Metastatic Pancreatic Adenocarcinoma
Conditions
Keywords
Pancreatic cancer, Vaccine, Immunotherapy, Pembrolizumab, PD-1, IDO, CRS-207, Epacadostat
Brief summary
This study will enroll patients who have metastatic pancreatic cancer and have progressed on prior chemotherapy. Part 1 (dose escalation) participants will receive epacadostat/pembrolizumab/cyclophosphamide(CY)/GVAX pancreas vaccine followed by epacadostat/pembrolizumab/CRS-207, Part 1X (dose escalation) participants will receive epacadostat/pembrolizumab/CRS-207. Part 2X (dose expansion) participants will receive epacadostat/pembrolizumab/CRS-207. The primary objectives of this study are to determine the recommended dose of epacadostat in this combination and assess survival of subjects in both treatment groups.
Interventions
DRUGEpacadostat
Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). Epacadostat (100, 300, or 600 mg) is taken by mouth twice a day, every day.
DRUGPembrolizumab
Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). Pembrolizumab (200 mg) will be administered IV on day 1 of Cycles 1-6.
BIOLOGICALCRS-207
CRS-207: Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). CRS-207 (1 × 10\^9 CFU) will be administered IV on Day 2 of Cycles 3-6.
DRUGCyclophosphamide
Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). Cyclophosphamide (200 mg/m\^2) will be administered IV on day 1 of Cycles 1 and 2.
BIOLOGICALGVAX Pancreas Vaccine
Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). GVAX will be administered on Day 2 of Cycles 1 and 2.
Sponsors
Merck Sharp & Dohme LLC
National Cancer Institute (NCI)
Incyte Corporation
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
(abbreviated): * Documented adenocarcinoma of the pancreas * Have disease progression after prior chemotherapy for metastatic pancreas cancer (or adjuvant or neoadjuvant if progression occurred within 6 months of completing this regimen) * Presence of at least one measurable lesion * Patient acceptance to have a tumor biopsy of an accessible lesion at 2 time points (baseline and on study) * ECOG performance status of 0 or 1 * Life expectancy of greater than 3 months * Adequate organ and marrow function defined by study-specified laboratory tests
Exclusion criteria
(abbreviated): * Brain metastases * Clinical or radiographic ascites (some trace amount may be allowed) * Rapidly progressing disease * Live vaccine within 30 days of study treatment (flu vaccine allowed) * Surgery within 28 days of study treatment (some exceptions for minor procedures) * Use of an investigational agent or device within 28 days of study treatment. * Chemotherapy, radiation, or biological cancer therapy within 14 days of study treatment. * Prior treatment with anti-CTLA-4, anti-PD-1, anti-PD-L1, or anti PD-L2, or with IDO inhibitor. * Use of growth factors within 14 days of study treatment * Use of any systemic steroids within 14 days of study treatment or other immunosuppressive agents within 7 days of study treatment. * Use of more than 2 g/day of acetaminophen * Use of any UGT1A9 inhibitor * Use of warfarin * Use of MAOIs or drugs with significant MAOI activity within the 21 days of screening * History of Seratonin Syndome * Known allergy to both penicillin and sulfa * Known or suspected hypersensitivity to any monoclonal antibody or any study drug component * Have artificial joints or implants that cannot be easily removed or a history of infection associated with an implant * Significant or malignant pleural effusion * New pulmonary embolism, extremity deep venous thromboembolism, or portal vein thrombosis within 2 months of study enrollment * History of autoimmune disease (exceptions for Graves or Hashimoto's disease, vitiligo, and type I diabetes mellitus) * Gastrointestinal condition that may affect drug absorption * Significant heart disease or heart disease requiring antibiotic for prevention of endocarditis * History of abnormal electrocardiogram (ECG) that is deemed meaningful by the investigator * History of (non-infectious) pneumonitis that required steroids, evidence of interstitial lung disease or active, non-infectious pneumonitis * Pulse oximetry of \< 92% on room air or the need for supplemental home oxygen * Infection with HIV, hepatitis B or hepatitis C * Other 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 * Pregnant or breastfeeding women * Unwillingness or inability to follow the study schedule for any reason
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) of Epacadostat | 9 weeks | Dose escalation (part I of the trial only) to determine the maximum tolerated dose (MTD) in mg BID. Epacadostat (100, 300, or 600 mg) was taken by mouth twice a day, every day. |
| 6 Month Survival | 6 months | Number of subjects who are alive 6 months or longer after the date of first treatment. |
Secondary
| Measure | Time frame |
|---|---|
| Number of Participants Experiencing Drug-Related Adverse Events (AEs) Requiring Treatment Discontinuation | 15 months |
Countries
United States
Participant flow
Pre-assignment details
One participant was excluded from analysis because they did not receive the study drug due to their inability to maintain eligibility after enrollment.
Participants by arm
| Arm | Count |
|---|---|
| Part 1: Dose Level 1 Epacadostat/Pembrolizumab/CY/GVAX/CRS-207
Epacadostat: Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). Epacadostat (100 mg) is taken by mouth twice a day, every day.
Pembrolizumab: Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). Pembrolizumab (200 mg) will be administered IV on day 1 of Cycles 1-6.
Cyclophosphamide: Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). Cyclophosphamide (200 mg/m\^2) will be administered IV on day 1 of Cycles 1 and 2.
GVAX Pancreas Vaccine: Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). GVAX will be administered on Day 2 of Cycles 1 and 2.
CRS-207: CRS-207: Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). CRS-207 (1 × 10\^9 CFU) will be administered IV on Day 2 of Cycles 3-6. | 6 |
| Part 1: Dose Level 2 Epacadostat/Pembrolizumab/CY/GVAX/CRS-207
Epacadostat: Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). Epacadostat (300 mg) is taken by mouth twice a day, every day.
Pembrolizumab: Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). Pembrolizumab (200 mg) will be administered IV on day 1 of Cycles 1-6.
Cyclophosphamide: Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). Cyclophosphamide (200 mg/m\^2) will be administered IV on day 1 of Cycles 1 and 2.
GVAX Pancreas Vaccine: Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). GVAX will be administered on Day 2 of Cycles 1 and 2.
CRS-207: CRS-207: Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). CRS-207 (1 × 10\^9 CFU) will be administered IV on Day 2 of Cycles 3-6. | 4 |
| Part 1X: Dose Level 2 Epacadostat/Pembrolizumab/CRS-207
Epacadostat: Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). Epacadostat (300 mg) is taken by mouth twice a day, every day.
Pembrolizumab: Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). Pembrolizumab (200 mg) will be administered IV on day 1 of Cycles 1-6.
CRS-207: CRS-207: Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). CRS-207 (1 × 10\^9 CFU) will be administered IV on Day 2 of Cycles 3-6. | 3 |
| Part 1X: Dose Level 3 Epacadostat/Pembrolizumab/CRS-207
Epacadostat: Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). Epacadostat (600 mg) is taken by mouth twice a day, every day.
Pembrolizumab: Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). Pembrolizumab (200 mg) will be administered IV on day 1 of Cycles 1-6.
CRS-207: CRS-207: Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). CRS-207 (1 × 10\^9 CFU) will be administered IV on Day 2 of Cycles 3-6. | 7 |
| Part 2: Dose Expansion Epacadostat/Pembrolizumab/CRS-207
Epacadostat: Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). Epacadostat (600 mg) is taken by mouth twice a day, every day.
Pembrolizumab: Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). Pembrolizumab (200 mg) will be administered IV on day 1 of Cycles 1-6.
CRS-207: CRS-207: Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). CRS-207 (1 × 10\^9 CFU) will be administered IV on Day 2 of Cycles 3-6. | 20 |
| Total | 40 |
Baseline characteristics
| Characteristic | Part 1: Dose Level 1 | Part 1: Dose Level 2 | Part 1X: Dose Level 2 | Part 1X: Dose Level 3 | Part 2: Dose Expansion | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 2 Participants | 5 Participants | 8 Participants | 16 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 3 Participants | 1 Participants | 2 Participants | 12 Participants | 24 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 4 Participants | 3 Participants | 7 Participants | 18 Participants | 38 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 4 Participants | 2 Participants | 7 Participants | 18 Participants | 36 Participants |
| Sex: Female, Male Female | 1 Participants | 4 Participants | 1 Participants | 1 Participants | 7 Participants | 14 Participants |
| Sex: Female, Male Male | 5 Participants | 0 Participants | 2 Participants | 6 Participants | 13 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 5 / 6 | 4 / 4 | 3 / 3 | 7 / 7 | 19 / 20 |
| other Total, other adverse events | 6 / 6 | 4 / 4 | 3 / 3 | 7 / 7 | 20 / 20 |
| serious Total, serious adverse events | 3 / 6 | 3 / 4 | 1 / 3 | 2 / 7 | 7 / 20 |
Outcome results
Primary
6 Month Survival
Number of subjects who are alive 6 months or longer after the date of first treatment.
Time frame: 6 months
Population: Per the clinical trial design, 6 month survival analyses included all subjects who received the MTD (Dose Level 3). Since the enrollment criteria and dose are the same, combining those who are treated at MTD at both parts increase the power and enable to estimate the treatment effect with increased precision. This included the 6 subjects evaluable in Part 1X portion of the trial and the 20 subjects enrolled in Part 2 portion of the trial for a total of 26 subjects.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Dose Escalation | 6 Month Survival | 12 Participants |
Primary
Maximum Tolerated Dose (MTD) of Epacadostat
Dose escalation (part I of the trial only) to determine the maximum tolerated dose (MTD) in mg BID. Epacadostat (100, 300, or 600 mg) was taken by mouth twice a day, every day.
Time frame: 9 weeks
Population: In Part 1 of the study (Epacadostat dose escalation), six patients were assessed in Dose Level 1 (DL1), seven patients were assessed in Dose Level 2 (DL2), and six patients were assessed in Dose Level 3 (DL3) since one patient was replaced because they came off treatment prior to completing the dose limiting toxicity (DLT) review period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Dose Escalation | Maximum Tolerated Dose (MTD) of Epacadostat | 600 mg BID |
Secondary
Number of Participants Experiencing Drug-Related Adverse Events (AEs) Requiring Treatment Discontinuation
Time frame: 15 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Dose Escalation | Number of Participants Experiencing Drug-Related Adverse Events (AEs) Requiring Treatment Discontinuation | 0 Participants |
| Part 1: Dose Level 2 | Number of Participants Experiencing Drug-Related Adverse Events (AEs) Requiring Treatment Discontinuation | 0 Participants |
| Part 1X: Dose Level 2 | Number of Participants Experiencing Drug-Related Adverse Events (AEs) Requiring Treatment Discontinuation | 0 Participants |
| Part 1X: Dose Level 3 | Number of Participants Experiencing Drug-Related Adverse Events (AEs) Requiring Treatment Discontinuation | 0 Participants |
| Part 2: Dose Expansion | Number of Participants Experiencing Drug-Related Adverse Events (AEs) Requiring Treatment Discontinuation | 0 Participants |