The purpose of this study is to assess the effectiveness and safety of intraperitoneal administration of heated nanoliposomal Irinotecan in cytoreductive surgery (CRS), which is surgery designed to remove as much of the cancer as possible, and heated intraperitoneal chemotherapy (HIPEC) procedures.

Cytoreductive surgery and heated intraperitoneal chemotherapy consists of two parts: the first is the surgical removal of all grossly visible deposits of cancer from the abdomen; and the second is application of heated chemotherapy in salt water at the same time as the removal of the visible cancer. HIPEC is an alternative method of delivering chemotherapy. Traditional chemotherapy is injected into a vein, while HIPEC applies chemotherapy drugs warmed up by an FDA-approved machine to 108 degrees Fahrenheit directly into the abdomen during surgery, making it an option for cancers that originated in or have spread to the abdominal cavity. Standard treatment in this manner usually includes Mitomycin C or Cisplatin as its chemotherapy agents. In this study, the investigators will use nanoliposomal irinotecan as the chemotherapy agent. Irinotecan is FDA approved for the treatment of pancreatic cancer.

Inclusion Criteria:

1. Patients with pseudomyxoma peritonei or peritoneal carcinomatosis of digestive origin or primary peritoneum: appendiceal mucinous tumor or adenocarcinoma (including goblet cell cancer and signet ring cell cancer), colorectal cancer, gastric cancer, primary peritoneal adenocarcinoma, and mesothelioma; regardless of the number of prior treatment lines. Diagnosis of peritoneal metastasis to be confirmed via either clinical or histopathology assessment.

2. Age ≥18 years

3. Eastern Cooperative Oncology Group performance status of 0 or 1

4. Patients must be candidates for grossly complete cytoreduction surgery with life expectancy greater than 3 months

5. Patients must have normal organ and marrow function as defined below:

   • absolute neutrophil count >1,500/microliter (mcL) and white blood cells > 4000/mm3
   • platelets >75,000/microliters
   • total bilirubin < 3x upper limit normal for institutional limits
   • aspartate aminotransferase (AST) / Alanine aminotransferase (ALT) <2.5x institutional upper limit of normal
   • creatinine within normal institutional limits

6. Documentation of resectable disease extent by radiographic peritoneal carcinomatosis index (PCI) score or preoperative diagnostic surgery/laparoscopy with preoperative measurements taken within 6 weeks of study entry.

7. Women of child-bearing potential and men must agree to use adequate contraception (barrier or hormonal plus barrier method of birth control; abstinence) prior to study entry and for the duration of study participation (at least first 6 months). Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

8. Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

1. Patients with peritoneal disease considered to be unresectable according to preoperative clinical criteria.
2. Patients who undergo debulking for palliation with persistence of gross residual disease (complete of cytoreduction score 3, CC=3) will be ineligible for the study.
3. Large burden visceral metastases or extra-abdominal metastases.
4. Patients who have had radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier. There is no limit on the number of prior lines of chemotherapy.
5. Patients may not be receiving any other investigational agents.
6. History of allergic reactions to nal-IRI or irinotecan.

7 Uncontrolled ongoing illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

8 Pregnant or breast-feeding women are excluded from this study.

9 HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy.

All eligible patients will be treated with the study drug.