form of birth control while on study. 10. Willing to provide tissue and blood samples. 11. Ability to understand and willingness to sign a written informed consent document.
Exclusion criteria
1. Chemotherapy, radiotherapy, investigational therapy, or surgery less than 3 weeks prior to trial registration 2. Prior treatment with epigenetic therapy (such as entinostat, panobinostat, vorinostat, romidepsin, 5-azacitidine, or decitabine) 3. Prior treatment with immunotherapy agents (including, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA4, etc.). 4. Hypersensitivity reaction to any monoclonal antibody. 5. 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). 6. Have significant and/or malignant pleural effusion 7. Has a pulse oximetry \< 92% on room air. 8. Known history or evidence of brain metastases. 9. 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. 10. Are pregnant or breastfeeding. 11. Infection with HIV or hepatitis B or C. 12. Patients on immunosuppressive agents. 13. Requiring concurrent administration of valproic acid. 14. Patients with diverticulitis, intra-abdominal abscess, or GI obstruction 15. Any contraindication to oral agents. 16. Another active malignancy ≤ 3 years prior to registration with the exception of non-melanotic skin cancer or carcinoma-in-situ of any type. 17. Unwilling or unable to follow the study schedule for any reason. 18. Evidence of ascites on imaging.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) Using Response Evaluation Criteria for Solid Tumors (RECIST 1.1) | 27 months | 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. Subjects who discontinue due to clinical progression prior to post-baseline tumor assessments were considered as non-responders. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Experiencing a Grade 3 or Above Treatment-related Adverse Event (AE) | 29 months | When calculating the incidence of AEs, each AE (as defined by NCI CTCAE v4.03) will be counted only once for a given subject. |
| Overall Survival (OS) | 38 months | 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. |
| Overall Survival (OS) at 6 Months | 6 months | OS is defined as the proportion of subjects who are alive at 6 months. Estimation based on the Kaplan-Meier curve. |
| Overall Survival (OS) at 24 Months | 24 months | OS is defined as the proportion of subjects who are alive at 24 months. Estimation based on the Kaplan-Meier curve. |
| Overall Survival (OS) at 12 Months | 12 months | OS is defined as the proportion of subjects who are alive at 12 months. Estimation based on the Kaplan-Meier curve. |
| Duration of Response (DOR) | 27 months | 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. |
| Progression Free Survival (PFS) at 6 Months | 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. |
| Progression Free Survival (PFS) at 12 Months | 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. |
| Progression Free Survival (PFS) at 24 Months | 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. |
| Overall Survival (OS) at 36 Months | 36 months | OS is defined as the proportion of subjects who are alive at 36 months. Estimation based on the Kaplan-Meier curve. |
Countries
United States
Participant flow
Pre-assignment details
1 enrolled participant withdrew consent prior to initiating treatment
Participants by arm
| Arm | Count |
|---|---|
| Arm A - Cholangiocarcinoma Entinostat: 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).
Nivolumab: After both lead-in doses of entinostat, nivolumab (240 mg) will be administered every 2 weeks (day 1 and day 15 of a cycle). | 13 |
| ARM B - Pancreatic Cancer Entinostat: 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).
Nivolumab: After both lead-in doses of entinostat, nivolumab (240 mg) will be administered every 2 weeks (day 1 and day 15 of a cycle). | 30 |
| Total | 43 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 1 |
| Overall Study | Disease Progression | 2 | 11 |
Baseline characteristics
| Characteristic | Arm A - Cholangiocarcinoma | ARM B - Pancreatic Cancer | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 14 Participants | 17 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 16 Participants | 26 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 27 Participants | 38 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 12 Participants | 28 Participants | 40 Participants |
| Region of Enrollment United States | 13 Participants | 30 Participants | 43 Participants |
| Sex: Female, Male Female | 4 Participants | 13 Participants | 17 Participants |
| Sex: Female, Male Male | 9 Participants | 17 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 1 / 30 |
| other Total, other adverse events | 12 / 13 | 27 / 30 |
| serious Total, serious adverse events | 4 / 13 | 3 / 30 |
Outcome results
Primary
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. Subjects who discontinue due to clinical progression prior to post-baseline tumor assessments were considered as non-responders.
Time frame: 27 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A - Cholangiocarcinoma | Objective Response Rate (ORR) Using Response Evaluation Criteria for Solid Tumors (RECIST 1.1) | 0 Participants |
| ARM B - Pancreatic Cancer | Objective Response Rate (ORR) Using Response Evaluation Criteria for Solid Tumors (RECIST 1.1) | 3 Participants |
Secondary
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.
Time frame: 27 months
Population: There were no responses (PR or CR) observed in Arm A; therefore, the number of analyzed participants is zero. 3 participants achieved response in Arm B.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ARM B - Pancreatic Cancer | Duration of Response (DOR) | 10.2 months |
Secondary
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.
Time frame: 29 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A - Cholangiocarcinoma | Number of Patients Experiencing a Grade 3 or Above Treatment-related Adverse Event (AE) | 5 Participants |
| ARM B - Pancreatic Cancer | Number of Patients Experiencing a Grade 3 or Above Treatment-related Adverse Event (AE) | 19 Participants |
Secondary
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.
Time frame: 38 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A - Cholangiocarcinoma | Overall Survival (OS) | 6.378 months |
| ARM B - Pancreatic Cancer | Overall Survival (OS) | 2.729 months |
Secondary
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.
Time frame: 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A - Cholangiocarcinoma | Overall Survival (OS) at 12 Months | 0.308 proportion of participants |
| ARM B - Pancreatic Cancer | Overall Survival (OS) at 12 Months | 0.138 proportion of participants |
Secondary
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.
Time frame: 24 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A - Cholangiocarcinoma | Overall Survival (OS) at 24 Months | 0.077 proportion of participants |
| ARM B - Pancreatic Cancer | Overall Survival (OS) at 24 Months | 0.035 proportion of participants |
Secondary
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.
Time frame: 36 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A - Cholangiocarcinoma | Overall Survival (OS) at 36 Months | 0.077 proportion of participants |
| ARM B - Pancreatic Cancer | Overall Survival (OS) at 36 Months | 0.035 proportion of participants |
Secondary
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.
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A - Cholangiocarcinoma | Overall Survival (OS) at 6 Months | 0.538 proportion of participants |
| ARM B - Pancreatic Cancer | Overall Survival (OS) at 6 Months | 0.277 proportion of participants |
Secondary
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.
Time frame: 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A - Cholangiocarcinoma | Progression Free Survival (PFS) at 12 Months | 0 proportion of participants |
| ARM B - Pancreatic Cancer | Progression Free Survival (PFS) at 12 Months | 0.067 proportion of participants |
Secondary
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.
Time frame: 24 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A - Cholangiocarcinoma | Progression Free Survival (PFS) at 24 Months | 0 proportion of participants |
| ARM B - Pancreatic Cancer | Progression Free Survival (PFS) at 24 Months | 0 proportion of participants |
Secondary
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.
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A - Cholangiocarcinoma | Progression Free Survival (PFS) at 6 Months | 0 proportion of participants |
| ARM B - Pancreatic Cancer | Progression Free Survival (PFS) at 6 Months | 0.067 proportion of participants |