Hepatic Artery Infusion Pump Chemotherapy With Floxuridine and Dexamethasone in Combination With Systemic Chemotherapy for Patients With Colorectal Cancer Metastatic to the Liver

A Single-Arm Phase II Study of Hepatic Artery Infusion Pump Chemotherapy With Floxuridine and Dexamethasone in Combination With Systemic Chemotherapy for Patients With Colorectal Cancer Metastatic to the Liver

Background:

Many people with colorectal cancer get liver metastases. Standard treatment for this is a combination of chemotherapy drugs. Directing the chemotherapy to the liver may be effective. A device that does this a pump that delivers drugs over 2 weeks at constant rate into the hepatic artery. The person s body temperature causes the drug to flow from the pump. Researchers want to see if this helps people with colorectal metastases to the liver.

Objective:

To study the effectiveness of a hepatic artery infusion pump at treating colorectal metastases to the liver.

Eligibility:

Adults at least 18 years old with colorectal metastases to the liver

Design:

Participants will be screened with:

Medical history

Physical exam

Heart, blood, and urine tests

Scans

Participants will stay in the hospital a few days. A small plastic tube (catheter) will be inserted in an artery into the liver. The catheter will be attached to the pump. That will lie under the skin on the abdomen. It will be small and participants will be able to feel it.

Participants will get treatment in 28-day cycles.

Every Day 1, they will have physical exam, symptom review, and blood tests.

Every 2 weeks, they will come to the clinic to get chemotherapy by a catheter or port.

Every 12 weeks, they will have a scan.

Tissue samples may be taken during the study.

When they finish the drug, participants may have the pump removed. They will repeat the Day 1 tests. They will be called every 6 months to see how they are doing.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Cancer; Liver Metastases; Colorectal Carcinoma; Colorectal Adenocarcinoma; Colorectal Cancer With Hepatic Metastases
• Intervention / Treatment: Device: Codman 3000 constant flow pump catheter; Drug: Panitumumab; Drug: FUDR-Dex; Drug: Oxaliplatin; Drug: 5FU; Drug: Irinotecan; Procedure: HAIP installation; Drug: cetuximab; Device: Medtronic SynchroMed II Pump

Detailed Description

Background:

• Nearly 60% of patients with colorectal cancers will develop liver metastases over the course of their disease.
• Of patients with metastatic colorectal cancer, the liver will be the sole site of recurrence or the survival-limiting site of disease for 20%.
• Liver directed therapy, which has taken many forms over the last several decades, is a potential means to prolong survival for properly selected patients and delay progression at that site.
• Hepatic artery infusion of floxuridine (FUDR) via an implantable hepatic artery infusion pump (HAIP) induces objective clinical response rates of nearly 50% in heavily pre-treated patients with metastatic colorectal cancer to the liver.
• The identification of patients likely to respond to HAIP and those likely to suffer pumprelated adverse events is currently unknown, and has limited the wide-spread adoption of this otherwise well tolerated intervention.

Objective:

• To assess the safety of hepatic artery infusion therapy using the Medtronic pump with the Codman catheter.
• To determine the response rate in patients with unresectable metastatic colorectal cancer treated with HAIP chemotherapy as measured by RECIST.

Eligibility:

• Histologically or cytologically confirmed colorectal adenocarcinoma metastatic to the liver.
• Patients with liver metastases not amenable to resection to No Evidence of Disease (NED) in one stage.
• Patients must have received systemic chemotherapy.
• Age greater than or equal to 18 years.

Design:

- Single arm, Phase II study of HAIP chemotherapy.

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Kathleen M Smith, R.N.; Phone Number: (240) 858-3531; Email: kathleen.smith3@nih.gov
• Study Contact Backup: Name: Jonathan M Hernandez, M.D.; Phone Number: (240) 760-6072; Email: jonathan.hernandez@nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Institutes of Health Clinical Center
      • Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office; Phone Number: 888-624-1937

Participation Criteria

Eligibility Criteria

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

Description

• INCLUSION CRITERIA:
• Patients must have histologically or cytologically confirmed diagnosis of colorectal adenocarcinoma.
• Patients must have measurable liver metastatic disease.
• Patients must have progressed on, been intolerant of or have residual disease after oxaliplatin- or irinotecan-containing, fluorouracil-based, chemotherapeutic regimen.
• Age greater than or equal to 18 years.
• ECOG performance status less than or equal to 1

• Patients must have adequate organ and marrow function as defined below:

  • leukocytes > 3,000/mcL
  • absolute neutrophil count > 1,500/mcL
  • platelets > 90,000/mcL
  • total bilirubin < 1.5 X institutional upper limit of normal
  • AST(SGOT)/ALT(SGPT) < 2.5 X institutional upper limit of normal
  • creatinine within normal institutional limits OR eGFR within normal as predicted by the CKD-EPI equation > 60 mL/min/1.73 m2.
• The hepatic artery infusion pump chemotherapy has potential teratogenic and/or abortifacient effects. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and after completion of study treatment : 3 months after the last study drug for men; 6 months after the last study drug for women. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
• Arterial anatomy on CT angiogram amenable to placement of the HAIP.
• Ability of subject to understand and the willingness to sign a written informed consent document.
• HIV-positive patients may be considered for this study only after consultation with an HIV trained physician.
• Patients must agree to co-enroll on the Surgical Oncology Program s tissue collection protocol 13C0176, 'Tumor, Normal Tissue and Specimens from Patients Undergoing Evaluation or Surgical Resection of Solid Tumors'

EXCLUSION CRITERIA:

• Patients with liver metastases amenable to resection to No Evidence of Disease (NED) in one stage.
• Patients who are receiving any other investigational agents.
• Patients with incontrovertible radiographic evidence of disease outside of the colon/rectum (primary) and liver given unlikelihood of benefit from liver-directed therapy.

Note: The exception to this exclusion is patients with fewer than five lung lesions greater than 1 cm that have not increased in size by more than 10% over a 4-month period of time, and are amenable to resection should subsequent problematic growth occur. Lesions less than 1 cm are indeterminant as far as etiology is concerned and will be ignored. Patients with liver metastases and oligometastatic lung lesions (we define oligometastatic as less than 5 amenable to thoracoscopic removal) are still likely to benefit from liver directed therapy.

• Patients who have undergone extra-hepatic metastasectomy and have a documented disease-free interval less than or equal to 4 months.
• MSI-high patients who need to be treated with check-point inhibitors
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. This also includes any condition, including the presence of laboratory abnormalities, which in the opinion of the Principal Investigator places the subject at unacceptable risk if they were to participate in the study or confounds the ability to interpret data from the study.
• Active concurrent malignancies within the last five years other than colorectal primary except basal cell skin carcinoma and thyroid carcinoma.
• Prior radiation to liver.
• Pregnant women are excluded from this study because of the potential for teratogenic or abortifacient effects of the HAIP chemotherapy. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with HAIP, breast-feeding should be discontinued if the mother is treated. These potential risks may also apply to other agents used in this study. Lactating women must-not breastfeed during study treatment and until at least 7 days after the final dose of study drug(s).
• Patients with active Hepatitis B or C infection because of the potential for increased liver toxicity given the damaging effects of the virus.
• History of allergic reactions attributed to compounds of similar chemical composition to FUDR or heparin.

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: 1/ Arm 1; HAIP chemotherapy + Systemic chemotherapy

Device: Codman 3000 constant flow pump catheter; implanted Medtronic SynchroMed II Pump with codman 3000 Constant Flow Pump Catheter; Drug: Panitumumab; 6 mg/kg, IV; Drug: FUDR-Dex; HAIP will be filled with mixture of Floxuridine and Dexamethasone. Pump will perfuse drugs to liver for 14 days. Floxuridine (0.12 mg/kg X pump volume X pump flow rate),Dexamethasone (1 mg/day X pump volume (30) X pump flow rate); Drug: Oxaliplatin; 85 mg/m2, IV; Drug: 5FU; 2000 mg/m2, IV 46-hour infusion of 5-Fluorouracil + 400 mg/m2, IV of Leucovorin; Drug: Irinotecan; 150 mg/m2, IV; Procedure: HAIP installation; HAI pump installation; Drug: cetuximab; 500 mg/m2, IV; Device: Medtronic SynchroMed II Pump; implanted Medtronic SynchroMed II Pump with Codman 3000 Constant Flow Pump Catheter

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response rate (RR)	The fraction of patients who experience a PR or CR using the study treatment	at progression

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	Median amount of time subject survives after therapy	death
Hepatic progression-free survival	The fraction of patients whose tumors in liver shrunk after therapy	at progression
Extra-hepatic progression-free survival	The fraction of patients whose tumors outside liver shrunk after therapy	at progression

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Jonathan M Hernandez, M.D., National Cancer Institute (NCI)

Publications and helpful links

General Publications

• Ammori JB, Kemeny NE, Fong Y, Cercek A, Dematteo RP, Allen PJ, Kingham TP, Gonen M, Paty PB, Jarnagin WR, D'Angelica MI. Conversion to complete resection and/or ablation using hepatic artery infusional chemotherapy in patients with unresectable liver metastases from colorectal cancer: a decade of experience at a single institution. Ann Surg Oncol. 2013 Sep;20(9):2901-7. doi: 10.1245/s10434-013-3009-3. Epub 2013 Jun 15.
• D'Angelica MI, Correa-Gallego C, Paty PB, Cercek A, Gewirtz AN, Chou JF, Capanu M, Kingham TP, Fong Y, DeMatteo RP, Allen PJ, Jarnagin WR, Kemeny N. Phase II trial of hepatic artery infusional and systemic chemotherapy for patients with unresectable hepatic metastases from colorectal cancer: conversion to resection and long-term outcomes. Ann Surg. 2015 Feb;261(2):353-60. doi: 10.1097/SLA.0000000000000614.
• Cercek A, D'Angelica M, Power D, Capanu M, Gewirtz A, Patel D, Allen P, Fong Y, DeMatteo RP, Jarnagin WR, Kemeny NE. Floxuridine hepatic arterial infusion associated biliary toxicity is increased by concurrent administration of systemic bevacizumab. Ann Surg Oncol. 2014 Feb;21(2):479-86. doi: 10.1245/s10434-013-3275-0. Epub 2013 Oct 24.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): June 24, 2019
• Primary Completion (Estimated): December 31, 2029
• Study Completion (Estimated): December 30, 2030

Study Registration Dates

• First Submitted: December 7, 2017
• First Submitted That Met QC Criteria: December 7, 2017
• First Posted (Actual): December 8, 2017

Study Record Updates

• Last Update Posted (Actual): March 13, 2024
• Last Update Submitted That Met QC Criteria: March 12, 2024
• Last Verified: March 11, 2024

More Information

Terms related to this study

• Keywords: Unresectable Liver Tumor; Response Rates; Progression-Free Survival; Patient Survival
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Neoplastic Processes; Colorectal Neoplasms; Neoplasm Metastasis; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Topoisomerase I Inhibitors; Oxaliplatin; Irinotecan; Panitumumab; Cetuximab
• Other Study ID Numbers: 180024; 18-C-0024

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: .All IPD recorded in the medical record will be shared with intramural investigators upon request.
• IPD Sharing Time Frame: Clinical data available during the study and indefinitely.
• IPD Sharing Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No