Mass-based drug screening to guide personalized HIPEC for high-grade appendiceal and colorectal cancer with peritoneal spread.

Inclusion Criteria:

* Has histologically confirmed peritoneal metastases with primary diagnosis of AJCC 8th Edition Stage IV

  1. Appendiceal adenocarcinoma (moderately/poorly differentiated, and/or signet ring cell tumors)
  2. Colorectal adenocarcinoma
  3. Suspected colon, small bowel, or appendiceal adenocarcinoma in setting of unknown primary
* Limited or no extraperitoneal metastases (any of the below)

  a) Any extraperitoneal metastases must be limited, stable and treatable
* Has adequate organ function, as described below; all screening laboratory tests should be performed within 30 days prior to the first HIPEC
* Expected survival at the time of first HIPEC is greater than 3 months
* Exhibits unresectable disease (bowel or mesenteric involvement) or PCI \> 19

Demographics

* Adult patient at least 18 years of age at the time of signing informed consent and less than 81 years of age at the time of signing informed consent.
* Has an ECOG performance status score of 0-2.

Male Participants

* A male participant must agree to use contraception (barrier birth control, abstinence) during the treatment period and for at least 95 days following completion, corresponding to time needed to eliminate any study intervention(s), and refrain from donating sperm during this period.

Female Participants

* A female participant of childbearing age is eligible to participate if she is not pregnant, not breastfeeding, and agrees to use contraception (hormonal, barrier birth control, or abstinence). Should a woman become pregnant or suspect that she is pregnant while participating in this study, she should inform her treating physician immediately.

Informed Consent

* The participant (or legally acceptable representative if applicable) provides written informed consent for the study. The participant may also provide consent for FBR. However, the participant may participate in the main study without participating in FBR.

Alternative Eligibility

* In addition to the criteria above, if a patient has undergone less than 8 rounds of chemotherapy at another institution (prior to initial diagnostic laparoscopy) and has not undergone radiation, ablative procedures, or cytoreductive surgery, then they are still eligible to enter the study at the second diagnostic laparoscopy step

Exclusion Criteria:

* Has a positive urine pregnancy test within 3 days prior to randomization or treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
* Has a known allergy to medications used in this study. Note: In the event that 3 days have elapsed between the screening pregnancy test and the first dose of study intervention, another pregnancy test (urine or serum) must be performed and must be negative for the participant to start receiving study medication.
* Has hypoxia as defined by pulse oximeter reading \<92% at rest or requires intermittent or chronic supplemental oxygen.
* No concurrent malignancy that may interfere with the study aims at the discretion of the investigator.

Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.

* Has known significant extraperitoneal metastasis.
* Has creatine clearance \<60 mL/m\^2 per the Cockcroft-Gault formula
* Has clinically significant cardiac disease, including unstable angina, acute myocardial infarction within 6 months from treatment initiation, or New York Heart Association Class III or IV congestive heart failure. Medially controlled arrhythmia stable on medication is permitted.
* Has poorly controlled hypertension defined as SBP ≥150mmHg and/or DBP ≥90mmHg.
* Has moderate to severe hepatic impairment (Child-Pugh B or C).
* Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study.
* Is unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption (severe dysphasia, bowel obstruction, malabsorption).
* Has progressive disease following the first 3 months of systemic chemotherapy prior to HIPEC who is not in a stable condition to continue with the trial.

Prior/Concomitant Therapy

* Has received radiation, ablative procedures, cytoreductive surgery, or systemic therapy including chemotherapy to treat metastatic disease within 3 months of initial laparoscopy.

Diagnostic Assessments

* Has an active infection requiring systemic therapy.
* Has a known active TB/ COVID infection.
* Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (dosing exceeding 10mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of the study intervention.
* Has a known history of poorly controlled HIV infection despite anti-retroviral therapy.
* Has a known history of HBV (defined as HBsAg reactive) or known active HCV (defined as HCV RNA \[qualitative\] is detected) infection that is poorly controlled.

Note: Testing for HBV and HCV is only required if mandated by the local health authority.

Other Exclusions

* Inability to receive chemotherapy due to medical/insurance reasons.
* Requires emergency surgery due to bleeding, perforation, or obstruction.
* Has undergone previous iterative intraperitoneal therapy.
* Has contraindication to chemotherapy of choice.