Individualized Response Assessment to Heated Intraperitoneal Chemotherapy (HIPEC) for the Treatment of Peritoneal Carcinomatosis From Ovarian, Colorectal, Appendiceal, or Peritoneal Mesothelioma Histologies

• ClinicalTrials.gov Identifier: NCT04847063
• Recruitment Status: Recruiting
• First Posted: April 15, 2021
• Last Update Posted: May 24, 2023
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Tracking Information

• First Submitted Date: April 14, 2021
• First Posted Date: April 15, 2021
• Last Update Posted Date: May 24, 2023
• Actual Study Start Date: October 19, 2021
• Estimated Primary Completion Date: December 30, 2030 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 14, 2021)

To determine the correlation between ex vivo simulated HIPEC in the SMART system and in vivo HIPEC with respect to two measures of response to treatment: percent necrosis and Ki-67 [ Time Frame: approx. 4 days post-HIPEC ]

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 and by in vivo intra-operative HIPEC

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 14, 2021)

• To determine the correlation between ex vivo simulated HIPEC in the SMART System and in vivo HIPEC with respect to two measures of response to treatment: percent necrosis and Ki-67, separately within each cohort and arm subset, as well as within... [ Time Frame: approx. 4 days post-HIPEC ]
  Tumor tissue responses to ex vivo simulated HIPEC and in vivo HIPEC regimens will be assessed by an intramural pathologist using percent tissue necrosis and Ki-67 scoring, both to the nearest 10 percent. These assessments will be incorporated into pathology reports following cytoreductive surgery with HIPEC
• To estimate the peritoneal progression-free survival probability, separately by arms and by cohorts, in a preliminary fashion [ Time Frame: baseline, every 3 months post-treatment for 2 years, than every 6 months for a total of 5 years ]
  median amount of time subject survives from time of cytoreduction until peritoneal progression, assessed for the individual cohorts and treatment arms and also compared between arms within cohorts
• To estimate the peritoneal progression-free survival probability as a function of tissue response to ex vivo simulated HIPEC in the SMART System and in vivo HIPEC, as assessed by percent necrosis and Ki-67, in a preliminary fashion [ Time Frame: baseline, every 3 months post-treatment for 2 years, than every 6 months for a total of 5 years ]
  median amount of time subject survives from time of cytoreduction until peritoneal progression, as assessed in tissue response by percent necrosis and Ki-67
• To evaluate overall survival for up to 5 years after CRS and HIPEC [ Time Frame: death or 5 years post-treatment ]
  median amount of time subject survives from CRS and HIPEC until death or for up to 5 years post-treatment
• To measure Quality of Life by FACT-C and EQ-5D-5L [ Time Frame: baseline, every 3 months post-treatment for 2 years, than every 6 months for a total of 5 years ]
  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

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Individualized Response Assessment to Heated Intraperitoneal Chemotherapy (HIPEC) for the Treatment of Peritoneal Carcinomatosis From Ovarian, Colorectal, Appendiceal, or Peritoneal Mesothelioma Histologies
• Official Title: Individualized Response Assessment to Heated Intraperitoneal Chemotherapy (HIPEC) for the Treatment of Peritoneal Carcinomatosis From Ovarian, Colorectal, Appendiceal, or Peritoneal Mesothelioma Histologies

Brief Summary

Background:

Cytoreductive surgery (CRS) removes tumors in the abdomen. HIPEC is heated chemotherapy that washes the abdomen. CRS and 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 results of CRS and HIPEC by choosing the chemotherapy drugs used in HIPEC.

Objective:

To see if HIPEC after CRS can be improved, by testing different chemotherapy drugs, using a model called the SMART (Sample Microenvironment of Resected Metastatic Tumor) System.

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

Computed tomography (CAT) scan

Other imaging scans, as needed

Electrocardiogram (EKG)

Tumor biopsy, if needed

Laparoscopy. Small cuts will be made in the abdomen. A tube with a light and a camera will be used to see their organs.

Some screening tests will be repeated in the study.

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

Participants will have CRS. As many of their visible tumors will be removed as possible. They will also have HIPEC. Two thin tubes will be put in their abdomen. They will get chemotherapy through one tube. It will be drained out through the other tube. They will be in the hospital for 7-21 days after surgery.

Participants will give tumor, blood, and fluid samples for research. They will complete surveys about their health and quality of life.

Participants will have follow-up visits over 5 years.

Detailed Description

Background:

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

The SMART System provides an ideal platform upon which to perfuse small peritoneal tumor tissue implants and simulate HIPEC treatment ex vivo.

Tissue response to simulated ex vivo HIPEC treatment in the SMART System 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 and in vivo HIPEC with respect to two measures of response to treatment: percent necrosis and Ki-67

Eligibility:

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

Absence of extra-abdominal metastatic disease

Participant deemed able to undergo complete cytoreduction

Age >= 18 years of age

Design:

This is a Phase I study of cytoreductive surgery (CRS) and heated 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 the SMART System, exposed to simulated ex vivo HIPEC treatment, and then perfused, with subsequent assessment of percent necrosis and Ki-67.

Tumor nodules harvested after intra-operative HIPEC will be placed in the SMART System and perfused, 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
• Study Phase: Phase 1
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Diagnostic

Condition

• Peritoneal Carcinomatosis
• Peritoneal Mesothelioma
• Ovarian Cancer
• Gastrointestinal Cancer
• Appendiceal Cancer

Intervention

• 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
• Procedure: Heated Intraperitonial Chemotherapy
  Heated Intraperitonial Chemotherapy (HIPEC) with with standardized doses of chemotherapeutic agents as indicated by the subject's Arm assignment
• Drug: Doxorubicin
  Part of Arm 3: intraperitoneal (IP) Doxorubicin co-therapy 15 mg/m2 for 60 minutes, given at time = 0 with cisplatin
• 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
• 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

Study Arms

• Experimental: 1/ HIPEC: Oxaliplatin Randomized treatment assignment
  HIPEC with intraperitoneal oxaliplatin and IV 5-FU, randomly assigned
  Interventions:

  • Procedure: Heated Intraperitonial Chemotherapy
  • Drug: Oxaliplatin
  • Drug: 5-Fluorouracil
• Experimental: 2/ HIPEC: Mitomycin C Randomized treatment assignment
  HIPEC with intraperitoneal mitomycin C, randomly assigned
  Interventions:

  • Drug: Mitomycin C
  • Procedure: Heated Intraperitonial Chemotherapy
• Experimental: 3/ HIPEC: Cisplatin, Doxorubicin Randomized treatment assignme
  HIPEC with intraperitoneal cisplatin and doxorubicin, in addition to IV sodium thiosulfate, randomly assigned
  Interventions:

  • Drug: Cisplatin
  • Procedure: Heated Intraperitonial Chemotherapy
  • Drug: Doxorubicin
  • Drug: Sodium Thiosulfate
• Experimental: 4/ HIPEC: Cisplatin, Mitomycin C Randomized treatment assignme
  HIPEC with intraperitoneal cisplatin and mitomycin C, in addition to IV sodium thiosulfate, randomly assigned
  Interventions:

  • Drug: Mitomycin C
  • Drug: Cisplatin
  • Procedure: Heated Intraperitonial Chemotherapy
  • Drug: Sodium Thiosulfate

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: April 14, 2021): 60
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 30, 2031
• Estimated Primary Completion Date: December 30, 2030 (Final data collection date for primary outcome measure)

Eligibility Criteria

• INCLUSION CRITERIA:
• Confirmation of peritoneal carcinomatosis from appendiceal, colorectal, ovarian, or peritoneal mesothelioma 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 complete cytoreduction, with PCI score <= 30 at the time of laparoscopy.
• Age >= 18 years.
• ECOG performance status <= 1 (Karnofsky >= 80%).

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

  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count >= 1,000/mcL
  • Platelets >= 75,000/mcL
  • Total bilirubin within normal institutional limits
  • AST (SGOT)/ ALT (SGPT) <= 3x institutional upper limit of normal (ULN)
  • 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, women of childbearing potential and men 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; should a woman suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
• Ability of participant to understand and the willingness to sign a written informed consent document.
• Ability and willingness 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 deificiency (appendiceal or colorectal

cancer patients only).

• 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 women are excluded from this study because the protocol involves major abdominal surgery and chemotherapeutic agents 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, breastfeeding should be discontinued if the mother is undergoing treatment.
• 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Audra A Satterwhite, R.N.; (240) 858-3552; audra.satterwhite@nih.gov

Contact: Andrew M Blakely, M.D.; (240) 760-7647; andrew.blakely@nih.gov

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04847063
• Other Study ID Numbers: 210012; 21-C-0012
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: .All IPD recorded in the medical record will be shared with intramural investigators upon request.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Time Frame: Clinical data available during the study and indefinitely.
• Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI.

• Current Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
• Original Responsible Party: Same as current
• Current Study Sponsor: National Cancer Institute (NCI)
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

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

• PRS Account: National Institutes of Health Clinical Center (CC)
• Verification Date: May 19, 2023