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

Study Overview
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Brief Summary
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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

Official Title
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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

Conditions
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2nd-line, 3rd-line and Greater Metastatic Pancreatic Cancer

Intervention / Treatment
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* Biological: GVAX Pancreas Vaccine
* Biological: CRS-207
* Drug: Chemotherapy
* Drug: cyclophosphamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have histologically proven malignant adenocarcinoma of the pancreas; measurable disease is not required, mixed histology is not allowed; subjects must have metastatic disease 2nd line, 3rd line or greater At least 18 years of age Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 Anticipated life expectancy >12 weeks For women and men of childbearing potential, a medically acceptable method of highly effective contraception (oral hormonal contraceptive, condom plus spermicide, or hormone implants) must be used throughout the study period and for 28 days after their final vaccine administration. A barrier method of contraception must be employed by all subjects (male and female), regardless of other methods. Have adequate organ function as defined by specified laboratory values Exclusion Criteria: Allergy to both penicillin & sulfa or suspected hypersensitivity to granulocyte-macrophage colony stimulating factor (GM-CSF), dimethyl sulfoxide, fetal bovine serum, trypsin, yeast, glycerol or other component of the therapy options Known history or evidence of brain metastases, immunodeficiency disease or immunocompromised state or history of autoimmune disease requiring systemic steroids or other immunosuppressive treatment Have any evidence of hepatic cirrhosis or clinical or radiographic ascites Have prosthetic heart valves, major implant or device placed in the last 12 months or history of infection with implant/device that cannot be easily removed Rapidly progressing disease Clinically significant and/or malignant pleural effusion Received prior GVAX pancreas vaccine or CRS-207 Major surgery or significant traumatic injury (or unhealed surgical wounds) occurring within 28 days prior to receiving study drug, or planned surgery requiring general anesthesia Infection with HIV or hepatitis B or C at screening Valvular heart disease that requires antibiotic prophylaxis for prevention of endocarditis Pregnant or breastfeeding Unable to avoid close contact with another individual known to be at high risk of listeriosis (e.g., newborn infant, pregnant woman, HIV-positive individual) during the course of CRS-207 treatment until completion of antibiotic regimen 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

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Primary Cohort: Cy/GVAX + CRS-207<br>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. | Biological: GVAX Pancreas Vaccine<br> <br> * Other names: GVAX;Biological: CRS-207<br> <br> Drug: cyclophosphamide<br> <br> * Other names: Cytoxan;|
| Experimental: Primary Cohort: CRS-207<br>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. | Biological: CRS-207<br> <br> |
| Active Comparator: Primary Cohort: Chemotherapy<br>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. | Drug: Chemotherapy<br>* Investigator's choice of one of the following commercially available products: gemcitabine; capecitabine; fluorouracil with or without leucovorin; irinotecan; or erlotinib.<br>|
| Experimental: 2nd-line Cohort: Cy/GVAX + CRS-207<br>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. | Biological: GVAX Pancreas Vaccine<br> <br> * Other names: GVAX;Biological: CRS-207<br> <br> Drug: cyclophosphamide<br> <br> * Other names: Cytoxan;|
| Experimental: 2nd-line Cohort: CRS-207<br>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. | Biological: CRS-207<br> <br> |
| Active Comparator: 2nd-line Cohort: Chemotherapy<br>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. | Drug: Chemotherapy<br>* Investigator's choice of one of the following commercially available products: gemcitabine; capecitabine; fluorouracil with or without leucovorin; irinotecan; or erlotinib.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary Cohort: Overall Survival (OS) Censored at 138 Deaths (ITT Set) | 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. | Subjects were followed from date of randomization to the date of death by any cause, whichever came first, assessed up to 32 months. Analysis conducted when 138 deaths reached in the Primary Cohort in the FAS. | 
| Primary Cohort: OS (All Data, FAS) | 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. | Subjects followed for survival from date of randomization until lost to follow-up, withdrawal of consent, or death, whichever came first, assessed up to 32 months. | 
| 2nd-line Cohort: OS (All Data, FAS) | 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). | Subjects followed for survival from date of randomization until lost to follow-up, withdrawal of consent, or death, whichever came first, assessed up to 32 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events in Each Treatment Arm Treatment Regimen | 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. | From the start of the first study drug administration on Day 1, Week 1, through 28 days after the last study drug dose, assessed up to 32 months from the date of randomization. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cancer, cancer vaccine, Listeria monocytogenes, Listeria-based vaccine, GVAX, cyclophosphamide, Cytoxan, immunotherapy, mesothelin