This single-center, Phase 1 dose-escalation study will evaluate the safety, tolerability, and recommended Phase 2 dose (RP2D) of pressurized intraperitoneal aerosol chemotherapy with mitomycin C (PIPAC-MMC) for patients with unresectable peritoneal carcinomatosis from gastrointestinal primaries (colorectal, high-grade appendiceal, or small bowel). Up to three PIPAC procedures are planned at 8-week intervals while patients continue 5-fluorouracil/leucovorin (5-FU/LV) between procedures. The trial uses a Bayesian optimal interval (BOIN) design to determine dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD). Pharmacokinetics (PK), pharmacodynamics (PD), and quality of life (QoL) will be assessed.

Inclusion Criteria:

• Participants must have histologically confirmed peritoneal disease from colorectal, small bowel, or high grade appendiceal adenocarcinoma. High grade appendiceal cancers include moderate or poorly differentiated mucinous or non-mucinous adenocarcinoma, signet ring cell adenocarcinoma, or goblet cell adenocarcinoma. This can be established by image guided biopsy, diagnostic laparoscopy, or previous surgery.
• Patients must be ineligible for CRS/HIPEC through one of the following criteria: a) PCI score ≥16. b) Inability to achieve complete cytoreduction due to extent of disease. c) Significant small bowel involvement precluding a complete CRS. d) Unresectable disease in porta hepatis, pelvic side wall or other critical structure. e) Patients who decline invasive cytoreduction.
• Participants must be 18 years of age or older.
• Participants must have completed at least 4 months of first-line systemic therapy (5-FU based approach with or without biologic therapy).
• Participants must have Eastern Cooperative Oncology Group (ECOG) Performance status of 0 or 1.
• Participants must have adequate organ and marrow function as defined below: a) absolute neutrophil count ≥1500/mcL. b) platelets ≥100,000/mcL. c) total bilirubin ≤ institutional upper limit of normal (ULN). d) AST(SGOT)/ALT(SGPT) ≤3 × institutional ULN. e) creatinine ≤ 1.5 institutional ULN. or f) glomerular filtration rate (GFR) ≥60 mL/min/1.73 m2.
• Human immunodeficiency virus (HIV)-infected participants on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
• For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
• Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
• Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should undergo a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification (see Appendix C).

To be eligible for this trial, participants should be class 2B or better.

• MMC is a known teratogen, for this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of study drug administration. For women of child-bearing potential a negative urine pregnancy test is required on the morning of surgery.
• Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

• Participants who have received targeted therapy, immunotherapy, or radiotherapy within 4 weeks (6 weeks for VEGF inhibitors, nitrosoureas or mitomycin C) prior to entering the study.
• Participants who have not recovered from adverse events (AEs) due to prior anti-cancer therapy (i.e., have residual toxicities > Grade 1), except for alopecia and chemotherapy induced peripheral neuropathy < 2.
• Patients with extensive metastatic liver disease (>50% liver volume) are excluded from the trial as are patients with brain metastases. Patients with non-peritoneal metastatic disease are otherwise eligible provided they meet the survival expectations of >6 months.
• Patients with brain metastases are excluded
• Patients with bowel obstruction or need for nutritional support (i.e., TPN or tube feeds).
• Participants who are receiving any other investigational agents or enrolled on other research protocols that may interfere with compliance with requirements of the study.
• History of allergic reactions or poor tolerance attributed to compounds of similar chemical or biologic composition to MMC, fluoropyrimidines, or anesthesia medications.
• Participants with uncontrolled intercurrent illnesses.
• Participants with psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant women are excluded from this study because MMC is an antibiotic alkylating antineoplastic agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with MMC, breastfeeding should be discontinued if the mother is treated with MMC.
• Inability to safely perform laparoscopy due to previously noted adhesions or extensive prior surgery which the treating surgeon feels would exclude safe abdominal access.
• Life expectancy less than 6 months.
• Patients with history of thromboembolic complications that cannot discontinue for the perioperative duration.