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Gland and Hormone Related Diseases

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Gastrointestinal Diseases

Pancreatic Diseases

Endocrine System Diseases

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All Drugs and Chemicals

Gastrointestinal Agents

Vaccines

Pancrelipase

Pancreatin

Participants receive booster vaccination every 6 months, given intradermally.

Participants will receive GVAX pancreas priming vaccinations once every month for a total of 3 months and every 6 months after that, given intradermally.

GVAX pancreas vaccine

Daniel A. Laheru, MD

This is an open label, phase II trial study of adjuvant GVAX pancreas vaccine in patients with pancreatic cancer.

Eligible participants will receive by intradermal administration the GVAX pancreas vaccine consisting of two irradiated allogeneic pancreatic tumor cell lines transfected with the granulocyte macrophage-colony stimulating factor (GM-CSF) gene.

There will be two cohorts of research participants:

1. Participants previously vaccinated with GVAX pancreas vaccine. These participants will receive booster vaccinations as a continuation of care. Vaccination repeats every 6 months in the absence of disease progression or unacceptable toxicity.
2. Participants who were not previously vaccinated with GVAX pancreas vaccine (vaccine naive). These participants received priming vaccinations once a month for 3 months followed by booster vaccinations every 6 months.

Adjuvant GVAX Vaccine Therapy in Patients With Pancreatic Cancer

A Safety and Efficacy Trial of Vaccine Boosting With Lethally Irradiated Allogeneic Pancreatic Tumor Cells Transfected With the GM-CSF Gene for the Treatment of Pancreatic Adenocarcinoma

When calculating the incidences of adverse events, each adverse event (as defined by NCI CTCAE v3) will be counted only once for a given subject.

OS will be measured from date of first dose until death or end of follow-up (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.

DFS is defined as the time from the first dose until evidence of disease recurrence or progression confirmed by first scan. DFS will be censored at the date of the last scan for subjects without documentation of disease recurrence or progression at the time of analysis. Estimation based on the Kaplan-Meier curve.

The Skip Viragh Foundation

National Cancer Institute (NCI)

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

This study used the descriptions and grading scales found in the revised National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 for adverse event reporting. During the survival follow-up portion of the trial, patients were evaluated for all-cause mortality past the time frame for treatment and the assessment of adverse events. Adverse events were assessed for up to 14 years. All-Cause Mortality was assessed for up to 16 years.

Participants receive booster vaccination every 6 months, given intradermally

Previously Vaccinated With GVAX Pancreas Vaccine

GVAX Pancreas Vaccine Naive

Total

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Daniel Laheru, MD

Number of Patients Experiencing a Grade 3 or Above Treatment- Related Toxicity

Overall Survival (OS)

Disease-free Survival (DFS)

Overall Study

Carcinoma

Antineoplastic Agents

Antirheumatic Agents

Cyclophosphamide

Immunomodulating Agents

Nivolumab

Ipilimumab

Immunologic Factors

Immunosuppressive Agents

Antineoplastic Agents, Alkylating

Alkylating Agents

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). Cyclophosphamide (200 mg/m2) will be administered IV on day 1 of Cycles 1 and 2.

Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). Nivolumab (360 mg) will be administered IV on day 1 of Cycles 1-6.

Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). Ipilimumab (1 mg/kg) will be administered IV on Day 1 of Cycles 1, 3, and 5.

Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). Vaccine will be administered on Day 2 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). CRS-207 (1 × 109 CFU) will be administered IV on Day 2 of Cycles 3-6.

CRS-207

Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). CRS-207 (1 × 109 CFU) will be administered IV on Day 2 of Cycles 1-6.

Dung Le, MD

The purpose of this study is to study the safety and clinical activity of nivolumab and ipilimumab in combination with either sequential administration of CY/GVAX pancreas vaccine followed by CRS-207 (Arm A) or with administration of CRS-207 alone (Arm B) in patients with pancreatic cancer.

Study of CRS-207, Nivolumab, and Ipilimumab With or Without GVAX Pancreas Vaccine (With Cy) in Patients With Pancreatic Cancer

A Randomized Phase 2 Study of the Safety, Efficacy, and Immune Response of CRS-207, Nivolumab, and Ipilimumab With or Without GVAX Pancreas Vaccine (With Cyclophosphamide) in Patients With Previously Treated Metastatic Pancreatic Adenocarcinoma

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. Participants who discontinue due to toxicity or clinical progression prior to post-baseline tumor assessments will be considered as non-responders. Participants who discontinue for other reasons prior to their first dose of study drug will not included in the analysis.

When calculating the incidence of AEs, each AE (as defined by NCI CTCAE v4.03) will be counted only once for a given subject. Laboratory abnormalities that were asymptomatic and not clinically significant were excluded.

Aduro Biotech, Inc.

Bristol-Myers Squibb

Only 30 participants in Arm A and 27 participants in Arm B were assessed for Serious and Other (Not Including Serious) Adverse Events. Four participants were withdrawn prior to their first dose of study drug (1 in Arm A and 3 in Arm B) and were therefore not assessed for Serious and Other (Not Including Serious) Adverse Events.

Cyclophosphamide: Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). Cyclophosphamide (200 mg/m2) will be administered IV on day 1 of Cycles 1 and 2.

Nivolumab: Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). Nivolumab (360 mg) will be administered IV on day 1 of Cycles 1-6.

Ipilimumab: Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). Ipilimumab (1 mg/kg) will be administered IV on Day 1 of Cycles 1, 3, and 5.

GVAX Pancreas Vaccine: Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). Vaccine will be administered on Day 2 of Cycles 1 and 2.

CRS-207: Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). CRS-207 (1 × 109 CFU) will be administered IV on Day 2 of Cycles 3-6.

Arm A: CY, Nivolumab, Ipilimumab, Pancreas GVAX, CRS-207

Nivolumab: Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). Nivolumab (360 mg) will be administered IV on day 1 of Cycles 1-6.

Ipilimumab: Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). Ipilimumab (1 mg/kg) will be administered IV on Day 1 of Cycles 1, 3, and 5.

CRS-207: Patients will receive treatment every 3 weeks for 6 cycles of treatment within a course (total of 18 weeks). CRS-207 (1 × 109 CFU) will be administered IV on Day 2 of Cycles 1-6.

Arm B: Nivolumab, Ipilimumab, CRS-207

Arm A: CY, Nivolumab, Ipilimumab, GVAX, CRS-207

Only 29/30 participants in Arm A were evaluable for this endpoint. One participant was not evaluable after they discontinued prior to their first scan for a reason other than toxicity or progression.

Objective Response Rate (ORR) Using Response Evaluation Criteria for Solid Tumors (RECIST 1.1)

Number of Participants Experiencing Grade 3 or Above Study Drug-related Adverse Events (AEs)

Micronutrients

Gemcitabine

Capecitabine

Irinotecan

Leucovorin

Fluorouracil

Erlotinib Hydrochloride

* 200 mg per square meter (mg/m\^2) cyclophosphamide (Cy) administered by intravenous (IV) infusion on Day 1 of Weeks 1 and 4; GVAX pancreas vaccine (GVAX, 5 × 10e8 cells) administered by intradermal injection on Day 2 of Weeks 1 and 4; CRS-207 (1 × 10e9 colony forming units \[CFU\]) administered by IV infusion on Day 1 of Weeks 7, 10, 13, 16.
* The Primary Cohort comprised those subjects who failed at least 1 gemcitabine-based regimen administered for pancreatic cancer in any setting and failed at least 2 prior chemotherapy regimens administered for pancreatic cancer in the metastatic setting.

* CRS-207 (1 × 10e9 CFU) administered by IV infusion on Day 1 of Weeks 1, 4, 7, 10, 13, 16.
* The Primary Cohort comprised those subjects who failed at least 1 gemcitabine-based regimen administered for pancreatic cancer in any setting and failed at least 2 prior chemotherapy regimens administered for pancreatic cancer in the metastatic setting.

* Investigator's choice of one of the following: gemcitabine (1000 mg/m\^2) administered by IV infusion on Days 1, 8, and 15 of a 28-day cycle; capecitabine (1000 mg/m\^2) administered orally twice a day on Days 1 through 14 of a 21-day cycle; fluorouracil with or without leucovorin (2400 mg\^m2) administered by IV infusion over 46 hours on Days 1 and 15 of a 28-day cycle; irinotecan (150 mg/m\^2) administered by IV infusion on Days 1 and 15 of a 28-day cycle; or erlotinib (100 mg) administered orally once a day for a 21-day cycle.
* The Primary Cohort comprised those subjects who failed at least 1 gemcitabine-based regimen administered for pancreatic cancer in any setting and failed at least 2 prior chemotherapy regimens administered for pancreatic cancer in the metastatic setting.

* 200 mg/m\^2 Cy administered by IV infusion on Day 1 of Weeks 1 and 4; GVAX pancreas vaccine (5 × 10e8 cells) administered by intradermal injection on Day 2 of Weeks 1 and 4; CRS-207 (1 × 10e9 CFU) administered by IV infusion on Day 1 of Weeks 7, 10, 13, 16.
* The 2nd-line Cohort comprised those subjects who received and failed 1 prior chemotherapy regimen administered for pancreatic cancer in the metastatic setting.

* CRS-207 (1 × 10e9 CFU) administered by IV infusion on Day 1 of Weeks 1, 4, 7, 10, 13, 16.
* The 2nd-line Cohort comprised those subjects who received and failed 1 prior chemotherapy regimen administered for pancreatic cancer in the metastatic setting.

* Investigator's choice of one of the following: gemcitabine (1000 mg/m\^2) administered by IV infusion on Days 1, 8, and 15 of a 28-day cycle; capecitabine (1000 mg/m\^2) administered orally twice a day on Days 1 through 14 of a 21-day cycle; fluorouracil with or without leucovorin (2400 mg\^m2) administered by IV infusion over 46 hours on Days 1 and 15 of a 28-day cycle; irinotecan (150 mg/m\^2) administered by IV infusion on Days 1 and 15 of a 28-day cycle; or erlotinib (100 mg) administered orally once a day for a 21-day cycle.
* The 2nd-line Cohort comprised those subjects who received and failed 1 prior chemotherapy regimen administered for pancreatic cancer in the metastatic setting.

Investigator's choice of one of the following commercially available products: gemcitabine; capecitabine; fluorouracil with or without leucovorin; irinotecan; or erlotinib.

Chemotherapy

cyclophosphamide

Test the safety, immune response and efficacy of GVAX pancreas vaccine (with cyclophosphamide) and CRS-207 compared to chemotherapy or CRS-207 alone in adults with previously treated metastatic pancreatic adenocarcinoma

Safety and Efficacy of Combination Listeria/GVAX Pancreas Vaccine in the Pancreatic Cancer Setting

A Phase 2B, Randomized, Controlled, Multicenter, Open-Label Study of the Efficacy and Immune Response of GVAX Pancreas Vaccine (With Cyclophosphamide) and CRS 207 Compared to Chemotherapy or to CRS-207 Alone in Adults With Previously-Treated Metastatic Pancreatic Adenocarcinoma

OS was estimated using Kaplan-Meier (KM) methods with 95% confidence intervals (CIs), with censoring at the date when 138 deaths were reached in the Primary Cohort in the FAS. Subjects without documentation of death at the time of final analysis were censored as of the date the subject was last known to be alive on/prior to the primary analysis data cut.

For all treated subjects, OS was calculated using KM methods with 95% CIs. Subjects without documentation of death at the time of the analysis were censored as of the date the subject was last known to be alive on/prior to the final analysis data cut.

For all treated subjects, OS was calculated using KM methods with 70% CIs. Subjects without documentation of death at the time of the analysis were censored as of the date the subject was last known to be alive on/prior to the final analysis cut. 70% CIs were selected to provide an 80% probability to rule out differences in median survival less than -2.4 months between the 2nd-line Cohort: Chemotherapy arm and the 2nd-line Cohort: Cy/GVAX + CRS-207 and 2nd-line Cohort: CRS-207 arms, based upon the assumptions made in the statistical analysis plan (SAP).

Safety was assessed based upon the number of adverse events (AEs) that occurred in the FAS of each treatment arm, including serious AEs and total AEs. Total AEs included both serious and non-serious AEs.

Johns Hopkins University

Adverse events reported for the FAS study population. Study data were not compiled for other (not including serious) adverse events as an individual category. Therefore, the reported data in the "Other (Not Including Serious) Adverse Events" section includes all adverse events reported in the study and occurring with a 5% or greater frequency, including both serious and non-serious adverse events.

* 200 mg/m\^2 Cy administered by IV infusion on Day 1 of Weeks 1 and 4; GVAX pancreas vaccine (5 × 10e8 cells) administered by intradermal injection on Day 2 of Weeks 1 and 4; CRS-207 (1 × 10e9 CFU) administered by IV infusion on Day 1 of Weeks 7, 10, 13, 16.
* Participants from both the Primary and 2nd-Line Cohorts receiving at least 1 Cy/GVAX + CRS-207 treatment were combined to form the Pooled Cohort.

Pooled Cohort: Cy/GVAX + CRS-207

* CRS-207 (1 × 10e9 CFU) administered by IV infusion on Day 1 of Weeks 1, 4, 7, 10, 13, 16.
* Participants from both the Primary and 2nd-Line Cohorts receiving at least 1 CRS-207 treatment were combined to form the Pooled Cohort.

Pooled Cohort: CRS-207

* Investigator's choice of one of the following: gemcitabine (1000 mg/m\^2) administered by IV infusion on Days 1, 8, and 15 of a 28-day cycle; capecitabine (1000 mg/m\^2) administered orally twice a day on Days 1 through 14 of a 21-day cycle; fluorouracil with or without leucovorin (2400 mg\^m2) administered by IV infusion over 46 hours on Days 1 and 15 of a 28-day cycle; irinotecan (150 mg/m\^2) administered by IV infusion on Days 1 and 15 of a 28-day cycle; or erlotinib (100 mg) administered orally once a day for a 21-day cycle.
* Participants from both the Primary and 2nd-Line Cohorts receiving at least 1 chemotherapy treatment were combined to form the Pooled Cohort.

Pooled Cohort: Chemotherapy

Primary Cohort: Cy/GVAX + CRS-207

Primary Cohort: CRS-207

Primary Cohort: Chemotherapy

2nd-line Cohort: Cy/GVAX + CRS-207

2nd-line Cohort: CRS-207

2nd-line Cohort: Chemotherapy

Age, Continuous

Baseline analysis provided for all randomized subjects who were administered at least 1 dose of protocol-specified drug (the Full Analysis Set \[FAS\]).

A high number of patients in the chemotherapy arm withdrew from the study before receiving treatment. This high dropout rate may have an impact on interpretation of the study results.

Corporate Communications

Analysis based on subjects in the Primary Cohort in the intent-to-treat (ITT) set. The ITT set is the analysis population that included all randomized study subjects.

Primary Cohort: Overall Survival (OS) Censored at 138 Deaths (ITT Set)

Analysis based on subjects in the Primary Cohort in the FAS.

Primary Cohort: OS (All Data, FAS)

Analysis based on subjects in the 2nd-line Cohort in the FAS.

2nd-line Cohort: OS (All Data, FAS)

Serious AEs

Total AEs

Analysis conducted for the FAS of each study arm.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Adjuvant GVAX Vaccine Therapy in Patients With Pancreatic Cancer	NCT00389610	Pancreatic Canc...	GVAX pancreas v...	18 Years -	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study of CRS-207, Nivolumab, and Ipilimumab With or Without GVAX Pancreas Vaccine (With Cy) in Patients With Pancreatic Cancer	NCT03190265	Pancreatic Canc...	Cyclophosphamid... Nivolumab Ipilimumab GVAX Pancreas V... CRS-207 CRS-207	18 Years -	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Safety and Efficacy of Combination Listeria/GVAX Pancreas Vaccine in the Pancreatic Cancer Setting	NCT02004262	2nd-line, 3rd-l...	GVAX Pancreas V... CRS-207 Chemotherapy cyclophosphamid...	18 Years -	Aduro Biotech, Inc.
Adjuvant GVAX Vaccine Therapy in Patients With Pancreatic Cancer	NCT00389610	Pancreatic Canc...	GVAX pancreas v...	18 Years -	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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