Hyperthermic Intraperitoneal Oxaliplatin for Peritoneal Malignancies

Phase I Hyperthermic Intraperitoneal Oxaliplatin for Peritoneal Malignancies

RATIONALE: Drugs used in chemotherapy, such as oxaliplatin, leucovorin, and fluorouracil, 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. Peritoneal infusion of heated and nonheated chemotherapy drugs after surgery may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of hyperthermic intraperitoneal oxaliplatin followed by intraperitoneal leucovorin and fluorouracil in treating patients with peritoneal cancer.

Study Overview

• Status: Completed
• Conditions: Peritoneal Cavity Cancer
• Intervention / Treatment: Drug: fluorouracil; Drug: leucovorin calcium; Drug: oxaliplatin; Procedure: cytoreductive surgery

Detailed Description

OBJECTIVES:

Primary

• To determine the safety and optimal dose of hyperthermic intraperitoneal oxaliplatin when administered during cytoreductive surgery and followed by intraperitoneal leucovorin calcium and fluorouracil in patients with peritoneal malignancies.

Secondary

• To determine the outcome of cytoreductive surgery in these patients.
• To determine the time to disease progression and pattern of failure in patients treated with this regimen.
• To determine the 1 and 5 year survival in patients treated with this regimen.
• To compare quality-of-life pre- and post-surgery in these patients.
• To characterize total- and free-platinum pharmacokinetics in the plasma and total platinum in the intraperitoneal space at baseline, during, and after hyperthermic intraperitoneal chemotherapy (HIPC).
• To assess for the presence of genetic polymorphisms in the XDP and XRCC1 DNA repair genes.
• To assess tumor and normal tissue concentrations for total platinum obtained at baseline and immediately after HIPC.

OUTLINE:

• Cytoreductive Surgery: Patients undergo an exploratory laparotomy to remove all tumor nodules from all peritoneal surfaces prior to gastrointestinal anastomoses. An intraperitoneal drain is placed for postoperative intraperitoneal chemotherapy.
• Hyperthermic peritoneal chemotherapy (HIPC): After cytoreductive surgery, but before intestinal anastomosis, patients receive oxaliplatin into the abdomen cavity at approximately 1 liter/min at 41-42º C and held for 30 minutes at the maximum tolerated dose. A heat exchanger maintains the fluid temperature at 44-46º C to maintain the intraperitoneal temperature at 41-42º C. Patients may receive fluid challenges, furosemide, mannitol, or renal dose dopamine to maintain a brisk diuresis at the discretion of the anesthesiologist.
• Intraperitoneal chemotherapy: After HIPC, patients receive leucovorin calcium intraperitoneally through an intraperitoneal drain where it will remain for 2 hours and then drained. Patients then receive fluorouracil intraperitoneally through the intraperitoneal drain on day 1 and remain in the peritoneal fluid for 23 hours and then drained. The infusion will be repeated on day 2.

Blood samples are collected prior to surgery for pharmacogenetic studies and analyzed for the presence of genetic polymorphisms in the XPD and XRCC1 DNA repair genes and the GSTP1 and GSTM1 glutathione-S-transferase enzymes (i.e., XPD, Asp312Asn, XPD K751Q, XRCC1 Arg399GIn, XRCC1 Arg399Q, GSTP1 l105V, and GSTM1 DEL). Blood samples are also collected periodically for pharmacokinetic studies and analyzed for oxaliplatin concentrations. Normal and tumor tissue are collected periodically and analyzed for total platinum concentrations.

Quality of life is assessed at baseline and at 4, 8, and 12 months.

After completion of study treatment, patients are followed every 4 months for 2 years and then every 6 months for at least 5 years.

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Masonic Cancer Center, University of Minnesota

Participation Criteria

Eligibility Criteria

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

Description

Inclusion criteria:

• Patients must have histologic proof of peritoneal metastases (includes adenomucinosis)
• Complete tumor resection possible (may include liver metastasis if treatable by resection or radiofrequency ablation)
• Patients may have received previous chemotherapy (except peritoneal) and/or immunotherapy. If previous chemotherapy, at least 4 weeks must have passed since last dose.
• Patients may have received previous radiation therapy, however radiation to the large bowel, small bowel and/or stomach will make the patient ineligible for this study.
• Patients must have a Karnofsky performance score of ≥ 80%.

• Adequate hematologic, renal and hepatic function within 14 days of registration defined as:

  • White blood count (WBC) ≥ 3,000
  • platelet count ≥ 70,000,
  • serum bilirubin ≤ 2.0 mg/dL,
  • serum creatinine ≤ 1.5 mg/dL
• Patients must be at least 18 years of age
• Patients must be able to provide informed consent

Exclusion criteria:

• Metastatic disease is present outside the peritoneal cavity
• Diagnosis of mesothelioma
• Grade 2 or higher sensory neuropathy at time of study enrollment
• History of allergic reaction to platinum compounds
• Pregnant or lactating women. Pregnancy is a contraindication for receiving therapy, thus where relevant, patients will be required to use effective birth control. The agents used in this study include those which are pregnancy category D - clear evidence of risk in pregnancy. There is no information on the excretion of agents into breast milk therefore patients must refrain from breastfeeding while receiving study therapy.
• Previous peritoneal chemotherapy.
• Patients with uncontrolled concurrent medical problems (i.e. diabetes mellitus) or history of uncontrolled cardiovascular disease (no history of hospitalization for acute myocardial infarction or congestive heart failure (CHF) within 3 months prior to registration).
• Patients have psychiatric or addictive disorders that preclude obtaining informed consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Hyperthermic Treatment; Patients receiving combination of hyperthermic intraperitoneal chemotherapy (HIPC) with oxaliplatin plus intraperitoneal 5-Fu and intraperitoneal leucovorin with peritoneal metastases.

Drug: fluorouracil; Post-operative day 1 and day 2, 600mg/m^2 intraperitoneal (IP) held for 23 hours; Other Names: 5-FU; Drug: leucovorin calcium; Day 0 200 mg/m^2 intraperitoneal held for 2 hours; Drug: oxaliplatin; Day 0 hyperthermic intraperitoneal oxaliplatin held for 30 minutes - assigned dose level: Levels 1 through 7 - 300 to 600 mg/m^2; Other Names: Eloxatin; Procedure: cytoreductive surgery; Day 0 Cytoreductive surgery is a systematic attempt to remove all or nearly all peritoneal nodules.; Other Names: conventional surgery

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Maximum tolerated dose of hyperthermic intraperitoneal oxaliplatin	30 Days Post Treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in quality-of-life	Using the Functional Assessment of Cancer Therapy for Colorectal Cancer (FACT-C) and SF-36 (Quality of Life Evaluation in Dialysis Patients) questionnaires, the quality of life following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPC) will be reported and compared to the preoperative baseline.	Baseline and at 4, 8, and 12 months
Overall survival		1 Year and 5 Years
Time to Disease Progression		Monthly

Collaborators and Investigators

• Sponsor: Masonic Cancer Center, University of Minnesota
• Investigators: Principal Investigator: Todd M. Tuttle, MD, Masonic Cancer Center, University of Minnesota

Study record dates

Study Major Dates

• Study Start: October 1, 2007
• Primary Completion (Actual): January 1, 2010
• Study Completion (Actual): September 1, 2011

Study Registration Dates

• First Submitted: February 27, 2008
• First Submitted That Met QC Criteria: February 27, 2008
• First Posted (Estimate): February 28, 2008

Study Record Updates

• Last Update Posted (Actual): November 29, 2017
• Last Update Submitted That Met QC Criteria: November 27, 2017
• Last Verified: November 1, 2017

More Information

Terms related to this study

• Keywords: peritoneal cavity cancer
• Additional Relevant MeSH Terms: Wounds and Injuries; Body Temperature Changes; Heat Stress Disorders; Hyperthermia; Fever; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Micronutrients; Vitamins; Calcium-Regulating Hormones and Agents; Antidotes; Vitamin B Complex; Fluorouracil; Oxaliplatin; Leucovorin; Calcium; Levoleucovorin
• Other Study ID Numbers: 2005LS068; 0601M79448 (Other Identifier: IRB, University of Minnesota)