Individual Response to Hyperthermic Intraperitoneal Chemotherapy (HIPEC) Treatment of Peritoneal Carcinomatosis From Peritoneal Mesothelioma or Atypical Mesothelial Proliferation or From Ovarian, Colorectal, or Appendiceal Histologies

Individualized Response Assessment to Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for the Treatment of Peritoneal Carcinomatosis From Peritoneal Mesothelioma or Atypical Mesothelial Proliferation or From Ovarian, Colorectal, or Appendiceal Primaries

Background:

Cytoreductive surgery (CRS) removes tumors in the abdomen. HIPEC is hyperthermic (heated) chemotherapy that washes the inside of the abdomen. CRS with HIPEC may help people with peritoneal carcinomatosis. These are tumors that have spread to the lining of the abdomen from other cancers. Researchers think they can improve the results of CRS with HIPEC treatment on these tumors by choosing the chemotherapy drugs used in HIPEC.

Objective:

To see if HIPEC after CRS can be improved, using either a model called the SMART (Sustained Microenvironment for Analysis of Resected Tissue) System or using 3-D cell culture (organoid) models, in order to test different chemotherapy drugs on tumors that were surgically removed prior to HIPEC treatment (these models are not attached to the body) versus tumors that were treated with HIPEC while still inside the body before being immediately surgically removed.

Eligibility:

Adults ages 18 and older who have peritoneal carcinomatosis that cannot be fully removed safely with surgery.

Design:

Participants will be screened with:

Medical history

Physical exam

Blood and urine tests

Electrocardiogram (EKG)

Computed tomography (CT) scan

Other imaging scans, as needed

Tumor biopsy, if needed

Laparoscopy (small cuts are made in the abdomen, and a tube with a light and a camera is used to see the organs in the abdomen), if needed

Participants will enroll in NIH protocol #13C0176. This allows their tumor samples to be used in future research.

Some screening tests may be repeated in the study.

Participants will have CRS. As many of their visible tumors will be removed as possible during surgery except for a few specific tumors left to receive the HIPEC treatment. Then they will receive HIPEC and the remaining tumors will be immediately removed. Participants will be in the hospital for 7-21 days after this surgery (CRS with HIPEC).

Participants will give tumor, fluid samples (from the abdomen during surgery), blood, saliva, cheek swab, and stool for research. They will complete surveys about their health and quality of life.

Participants with peritoneal mesothelioma (mesothelioma primary only) will have genetic (DNA) testing to determine clinical (CLIA level) germline BAP1 status for research use.

Participants will have follow-up visits for up to 5 years from CRS with HIPEC.

If there is disease progression, participants may have CRS with HIPEC again. Participants will then have follow-up visits for up to 5 years from the date of last CRS with HIPEC.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Cancer; Ovarian Cancer; Gastrointestinal Cancer; Peritoneal Carcinomatosis; Peritoneal Mesothelioma; Appendiceal Cancer; Atypical Mesothelial Proliferation
• Intervention / Treatment: Drug: Oxaliplatin; Drug: 5-Fluorouracil; Drug: Mitomycin C; Drug: Cisplatin; Drug: Doxorubicin; Drug: Sodium Thiosulfate; Procedure: Hyperthermic Intraperitonial Chemotherapy

Detailed Description

Background:

Peritoneal carcinomatosis is uniformly fatal if untreated; improved outcomes are seen with aggressive cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC).

The selection of chemotherapeutic agent for HIPEC is largely based on primary tumor histology and provider preference as opposed to knowledge of the potential efficacy of a specific agent for an individual patient.

HIPEC is intended to target small or microscopic residual disease following complete cytoreduction; however, the actual efficacy and additional benefit of HIPEC is in question.

Tissue response to simulated ex vivo HIPEC treatment in the SMART System or 3-D cell culture (organoid) models could inform chemotherapeutic agent selection for subsequent cytoreduction and intra-operative in vivo HIPEC treatments.

Objective:

To determine the correlation between ex vivo simulated HIPEC in the SMART System or 3-D cell culture (organoid) models, and in vivo HIPEC with respect to two measures of response to treatment: percent necrosis and Ki-67

Eligibility:

Histologically confirmed peritoneal carcinomatosis from peritoneal mesothelioma or atypical mesothelial proliferation, or from appendiceal, colorectal, or ovarian, histologies

Absence of extra-abdominal metastatic disease

Participant deemed able to undergo optimal cytoreduction

Age >= 18 years of age

Design:

This is a Phase I study of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), with randomization to one of two accepted HIPEC treatment regimens as determined by primary histology.

At the time of cytoreduction, representative peritoneal tumor biopsies will be obtained before and after intra-operative in vivo HIPEC treatment.

Tumor nodules harvested before intra-operative HIPEC will be placed in either the SMART System or 3-D cell culture (organoid) models, exposed to simulated ex vivo HIPEC treatment, and then perfused or maintained in culture, with subsequent assessment

of percent necrosis and Ki-67.

Tumor nodules harvested immediately after intra-operative HIPEC will be placed in the SMART System or 3-D cell culture (organoid) models and perfused or maintained in culture, with subsequent assessment of percent necrosis and Ki-67.

The correlation of percent necrosis and Ki-67 assessment following simulated ex vivo HIPEC and intra-operative in vivo HIPEC will be determined.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Andrew M Blakely, M.D.; Phone Number: (240) 760-7647; Email: andrew.blakely@nih.gov
• Study Contact Backup: Name: Stephanie N Canady, R.N.; Phone Number: (240) 858-7573; Email: stephanie.canady@nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Institutes of Health Clinical Center
      • Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office; Phone Number: 888-624-1937

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

• INCLUSION CRITERIA:
• Confirmation of peritoneal carcinomatosis from peritoneal mesothelioma or atypical mesothelial proliferation, or from appendiceal, colorectal, or ovarian, histologies by the Laboratory of Pathology, NCI.
• Measurable or evaluable disease as defined by RECIST v1.1. criteria and/or by peritoneal carcinomatosis index (PCI) score.

• Participants must be assessed to be able to undergo optimal cytoreduction (i.e., completeness of cytoreduction score of 1 or 0) with laparoscopically assessed PCI score threshold as indicated below:

  • Primary Histology: Appendiceal/Colorectal/Ovarian / PCI Cutoff for Eligibility: Total Score < 20 (out of 39 possible points)
  • Primary Histology: Mesothelioma or atypical mesothelial proliferation / PCI Cutoff for Eligibility: Total Score <= 30 (out of 39 possible points)
• Age >= 18 years.
• ECOG performance status <= 1 (Karnofsky >= 80%).

• Participants must have adequate organ and marrow function as defined below:

  • Absolute neutrophil count >= 1,000/mcL
  • Platelets >= 75,000/mcL
  • Total bilirubin within <=1.5x institutional upper limit of normal (ULN)
  • AST (SGOT)/ ALT (SGPT) <= 3x institutional upper limit of normal (ULN), or <= 5.0x ULN in participants with liver metastases (only)
  • Creatinine within normal institutional limits

OR

--Creatinine clearance >= 60 mL/min/1.73 m^2 for participants with creatinine levels above institutional normal calculated using eGFR.

• Because therapeutic agents used in this trial are known to be teratogenic, individuals of child-bearing potential (IOCBP) and individuals who are able to father a child must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for 180 days after last study treatment.
• Ability of participant to understand and the willingness to sign a written informed consent document.
• Ability and willingness of the participant to co-enroll on the tissue collection protocol 13C0176, Tumor, Normal Tissue and Specimens from Patients Undergoing Evaluation or Surgical Resection of Solid Tumors .

EXCLUSION CRITERIA:

• Participants with known extra-abdominal metastatic disease from the participant s appendiceal, colorectal, ovarian, or peritoneal mesothelioma primary.
• Participants who have received intraperitoneal chemotherapy or other anti-cancer therapy within the last 4 weeks prior to the start of study treatment.
• Participants who have undergone major surgery within the last 12 weeks prior to the start of study treatment.
• History of allergic reactions attributed to platinum-containing compounds.
• History of dihydropyrimidine dehydrogenase deficiency (only participants with appendiceal or colorectal cancer).
• Uncontrolled intercurrent 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.
• Pregnant individuals are excluded from this study because the protocol involves major abdominal surgery and chemotherapeutic agents with the potential for teratogenic or abortifacient effects. Note: Due to an unknown but potential risk for adverse events in nursing infants secondary to treatment of the participant, nursing (including breastfeeding) should be discontinued if the participant is undergoing treatment (i.e., nursing participants must agree to discontinue nursing activities).
• HIV-positive participants with detectable viral load despite antiretroviral therapy are ineligible because of participants increased risk of lethal infections when treated with marrow-suppressive therapy. HIV-positive participants who have undetectable viral load on antiretroviral therapy may be considered for this study only after consultation with a NIAID physician.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1/ HIPEC: Oxaliplatin Randomized treatment assignment; HIPEC with intraperitoneal oxaliplatin and IV 5-FU, randomly assigned	Drug: Oxaliplatin; Arm 1, intraperitoneal (IP) Oxaliplatin: 200 mg/m2 for 90 minutes, mixed in 250 mL of 5% dextrose solution. For oxaliplatin-based HIPEC, intravenous 5-fluorouracil given at a dose of 400 mg/m2 in 250 mL 0.9% sodium chloride over 10 minutes, co-administered with intravenous leucovorin at 20 mg/m2 in a separate bag of 250 mL 0.9% sodium chloride; Drug: 5-Fluorouracil; Part of Arm 1, for oxaliplatin-based HIPEC: intravenous 5-fluorouracil given at a dose of 400 mg/m2 in 250 mL 0.9% sodium chloride over 10 minutes, co-administered with intravenous leucovorin at 20 mg/m2 in a separate bag of 250 mL 0.9% sodium chloride; Procedure: Hyperthermic Intraperitonial Chemotherapy; Hyperthermic Intraperitonial Chemotherapy (HIPEC) with with standardized doses of chemotherapeutic agents as indicated by the subject's Arm assignment
Experimental: 2/ HIPEC: Mitomycin C Randomized treatment assignment; HIPEC with intraperitoneal mitomycin C, randomly assigned	Drug: Mitomycin C; Arm 2, intraperitoneal (IP) Mitomycin C monotherapy: dosing divided into two 60-mL syringes, 30 mg per syringe. 30 mg will be given at time = 0, and the remaining 10 mg of the dose will be given at time = 60 minutes. Part of Arm 4: Mitomycin C co-therapy 15 mg/m2 for 60 minutes, given at time = 0 with cisplatin; Procedure: Hyperthermic Intraperitonial Chemotherapy; Hyperthermic Intraperitonial Chemotherapy (HIPEC) with with standardized doses of chemotherapeutic agents as indicated by the subject's Arm assignment
Experimental: 3/ HIPEC: Cisplatin, Doxorubicin Randomized treatment assignment; HIPEC with intraperitoneal cisplatin and doxorubicin, in addition to IV sodium thiosulfate, randomly assigned	Drug: Cisplatin; Part of Arms 3 and 4, intraperitoneal (IP)cisplatin co-therapy: 75 mg/m2 for 60 minutes, mixed in 1 L of 0.9% sodium chloride. For cisplatin-based HIPEC, intravenous sodium thiosulfate given as a loading dose of 7.5 g/m2 in 150 mL 0.9% sodium chloride at the time of introducing cisplatin into the perfusion circuit, followed by a 12-hour pump-based infusion of 25.56 g/m2 in 1 L 0.9% sodium chloride; Drug: Doxorubicin; Part of Arm 3: intraperitoneal (IP) Doxorubicin co-therapy 15 mg/m2 for 60 minutes, given at time = 0 with cisplatin; Drug: Sodium Thiosulfate; Part of Arms 3 and 4, for cisplatin-based HIPEC: intravenous sodium thiosulfate given as a loading dose of 7.5 g/m2 in 150 mL 0.9% sodium chloride at the time of introducing cisplatin into the perfusion circuit, followed by a 12-hour pump-based infusion of 25.56 g/m2 in 1 L 0.9% sodium chloride; Procedure: Hyperthermic Intraperitonial Chemotherapy; Hyperthermic Intraperitonial Chemotherapy (HIPEC) with with standardized doses of chemotherapeutic agents as indicated by the subject's Arm assignment
Experimental: 4/ HIPEC: Cisplatin, Mitomycin C Randomized treatment assignment; HIPEC with intraperitoneal cisplatin and mitomycin C, in addition to IV sodium thiosulfate, randomly assigned	Drug: Mitomycin C; Arm 2, intraperitoneal (IP) Mitomycin C monotherapy: dosing divided into two 60-mL syringes, 30 mg per syringe. 30 mg will be given at time = 0, and the remaining 10 mg of the dose will be given at time = 60 minutes. Part of Arm 4: Mitomycin C co-therapy 15 mg/m2 for 60 minutes, given at time = 0 with cisplatin; Drug: Cisplatin; Part of Arms 3 and 4, intraperitoneal (IP)cisplatin co-therapy: 75 mg/m2 for 60 minutes, mixed in 1 L of 0.9% sodium chloride. For cisplatin-based HIPEC, intravenous sodium thiosulfate given as a loading dose of 7.5 g/m2 in 150 mL 0.9% sodium chloride at the time of introducing cisplatin into the perfusion circuit, followed by a 12-hour pump-based infusion of 25.56 g/m2 in 1 L 0.9% sodium chloride; Drug: Sodium Thiosulfate; Part of Arms 3 and 4, for cisplatin-based HIPEC: intravenous sodium thiosulfate given as a loading dose of 7.5 g/m2 in 150 mL 0.9% sodium chloride at the time of introducing cisplatin into the perfusion circuit, followed by a 12-hour pump-based infusion of 25.56 g/m2 in 1 L 0.9% sodium chloride; Procedure: Hyperthermic Intraperitonial Chemotherapy; Hyperthermic Intraperitonial Chemotherapy (HIPEC) with with standardized doses of chemotherapeutic agents as indicated by the subject's Arm assignment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To determine the correlation between ex vivo simulated HIPEC in the SMART System or 3-D cell culture (organoid) models, and in vivo HIPEC with respect to two measures of response to treatment: percent necrosis and Ki-67	percent necrosis and Ki-67 scores will be obtained and used to determine the correlation between each measure by ex vivo simulated HIPEC in the SMART System or 3-D cell culture (organoid) models, and by in vivo intra-operative HIPEC	approx. 4 days post-HIPEC

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To measure Quality of Life by FACT-C and EQ-5D-5L	outcomes from QOL will be reported using descriptive statistics, as well as comparing the results from before to after treatment: physical and mental health-related quality of life, social and emotional wellbeing, and disease-related symptoms	baseline, every 3 months post-treatment for 2 years, than every 6 months for a total of 5 years
To evaluate overall survival for up to 5 years after (last) CRS and HIPEC	median amount of time participant survives from (last) CRS and HIPEC until death or for up to 5 years post-treatment	death or 5 years post-treatment
To assess germline BAP1 status as a prognostic indicator for progression-free survival (PFS) in participants with peritoneal mesothelioma treated with CRS and HIPEC	Kaplan Meier curves reported separately by BAP1 germline mutation status to describe PFS in participants with peritoneal mesothelioma (only) with and without BAP1 germline mutations	baseline
To estimate the peritoneal progression-free survival probability	median amount of time participant survives from time of cytoreduction until peritoneal progression, determined for the individual cohorts and treatment arms and compared between arms within cohorts	baseline, every 3 months post-treatment for 2 years, than every 6 months for a total of 5 years

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Andrew M Blakely, M.D., National Cancer Institute (NCI)

Publications and helpful links

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): October 19, 2021
• Primary Completion (Estimated): December 30, 2033
• Study Completion (Estimated): December 30, 2034

Study Registration Dates

• First Submitted: April 14, 2021
• First Submitted That Met QC Criteria: April 14, 2021
• First Posted (Actual): April 15, 2021

Study Record Updates

• Last Update Posted (Actual): April 14, 2026
• Last Update Submitted That Met QC Criteria: April 11, 2026
• Last Verified: March 26, 2026

More Information

Terms related to this study

• Keywords: Ki-67; cytoreduction; cytoreductive surgery (CRS); SMART System; necrosis; Peritoneal Metastasis; organoid model; cell culture model
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Endocrine System Diseases; Pathologic Processes; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Intestinal Diseases; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Genital Diseases, Female; Endocrine Gland Neoplasms; Colonic Diseases; Ovarian Diseases; Adnexal Diseases; Genital Neoplasms, Female; Gonadal Disorders; Peritoneal Diseases; Abdominal Neoplasms; Cecal Neoplasms; Cecal Diseases; Pathological Conditions, Signs and Symptoms; Necrosis; Colorectal Neoplasms; Ovarian Neoplasms; Gastrointestinal Neoplasms; Peritoneal Neoplasms; Appendiceal Neoplasms; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Hydrocarbons; Hydrocarbons, Cyclic; Carbohydrates; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Glycosides; Indoles; Inorganic Chemicals; Chlorine Compounds; Nitrogen Compounds; Coordination Complexes; Pyrimidines; Uracil; Pyrimidinones; Anthracyclines; Naphthacenes; Aminoglycosides; Platinum Compounds; Daunorubicin; Quinones; Azirines; Mitomycins; Indolequinones; Oxaliplatin; Fluorouracil; Doxorubicin; Cisplatin; Mitomycin; sodium thiosulfate
• Other Study ID Numbers: 210012; 21-C-0012

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All IPD recorded in the medical record will be shared with intramural investigators upon request.
• IPD Sharing Time Frame: Clinical data available during the study and indefinitely.
• IPD Sharing Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No