This phase I trial tests the safety, side effects, and best dose of intraperitoneal oxaliplatin and fluorouracil in treating patients with colorectal cancer that has spread to the peritoneal cavity (peritoneal metastasis). Oxaliplatin is in a class of medications called platinum-containing antineoplastic agents. It damages the cell's DNA and may kill cancer cells. Fluorouracil stops cells from making DNA and it may kill cancer cells. Both oxaliplatin and fluorouracil are approved by the Food and Drug Administration to treat patients with colorectal cancer, however administration of these drugs directly into the area between the muscles and organs in the abdomen (intraperitoneal) for the treatment of peritoneal metastases is experimental. Giving oxaliplatin and fluorouracil directly into the peritoneal space may be a safe and effective way of treating patients with peritoneal metastases from colorectal cancer.
Age >= 18 years
Biopsy proven colorectal cancer with peritoneal metastasis. Patients with extraperitoneal metastases will not be eligible. Patients with involvement of intra-abdominal lymph nodes may be eligible at the discretion of the treating physician
Primary colorectal cancer may either be left in place or have been resected prior to study enrollment
Patients are allowed to have received prior colorectal cancer-directed systemic therapy.
Patients who are receiving any other investigational drugs
Evidence of metastatic disease other than peritoneum based on standard of care (SOC) imaging
Patients with primary mucinous appendiceal tumors will not be eligible. These tumors often produce mucin, which may affect the penetration of IP chemotherapy. Patients with non-mucinous appendiceal adenocarcinomas will be eligible.
Patients with >= grade 2 peripheral neuropathy
Single group
Biopsy
Procedure/SurgeryUndergo biopsy
Biospecimen Collection
Procedure/SurgeryUndergo collection of blood and IP fluid samples
Computed Tomography
Procedure/SurgeryUndergo CT
Diagnostic Laparoscopy
Procedure/SurgeryUndergo diagnostic laparoscopy
Fluorouracil
DrugGiven via IP infusion
Magnetic Resonance Imaging
Procedure/SurgeryUndergo MRI
Oxaliplatin
DrugGiven via IP infusion
Surgical Procedure
Procedure/SurgeryUndergo placement of indwelling IP port
Maximum tolerated dose (MTD)
MTD will be determined based on isotonic regression. Specifically, the MTD will be selected as the dose for which the isotonic estimate of the toxicity rate is closest to the targeted dose limiting toxicities via Bayesian optimal interval software.
Incidence of adverse events
Adverse events (AEs) will be classified and attributed using National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 and will be summarized within and across dose levels using descriptive statistics. The overall number and percentage of patients experiencing AEs and toxicities will be summarized and reported as across all event types. All patients who have received at least one dose of the therapeutic agents will be evaluable for toxicity and tolerability.
Area under the curve
Will be computed using non-compartmental and compartmental methods. Will use graphical analyses as well as repeated measure models (linear or nonlinear mixed models, generalized estimating equations) to assess the pharmacokinetic markers in relation to clinical treatment outcomes, recognizing some inherent limitations due to sample size.
Clearance
Will be computed using non-compartmental and compartmental methods. Will use graphical analyses as well as repeated measure models (linear or nonlinear mixed models, generalized estimating equations) to assess the pharmacokinetic markers in relation to clinical treatment outcomes, recognizing some inherent limitations due to sample size.
Tumor-cell intrinsic effects in response to IP 5FU+oxaliplatin
Samples obtained from baseline and after 4 cycles will be studied. Data collected will be descriptive and exploratory, and provide limited estimates of variability given the small sample sizes at each dose level. Results will be summarized using descriptive statistics (i.e., means, standard deviations, 95% confidence intervals for continuous variables, and frequencies for discrete data.
Modulation of the tumor microenvironment in response to IP 5FU+oxaliplatin
Samples obtained from baseline and after 4 cycles will be studied. Data collected will be descriptive and exploratory, and provide limited estimates of variability given the small sample sizes at each dose level. Results will be summarized using descriptive statistics (i.e., means, standard deviations, 95% confidence intervals for continuous variables, and frequencies for discrete data.
Changes in the makeup of circulating immune cells in response to IP 5FU+oxaliplatin
Samples obtained from baseline and after 4 cycles will be studied. Data collected will be descriptive and exploratory, and provide limited estimates of variability given the small sample sizes at each dose level. Results will be summarized using descriptive statistics (i.e., means, standard deviations, 95% confidence intervals for continuous variables, and frequencies for discrete data.
Rate of conversion from unresectable to resectable
Resectable disease will be determined by peritoneal carcinomatosis index decreasing to \< 20. Will be summarized and 95% exact binomial confidence interval will be provided.
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Arjun Mittra
Lead sponsor
Ohio State University Comprehensive Cancer Center
Sponsor institution
National Cancer Institute (NCI)
Collaborator
