A Phase I / II Trial of the PD-L1 Inhibitor, Durvalumab (MEDI4736) plus CV301 in Combination with Maintenance Chemotherapy for Patients with Metastatic Colorectal or Pancreatic Adenocarcinoma
18 Years and older, Male and Female
This phase I / II trial studies the side effects and best dose of durvalumab when given with modified vaccinia Ankara-Bavarian Nordic-CV301 (MVA-BN-CV301), FPV vaccine CV301, and capecitabine with or without bevacizumab and to see how well they work in treating patients with colorectal or pancreatic cancer that has spread to other places in the body. Monoclonal antibodies, such as durvalumab, may interfere with the ability of tumor cells to grow and spread. Vaccines made from a gene-modified virus may help the body build an effective immune response to kill tumor cells. Giving booster vaccinations may make a stronger immune response and prevent or delay the recurrence of cancer. Drugs used in chemotherapy, such as capecitabine and bevacizumab, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Given durvalumab, MVA-BN-CV301, FPV vaccine CV301, and capecitabine with or without bevacizumab may work better in treating patients with colorectal or pancreatic cancer.
I. To determine the safety and tolerability, and the recommended phase II dose of durvalumab in the combination of durvalumab plus FPV vaccine CV301 (CV301). (Phase I)
II. To determine the 8.5 month progression free survival rate (PFS8.5mos) of durvalumab plus CV301 in combination with maintenance capecitabine and bevacizumab in patients with metastatic colorectal cancer, whose disease is stable on, or responding to first (1st) line therapy for metastatic disease. (Phase II Colorectal Cancer Arm)
III. To determine the progression free survival rate (PFS4mos) of durvalumab plus CV301 in combination with maintenance capecitabine in patients with metastatic pancreatic cancer, whose disease is stable on, or responding to 1st line therapy for metastatic disease. (Phase II Pancreatic Cancer Arm)
I. To determine, in patients treated with durvalumab plus CV301 whose disease is stable on, or responding to 1st line therapy for metastatic colorectal or pancreatic cancer: objective response rate (ORR) and duration of response, progression free survival (PFS), overall survival (OS), disease control rate (DCR) defined as ORR + rate of stable disease at 4 months), tolerability and safety of the combination.
II. To assess the predictive value of immune-inhibitory proteins, including PD-1, PD-L1 (B7H1), B7H3, B7H4, IDO, and arginase; and to assess the characteristics of the infiltrating T-cells in tumor samples.
III. Using a flow-based assay, to determine the number of immune cell subsets from peripheral blood mononuclear cell (PBMC) at baseline and during treatment and attempt to identify a pattern correlating with clinical benefit.
IV. To evaluate the antigen-specific T-cell activation against the target antigens of the vaccine, MUC-1 and carcinoembryonic antigen (CEA) as well as other potential cascade antigens, including but not limited to brachyury.
V. To evaluate serum soluble factors and serum cytokine expression profiles at baseline and on treatment and determine correlates of clinical benefit.
VI. To evaluate the relationship between tumor mutation burden and clinical benefit.
VII. To evaluate the expansion of peripheral and, potentially, intratumoral T cell clones as correlates and identify correlation with clinical benefit.
I. To assess, in patient tumor samples, the predictive value, and the changes in response to treatment of immune-inhibitory proteins and other cell signaling pathways as measured by reverse phase phosphoprotein pathway analysis of the laser capture microdissected tumor epithelium and tumor stroma/immune cell compartments.
II. To develop ex vivo models of patient tumors derived from patient tumor samples.
OUTLINE: This is a phase I, dose escalation study of durvalumab followed by a phase II study. Patients are assigned to 1 of 2 arms.
ARM I: Patients receive prime cancer vaccine MVA-BN-CV301 subcutaneously (SC) on days 1 and 29. Starting weeks 3, patients receive durvalumab intravenously (IV) over 1 hour every 2 weeks and capecitabine orally (PO) twice daily (BID) 5 days per week in the absence of disease progression or unacceptable toxicity. Patients may stop capecitabine by week 52 if achieve complete response. Patients also receive FPV vaccine CV301 SC on day 1 of weeks 9, 13, 17, 21, 25, and 37, and every 24 weeks starting week 53 in the absence of disease progression or unacceptable toxicity.
ARM II: Patients receive prime cancer vaccine MVA-BN-CV301 SC on days 1 and 29. Starting weeks 3, patients receive durvalumab IV over 1 hour every 2 weeks, capecitabine PO BID 5 days per week, and bevacizumab IV every 2 weeks in the absence of disease progression or unacceptable toxicity. Patients may stop capecitabine and bevacizumab by week 52 if achieve complete response. Patients also receive FPV vaccine CV301 SC on day 1 of weeks 9, 13, 17, 21, 25, and 37, and every 24 weeks starting week 53 in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 12 weeks for up to 12 months.