Intraperitoneal Hyperthermic Perfusion With Oxaliplatin in Treating Patients With Stage IV Peritoneal Cancer Due to Appendix Cancer or Colorectal Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Hyperthermia therapy kills tumor cells by heating them to several degrees above normal body temperature. Adding chemotherapy to hyperthermia and infusing it directly into the abdomen may kill more tumor cells. Giving this treatment after surgery may kill any tumor cells that remain after surgery. PURPOSE: This phase I trial is studying the side effects and best dose of intraperitoneal hyperthermic perfusion with oxaliplatin in treating patients with stage IV peritoneal cancer due to appendix cancer or colorectal cancer.

Detailed Description
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OBJECTIVES: Determine the toxicity of intraperitoneal hyperthermic chemoperfusion with oxaliplatin in patients with stage IV peritoneal surface malignancies from primary colorectal or appendiceal cancer. Determine the pharmacokinetics of this drug in perfusate, normal peritoneum, and peritoneal surface tumors in these patients. Evaluate the expression of proteins involved in the apoptotic and stress-inducible heat shock protein pathways (e.g., Fas, TRAIL, DISC components [FADD, TRADD, FLIP, and caspase 8], mitochondrial proteins [Bax, Bak, Bcl-2, Bcl-X_L], and heat shock proteins [HSPs 27, 40, 70 and 90]) before and after drug therapy. OUTLINE: This is a nonrandomized, open-label, dose-escalation study. Patients undergo gross tumor resection on day 1. After tumor debulking, patients receive oxaliplatin over 2 hours by intraperitoneal hyperthermic chemotherapy (IPHC). Cohorts of 3-6 patients in each stratum receive escalating doses of oxaliplatin until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. Patients undergo blood and tissue sampling before and after IPHC for pharmacokinetic studies and for evaluation of proteins involved in apoptosis and heat-shock-mediated cell death (e.g., Fas, TRAIL, FADD, TRADD, FLIP, caspase 8, Bax, Bak, Bcl-X, and heat shock proteins 27, 40, 70, and 90). After completion of study treatment, patients are followed periodically for at least 1 year. PROJECTED ACCRUAL: A total of 60 patients will be accrued for this study.

Official Title
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A Phase I Evaluation of Intraperitoneal Hyperthermic Chemoperfusion With Oxaliplatin for Peritoneal Surface Disemmination of Appendiceal and Colorectal Cancer

Conditions
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Carcinoma of the Appendix, Colorectal Cancer, Primary Peritoneal Cavity Cancer

Intervention / Treatment
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* Drug: oxaliplatin


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically or cytologically confirmed colorectal or appendiceal cancer Stage IV disease Peritoneal surface dissemination of disease (peritoneal carcinomatosis) Measurable disease according to RECIST criteria No active CNS metastases PATIENT CHARACTERISTICS: ECOG performance status 0-2 Absolute neutrophil count ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Creatinine ≤ 1.5 mg/dL OR creatinine clearance > 60 mL/min Bilirubin ≤ 1.5 mg/dL Alkaline phosphatase ≤ 3 times upper limit of normal (ULN) AST and ALT ≤ 3 times ULN No active infection or fever ≥ 101.3°F within the past 3 days No other malignancy within the past 5 years except curatively treated basal cell skin cancer, cervical intra-epithelial neoplasia, or localized prostate cancer with a current prostate-specific antigen of < 1.0 mg/dL on 2 successive evaluations, ≥ 3 months apart, with the last evaluation within the past 4 weeks No peripheral neuropathy ≥ grade 2 No other medical condition, mental illness, or substance abuse that, in the opinion of the principal investigator, would preclude study compliance No known hypersensitivity to any component of oxaliplatin No known HIV positivity No hepatitis B or C positivity (active, previously treated, or both) Not pregnant or nursing Negative pregnancy test Fertile patients and their partners must use effective contraception during and for 90 days after completion of study treatment PRIOR CONCURRENT THERAPY: Recovered from prior surgery, radiotherapy, and other anticancer therapies More than 30 days since prior and no other concurrent investigational therapy No prior radiotherapy to > 25% of bone marrow No prior allogeneic stem cell transplantation No concurrent antiretroviral therapy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hyperthermic Chemoperfusion with Oxaliplatin 200 mg/m2<br>Intraperitoneal Hyperthermic Chemoperfusion with Oxaliplatin 200 mg/m2 | Drug: oxaliplatin<br>* Intraperitoneal Hyperthermic Chemoperfusion with Oxaliplatin<br>|
| Experimental: Hyperthermic Chemoperfusion with Oxaliplatin 250 mg/m2<br>Intraperitoneal Hyperthermic Chemoperfusion with Oxaliplatin 250 mg/m2 | Drug: oxaliplatin<br>* Intraperitoneal Hyperthermic Chemoperfusion with Oxaliplatin<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose | Maximum tolerated dose will be determined by the absence of dose limiting toxicites (serious adverse events related to Oxaplatin dosing within 18 days of administration) | 18 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics | Evaluation of the pharmacokinetics of oxaliplatin in perfusate, normal peritoneum, and peritoneal surface tumors during intraperitoneal hyperthermic chemoperfusion | day of surgery (day one) | 
| Change in the phenotypic expression of proteins involved in the apoptotic and heat-stress inducible pathways | Analysis of the expression of proteins involved in the apoptotic and stress-inducible heat shock protein pathways before and after intraperitoneal hyperthermic chemoperfusion with oxaliplatin. These proteins shall include cellular levels of Fas and TRAIL, components of the DISC (FADD, TRADD, FLIP, and Caspase 8), mitochondrial proteins (Bax, Bak, Bcl-2, and Bcl-XL), and the heat shock protein family (HSPs 27, 40, 70, and 90). | Day of surgery (day one) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent colon cancer, stage IV colon cancer, carcinoma of the appendix, recurrent rectal cancer, stage IV rectal cancer, primary peritoneal cavity cancer