Intraperitoneal Oxaliplatin and Fluorouracil for the Treatment of Patients With Peritoneal Metastases From Colorectal Cancer

A Phase I Study of Intraperitoneal 5FU+Oxaliplatin in Patients With Colorectal Cancer With Isolated Peritoneal Metastasis

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.

Study Overview

• Status: Recruiting
• Conditions: Metastatic Colorectal Carcinoma; Stage IV Colorectal Cancer AJCC v8; Metastatic Malignant Neoplasm in the Peritoneum
• Intervention / Treatment: Procedure: Magnetic Resonance Imaging; Procedure: Computed Tomography; Procedure: Biopsy; Procedure: Diagnostic Laparoscopy; Procedure: Biospecimen Collection; Drug: Fluorouracil; Drug: Oxaliplatin; Procedure: Surgical Procedure

Detailed Description

PRIMARY OBJECTIVES:

I. Determine safety, tolerability, and maximally tolerated dose (MTD) of intraperitoneal (IP) fluorouracil (5FU)+oxaliplatin.

II. Determine pharmacokinetics (PK) of IP 5FU+oxaliplatin both in blood and peritoneal fluid.

SECONDARY OBJECTIVES:

I. Determine tumor-cell intrinsic effects, modulation of the tumor immune microenvironment, and changes in the makeup of circulating immune cells in response to IP 5FU+oxaliplatin.

II. Identify preliminary response from IP 5FU+oxaliplatin: assess the rate of conversion from unresectable to resectable (determined by peritoneal carcinomatosis index [PCI] decreasing to < 20) and response rates by imaging criteria.

OUTLINE: This is a dose-escalation study of 5FU and oxaliplatin followed by a dose-expansion study.

Patients undergo placement of indwelling IP port for chemotherapy infusion. Patients receive oxaliplatin and 5FU over 1-2 hours via IP infusion on days 1 and 15 of each cycle. Cycles repeat every 4 weeks for up to 16 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo diagnostic laparoscopy, biopsy, computed tomography (CT)/magnetic resonance imaging (MRI), and collection of blood samples at screening and on study and undergo collection of IP fluid samples on study.

After completion of study treatment, patients are followed up for 30 days. Patients with confirmed disease progression or who start a new anti-cancer therapy are followed up every 12 weeks until death, withdrawal of consent, or end of study.

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: The Ohio State University Comprehensive Cancer Center; Phone Number: 800-293-5066; Email: OSUCCCClinicaltrials@osumc.edu

Study Locations

• United States
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Recruiting
      • Ohio State University Comprehensive Cancer Center
      • Principal Investigator: Arjun Mittra, MD
      • Contact: Arjun Mittra, MD; Phone Number: 614-293-6529

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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 must not have not received colorectal cancer directed systemic therapy in the metastatic setting. Prior adjuvant chemotherapy is permitted, provided it has been >= 6 months since receiving the last dose of adjuvant chemotherapy at the time of study enrollment
• Expected to have PCI of > 20 in the opinion of the treating physician based on imaging
• Not previously undergone cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal cancer
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 at the time of enrollment
• Absolute neutrophil count (ANC) ≥ 1,500 /mcL
• Platelets ≥ 100,000 / mcL

• Serum creatinine ≤ 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance ≥ 60 mL/min for patient with creatinine levels > 1.5 x institutional ULN (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl])

  • Creatinine clearance should be calculated per institutional standard
• Serum total bilirubin ≤ 1.5 x ULN OR direct bilirubin ≤ ULN for patient with total bilirubin levels > 1.5 ULN

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN

  • Both values must be in the specified range
• Albumin >= 2.5 g/dL
• International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless patient is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants
• Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
• Patients on anticoagulation or antiplatelet agents may be enrolled at the discretion of the treating physician, provided these can be safely held as needed for surgical procedures
• Anticipated life expectancy of ≥ 6 months
• Willing to comply with study procedures
• Female subjects of childbearing potential must be willing to use an adequate method of contraception for the course of the study and at least 9 months after the last dose of study medication
• For female patients of childbearing potential, a negative pregnancy test is required at or within 7 days prior to enrollment
• Be willing and able to understand and sign the written informed consent document
• Be willing to undergo two diagnostic laparoscopies with tumor biopsy tissue. Patients must consent to on-treatment biopsies prior to initiation of clinical trial
• Be willing to provide peripheral blood samples for correlative studies

Exclusion Criteria:

• Patients who are receiving any other investigational drugs
• Evidence of metastatic disease other than peritoneum based on standard of care (SOC) imaging
• Patients with >= grade 2 peripheral neuropathy
• Uncontrolled concurrent illness including, but not limited to, ongoing or active infection, cardiac arrhythmia, active bleeding diatheses, and psychiatric illness/social situations that would limit compliance with study requirements
• Major surgical procedure or significant traumatic injury less than 3 weeks or those who receive minor surgical procedures within 1 week from first dose of study drug administration
• Known active chronic infections - uncontrolled human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), known active (i.e., with detectable polymerase chain reaction [PCR]) hepatitis B or C
• Cirrhosis (Child-Pugh B or worse) or cirrhosis with history of hepatic encephalopathy or clinically meaningful ascites resulting from cirrhosis. Clinically meaningful ascites is defined as ascites from cirrhosis requiring diuretics or paracentesis
• Pregnancy or breastfeeding
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating physician

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: Treatment (oxaliplatin, 5FU); Patients undergo placement of indwelling IP port for chemotherapy infusion. Patients receive oxaliplatin and 5FU over 1-2 hours via IP infusion on days 1 and 15 of each cycle. Cycles repeat every 4 weeks for up to 16 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo diagnostic laparoscopy, biopsy, CT/MRI, and collection of blood samples at screening and on study and undergo collection of IP fluid samples on study.

Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI; Procedure: Computed Tomography; Undergo CT; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Procedure: Biopsy; Undergo biopsy; Other Names: Bx; BIOPSY_TYPE; Procedure: Diagnostic Laparoscopy; Undergo diagnostic laparoscopy; Procedure: Biospecimen Collection; Undergo collection of blood and IP fluid samples; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Drug: Fluorouracil; Given via IP infusion; Other Names: 5-Fluracil; Fluracil; 5 Fluorouracil; 5 Fluorouracilum; 5 FU; 5-Fluoro-2,4(1H, 3H)-pyrimidinedione; 5-Fluorouracil; 5-Fu; 5FU; AccuSite; Carac; Fluoro Uracil; Fluouracil; Flurablastin; Fluracedyl; Fluril; Fluroblastin; Ribofluor; Ro 2-9757; Ro-2-9757; Drug: Oxaliplatin; Given via IP infusion; Other Names: 1-OHP; Dacotin; Dacplat; Eloxatin; Ai Heng; Aiheng; Diaminocyclohexane Oxalatoplatinum; Eloxatine; JM-83; Oxalatoplatin; Oxalatoplatinum; RP 54780; RP-54780; SR-96669; Procedure: Surgical Procedure; Undergo placement of indwelling IP port; Other Names: Operation; Surgery; Surgery Type; Surgical; Surgical Intervention; Surgical Interventions; Surgical Procedures; Type of Surgery; Surgery, NOS

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Up to 1 year
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.	Up to 30 days after completion of study treatment
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.	At the end of Cycle 1 (each cycle is 28 days)
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.	At the end of Cycle 1 (each cycle is 28 days)
Volume of distribution	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.	At the end of Cycle 1 (each cycle is 28 days)
Half-life	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.	At the end of Cycle 1 (each cycle is 28 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Up to 16 weeks
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.	Up to 16 weeks
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.	Up to 16 weeks
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.	At time of second laparoscopy, after 4 cycles of treatment (16 weeks)
Overall response rate	Will be evaluated using imaging criteria. Overall response rate (partial response + complete response) will be summarized and 95% exact binomial confidence interval will be provided.	Up to 16 weeks

Collaborators and Investigators

• Sponsor: Arjun Mittra
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Arjun Mittra, MD, Ohio State University Comprehensive Cancer Center

Publications and helpful links

Helpful Links

• The Jamesline

Study record dates

Study Major Dates

• Study Start (Estimated): April 30, 2024
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: January 9, 2024
• First Submitted That Met QC Criteria: February 13, 2024
• First Posted (Actual): February 21, 2024

Study Record Updates

• Last Update Posted (Actual): March 27, 2024
• Last Update Submitted That Met QC Criteria: March 26, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Neoplasms; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Fluorouracil; Oxaliplatin
• Other Study ID Numbers: OSU-23195; NCI-2023-10497 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); R21CA282536 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No