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: February 8, 2023
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Peritoneal Carcinomatosis; Peritoneal Mesothelioma; Ovarian Cancer; Gastrointestinal Cancer; Appendiceal Cancer	Drug: Mitomycin C; Drug: Cisplatin; Procedure: Heated Intraperitonial Chemotherapy; Drug: Doxorubicin; Drug: Oxaliplatin; Drug: 5-Fluorouracil; Drug: Sodium Thiosulfate	Phase 1

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Diagnostic
• Official Title: Individualized Response Assessment to Heated Intraperitoneal Chemotherapy (HIPEC) for the Treatment of Peritoneal Carcinomatosis From Ovarian, Colorectal, Appendiceal, or Peritoneal Mesothelioma Histologies
• Actual Study Start Date: October 19, 2021
• Estimated Primary Completion Date: December 30, 2030
• Estimated Study Completion Date: December 30, 2031

Arms and Interventions

Arm	Intervention/treatment
Experimental: 1/ HIPEC: Oxaliplatin Randomized treatment assignment; HIPEC with intraperitoneal oxaliplatin and IV 5-FU, randomly assigned	Procedure: Heated Intraperitonial Chemotherapy; Heated Intraperitonial Chemotherapy (HIPEC) with with standardized doses of chemotherapeutic agents as indicated by the subject's Arm assignment; 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
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: Heated Intraperitonial Chemotherapy; Heated 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 assignme; 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; 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: 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
Experimental: 4/ HIPEC: Cisplatin, Mitomycin C Randomized treatment assignme; 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; Procedure: Heated Intraperitonial Chemotherapy; Heated Intraperitonial Chemotherapy (HIPEC) with with standardized doses of chemotherapeutic agents as indicated by the subject's Arm assignment; 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

Outcome Measures

Primary Outcome Measures :

1. 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

Secondary Outcome Measures :

1. 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
2. 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
3. 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
4. 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
5. 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

Eligibility Criteria

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

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.

Contacts and Locations

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

Locations

United States, Maryland

National Institutes of Health Clinical Center; Recruiting

Bethesda, Maryland, United States, 20892

Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office 888-624-1937

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

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

More Information

Additional Information:

NIH Clinical Center Detailed Web Page 

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT04847063
• Other Study ID Numbers: 210012; 21-C-0012
• First Posted: April 15, 2021
• Last Update Posted: February 8, 2023
• Last Verified: January 27, 2023

Individual Participant Data (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; Statistical Analysis Plan (SAP); 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.

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

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):

cytoreductive surgery (CRS); SMART System; necrosis; Ki-67; Peritoneal Metastasis

Additional relevant MeSH terms:

Mesothelioma; Mesothelioma, Malignant; Gastrointestinal Neoplasms; Carcinoma; Peritoneal Neoplasms; Appendiceal Neoplasms; Neoplasms by Site; Neoplasms; Adenoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms, Mesothelial; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Pleural Neoplasms; Lung Diseases; Respiratory Tract Diseases; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Abdominal Neoplasms; Peritoneal Diseases; Cecal Neoplasms; Intestinal Neoplasms; Cecal Diseases; Intestinal Diseases; Sodium thiosulfate; Doxorubicin; Fluorouracil