Phase 3 Development

Currently in Phase 3 is BioSante’s GVAX pancreatic cancer vaccine.5 The vaccine, which comprises allogeneic, irradiated pancreatic cancer cells genetically modified to stimulate the immune system to produce the cytokine GM-CSF, amplifies the immune response. In Phase 1b clinical trials, the vaccine increased median survival of patients with previously treated, locally advanced or metastatic pancreatic adenocarcinoma from 3.3 months, when treated with ipilimumab (Yervoy, Bristol-Myers Squibb), to 5.5 months. In this 30-patient trial, the primary endpoint evaluated the safety of ipilimumab monotherapy compared to GVAX plus ipilimumab; secondary endpoints were overall survival (OS) and toxicity, and the induction of mesothelin-specific T-cell responses. The vaccine was generally well tolerated.

In a Phase 2 study, 60 pancreatic cancer patients received GVAX after pancreatic resection. Their median survival time increased from 17.3 months (95% CI, 14.6–22.8) to 24.8 months (95% CI, 21.2–31.6); GVAX also increased 1-year survival from 63% to 85%. Investigators reached their primary endpoint of disease-free survival, and secondary endpoints of OS, toxicity, and the induction of mesothelin-specific T-cell responses; the latter correlated with disease-free survival.6

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When vaccines are used in combination with chemotherapeutic agents, such as cyclophosphamide, they have a synergistic anti-tumor effect. It is not yet known whether vaccine therapy is more effective with or without cyclophosphamide in treating patients with pancreatic cancer. This is currently being evaluated in a randomized, open-label, treatment-based trial, where safety, feasibility, and immune response are the primary outcomes, and secondary outcome measures include (OS) and progression-free survival (PFS).7

Patients included in the trial are 18 years of age and older with newly diagnosed adenocarcinoma of the head, neck, or uncinate process of the pancreas; stage 1 or 2 disease, which was surgically resectable and non-metastatic. Patients must not have received anticancer, steroidal, or immunotherapy therapy for 28 days prior to enrollment in the study.

This trial is composed of 3 experimental arms. In all 3 arms, patients receive GVAX on Day 1; a pancreaticoduodenectomy on Day 15; a second dose of the vaccine on Day 1 at 6 to 10 weeks post-surgery; standard adjuvant chemoradiotherapy (gemcitabine, fluorouracil or capecitabine, plus radiotherapy) at 1 month after the second vaccination and for the next 18 to 26 weeks; a third dose of vaccine at approximately 4 to 8 weeks after completion of chemoradiotherapy; and additional vaccine doses every 28 days for a total of 4 courses. This is the regimen for patients in Arm A.

Patients randomized to Arm B receive the same regimen as patients in Arm A plus a low-dose cyclophosphamide, administered intravenously (IV), on Day 0 of the study, and on Day 0 at approximately 4 to 8 weeks after completion of chemoradiotherapy. Patients randomized to Arm C receive the same regimen as patients in Arm A plus a low-dose oral cyclophosphamide twice daily on Days 1 to 7; on Days 1 to 7 and Days 15 to 21, following pancreaticoduodenectomy; and on Days 1 to 7 and Days 15 to 21 at 4 to 8 weeks following the completion of chemotherapy. For patients randomized to Arms B and C, treatment with the vaccine and cyclophosphamide repeats every 28 days for 4 courses.