Pressurized Intraperitoneal Aerosolized Chemotherapy With Mitomycin for the Treatment of Unresectable Appendix or Colorectal Cancer With Peritoneal Metastases, The IMPACT Trial

PRIMARY OBJECTIVE: I. Evaluate the overall survival of patients treated with mitomycin PIPAC (MMC-PIPAC) in combination with systemic FOLFIRI in comparison to those treated with systemic FOLFIRI/bevacizumab as a 2nd line therapy in patients with appendiceal or colorectal cancer with peritoneal metastases. SECONDARY OBJECTIVES: I. Compare progression-free survival between the two arms. II. Rate of completion of cytoreductive surgery. III. Evaluate the Objective response rate by arm, assessed by: IIIa. Peritoneal Regression Grading Score (PRGS) via histologic assessment of biopsies performed at each PIPAC cycle; IIIb. Laparoscopic Peritoneal Carcinomatosis Index (PCI) reduction; IIIc. Radiographic response by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1; IIId. Tumor marker (CEA) response rate. IV. Patient-reported health state/quality of life and symptoms before treatment, at 6 months and at 1-year, as measured by European Organisation for the Research and Treatment of Cancer-Quality of Life Questionnaire (EORTC-QLQ30) and EORTC-Colorectal Cancer (CR29) for each arm. EXPLORATORY OBJECTIVES: I. Characterization of sub-clonal and tumor microenvironment evolution in response to therapy with a particular focus on immune and fibroblast subsets in the tumor and immune subsets in peripheral blood. II. Correlating cell free DNA, ribonucleic acid (RNA), proteins and/or metabolites in blood and peritoneal fluid with burden of disease, survival and response to therapy. III. Develop artificial intelligence and machine learning approaches for the characterization of peritoneal metastases by correlating video/photographic imaging features of peritoneal metastases to histologic features. IV. Establish the feasibility of generating patient-derived xenografts, organoids, and cell lines from pre-treated colorectal and appendiceal cancer peritoneal metastases (City of Hope \[COH\] only). V. Characterization of stool and tissue microbiome of patients on the study protocol. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive mitomycin via PIPAC during on day 1 of each cycle. Cycles repeat every 6 weeks for 3 cycles in the absence of disease progression or unacceptable toxicity. Beginning 2 weeks after each mitomycin PIPAC treatment, patients receive FOLFIRI regimen, consisting of irinotecan intravenously (IV) over 90 minutes on day 1 of each cycle, leucovorin IV over 30 minutes on day 1 of each cycle, and fluorouracil IV over 46-48 hours on day 1 of each cycle (i.e., weeks 2, 4, 8, 10, 14, 16, etc). Cycles of FOLFIRI regimen repeat every 2 weeks in the absence of disease progression or unacceptable toxicity. Beginning 4 weeks after last cycle of mitomycin PIPAC, patients may also receive bevacizumab IV over 30-90 minutes at the discretion of the treating physician. Cycles of bevacizumab repeat every 2 weeks in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive FOLFIRI regimen, consisting of irinotecan IV over 90 minutes on day 1 of each cycle, leucovorin IV over 30 minutes on day 1 of each cycle, and fluorouracil IV over 46-48 hours on day 1 of each cycle. Cycles repeat every 2 weeks in the absence of disease progression or unacceptable toxicity. Beginning 4 weeks after standard laparoscopy, patients also receive bevacizumab IV over 30-90 minutes on day 1 of each cycle. Cycles of bevacizumab repeat every 2 weeks in the absence of disease progression or unacceptable toxicity. Patients who experience disease progression may cross-over to Arm I (NOTE: Cross-over patients do not receive FOLFIRI regimen). All patients also undergo computed tomography (CT), collection of blood, ascites, and urine samples, as well as biopsies throughout the study. Patients may also undergo magnetic resonance imaging (MRI) during screening. After completion of study treatment, patients are followed up at 4 weeks and then every 8-12 weeks until death.