Flat Dose vs. Weight-based IP Chemotherapy for CRS/HIPEC

Study Overview
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Brief Summary
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Peritoneal carcinomatosis from advanced gastro-intestinal malignancy has historically been associated with poor overall survival (≤ 12 months) with few treatment options. Cytoreductive surgery (CRS), which involves removal of all macroscopic tumor nodules, combined with direct administration of heated intra-peritoneal (IP) chemotherapy (HIPEC) to the affected peritoneal surfaces, has been shown to be an effective treatment option that extends overall survival among certain cases of peritoneal carcinomatosis. IP chemotherapy allows delivery of a high dose of cytostatic drug directly onto the peritoneal surfaces at risk for microscopic residual disease while systemic exposure remains limited. Additionally, hyperthermia is known to enhance the cytotoxicity of several agents (including Mitomycin C) and improves the depth of peritoneal penetration. This trial will be a randomized phase 2 comparison of flat dose versus weight-based dose Mitomycin C. The hypothesis of this study is that HIPEC weight-based dosing may result in similarly effective peritoneal Mitomycin C concentrations with less systemic absorption and potential systemic toxicity, compared with the HIPEC flat dosing approach in patients undergoing CRS/HIPEC.

Official Title
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A Randomized Phase 2 Trial of Flat Dose vs. Weight-based Dose of Intra-peritoneal (IP) Chemotherapy for Patients Undergoing Cytoreductive Surgery and Heated Intra-peritoneal Chemotherapy (CRS/HIPEC) for Advanced Gastrointestinal Malignancy

Conditions
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Peritoneal Carcinomatosis

Intervention / Treatment
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* Drug: Mitomycin C, flat dose 40 mg
* Drug: Mitomycin C, weight-based dose 12.5 mg/m2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients diagnosed with one of the following: low-grade appendiceal mucinous neoplasm, appendiceal cancer with peritoneal carcinomatosis, colorectal cancer with peritoneal carcinomatosis ECOG performance status < 3 Candidate for grossly complete cytoreductive surgery Life expectancy greater than 3 months Adequate organ and marrow function Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Any extra-abdominal metastases Untreated lung metastases Liver metastases not amenable to resection or ablation Known brain metastases Chemotherapy or radiotherapy within 4 weeks prior to entering the study Presence of residual significant adverse events attributed to prior cancer treatment Currently receiving any other investigational therapeutic agents History of allergic reactions attributed to compounds of similar chemical or biologic composition to Mitomycin C. Pregnant or breast-feeding women Uncontrolled ongoing illness

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Flat Dose Mitomycin C<br>Participants in this group will receive flat doses of mitomycin C intra-operatively: 1) 30mg at minute 0 and 2) 10mg at minute 60. Mitomycin C will be delivered via HIPEC (hyperthermic intraperitoneal chemotherapy). | Drug: Mitomycin C, flat dose 40 mg<br>* Mitomycin C will be delivered as heated intraperitoneal chemotherapy (HIPEC) in two flat doses. Dose 1 will be 30mg at minute 0 and dose 2 will be 10 mg at minute 60.<br>|
| Experimental: Weight-Based Mitomycin C<br>Participants in this group will receive weight-based dosing of mitomycin C intra-operatively: 1) 9 mg/m2 at minute 0 and 2) 3.5 mg/m2 at minute 60 for total dose of 12.5 mg/m2. Mitomycin C will be delivered via HIPEC (hyperthermic intraperitoneal chemotherapy). | Drug: Mitomycin C, weight-based dose 12.5 mg/m2<br>* Mitomycin C will be delivered as heated intraperitoneal chemotherapy (HIPEC) in two weight-based doses of 9 mg/m2 at minute 0 and 3 mg/m2 at minute 60.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve (AUC) - Pharmacokinetics | Drug exposure will be measured by calculating the area under the curve (AUC) or integral of a plasma concentration-time curve. Samples will be collected at 0,15, 30, 60 and 90 minutes intra-operatively, and 2, 4, and 12 hours postoperatively. | Approximately 20 hours | 
| Drug Clearance (CL) - Pharmacokinetics | Drug clearance will be calculated as the volume of plasma cleared per unit time. Samples will be collected at 0,15, 30, 60 and 90 minutes intra-operatively, and 2, 4, and 12 hours postoperatively. | Approximately 20 hours | 
| Drug Half-Life (T1/2) - Pharmacokinetics | Drug half-life will be calculated as the time required for the plasma Mitomycin C concentration to be half of its maximum concentration. Samples will be collected at 0,15, 30, 60 and 90 minutes intra-operatively, and 2, 4, and 12 hours postoperatively. | Approximately 20 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cytoreductive surgery, colorectal cancer, pseudomyxoma peritonei, appendiceal mucinous neoplasm, mitomycin C, pharmacokinetics, CRS/HIPEC, HIPEC, Appendix cancer, LAMN