FOLFOX + Immunotherapy With Intrahepatic Oxaliplatin for Patients With Metastatic Colorectal Cancer (IMMUNOX)

FOLFOX + Immunotherapy With Intrahepatic Administration of Oxaliplatin for Patients With Multiple Non-resectable Liver Metastasis From Colorectal Cancer

In this trial chemotherapy regimen FOLFOX with intrahepatic administration of oxaliplatin is combined with immunotherapy (nivolumab and ipilimumab) for the group of patients with multiple liver metastasis from colorectal cancer. Investigators hope to increase the disease-free survival after 3 years from 10 % to 30%.

Study Overview

• Status: Withdrawn
• Conditions: Metastatic Colorectal Cancer
• Intervention / Treatment: Drug: Oxaliplatin; Drug: 5-Fluorouracil; Drug: Leucovorin; Drug: Nivolumab; Device: Ipilimumab

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• Denmark
  • Herlev, Denmark, 2730
    • Herlev University Hospital, Department of Oncology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 79 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Informed consent
• Age: 18 - 79 years
• Performance status 0-1.
• Histologically documented colorectal cancer (In case primary tumor has not yet been removed, it should be possible to be removed by surgery)
• Tumor is immunohistochemically microsatellite stable (MSS)
• More than 5 liver metastasis, not eligible for liver resection or radiofrequency ablation (RFA)
• Presence of liver metastasis documented on CT-scan with no documented extrahepatic disease except from primary tumor in situ.
• Measurable disease according to RECIST 1.1
• Involved liver tissue under 70 %
• Perfusion of liver metastasis possible via a. hepatica
• ANC >= 1,5 x 10¨9/ml og Platelets >= 100 x 10¨9/ml ,
• Estimated creatinine clearance >= 60 ml/min
• INR < 1,4 and bilirubin <= 1,5 x ULN

Exclusion Criteria:

• Current or prior second malignancy within 5 years, except from basal cell carcinoma or carcinoma in situ cervix uteri.
• Severe medical condition, such as severe cardiac disease or AMI within 1 year
• Uncontrolled infection.
• Patients positive for HIV, HBV-sAG or HCV antibody
• Participants with active, known or suspected autoimmune disease. Participants with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.

• Current or prior use of immunosuppressive medication within 14 days before the first dose of ipilimumab, nivolumab. The following are exceptions to this criterion:

  • Intranasal, inhaled, or topical steroids; or local steroid injections (e.g. intra-articular injection)
  • Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent
  • Steroids as premedication for hypersensitivity reactions (e.g. CT scan premedication)
• Patients requiring treatment with oral prednisolon of dose > 10 mg daily
• Previous severe, unexpected reaction related to treatment with fluoropyrimidine.
• Previous treatment with oxaliplatin or immunotherapy
• Neuropathy that is contraindicated for treatment with oxaliplatin
• Pregnant or breastfeeding women. Women with childbearing potential (WOCBP) should have a negative pregnancy test and agree to use highly effective method(s) of contraception during treatment and 6 months thereafter.
• Men who are sexually active with WOCBP who do not agree to use highly effective method(s) of contraception during treatment and 7 months after immunotherapy or 6 months after chemotherapy (which period is the longest)
• Patients who, for linguistic, intellectual or cultural reasons, will not be able to fully understand the concept of treatment and respond to any. complications.

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: FOLFOX + Immunotherapy; 8 cycles of FOLFOX every 2 weeks with intrahepatic administration of oxaliplatin in cycles 1-4, thereafter (cycles 5-8) oxaliplatin i given i.v.; starting from cycle 3 this is combined with i.v. administration of nivolumab (cycle 3-8) and ipilimumab (cycle 3 + 6) Immunotherapy: Starting from cycle 3: Nivolumab 3 mg/kg i.v. on day 3 (every 2nd week, total of 6 administrations), Ipilimumab 1 mg/kg i.v. on day 3 (every 6th week, total of 2 administrations)

Drug: Oxaliplatin; Day 1 in cycle 1-4: 100 mg/m2 intrahepatic administration Day 1 in cycle 5-8: oxaliplatin 85 mg/m2 i.v.; Drug: 5-Fluorouracil; Day 1 each cycle: 400 mg/m2 i.v. bolus, 2400 mg/m2 i.v.over 46 hrs; Drug: Leucovorin; Day 1 each cycle: 400 mg/m2 i.v.; Drug: Nivolumab; Day 3 in cycle 3 to 8: 3 mg/kg i.v.; Device: Ipilimumab; Day 3 in cycle 3 and 6: 1 mg/kg i.v.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease-free Survival at 3 years	Proportion of patients without signs of disease 3 years after treatment start	3 years from start of treatment within the trial

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patients becoming eligible for resection of liver metastasis	Number of patients with reduction of tumor burden to an extent that they become eligible for resection/radio frequency ablation of liver metastasis	Evaluation of resectability after 8 cycles (each cycle is 14 days) of treatment (i.e after 16 weeks)
Objective response rate	Proportion of patients with complete or partial response according to RECIST v1.1	Evaluation by CT-scan after 8 cycles (each cycle is 14 days) of treatment (i.e after 16 weeks)
Progression free survival	Time from start of treatment to progression of disease or death	Evaluation by CT-scan after 8 cycles of treatment each cycle is 14 days) and every 3 months thereafter until progression (max 3 years)
Overall survival	Time from start of treatment to death	Survival follow-up is planned for at least 3 years from treatment start
Safety and tolerability of the treatment	Incidence of treatment related Adverse Events	During the 16 weeks of treatment and 100 days thereafter (up to 31 weeks)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory analysis of immunological response in tumor tissue	Composition of immune infiltrates in order to define the immune cell subsets present within FFPE tumor tissue before and after exposure to therapy.	Tumor tissue samples taken at baseline and week 16
Explorative analysis of biomarkers predictive of response to the combination of nivolumab, ipilimumab in combination with FOLFOX	Biomarker analyses include, but are not limited to a range of molecules with different characteristics such as DNA, Single Nucleotide Polymorphism (SNPs), RNA, microRNA, proteins and metabolites	Blood samples are drawn at baseline through study completion (up to 3 years)

Collaborators and Investigators

• Sponsor: Dorte Nielsen
• Collaborators: Danish Cancer Society
• Investigators: Principal Investigator: Ole Larsen, MD, PhD, Herlev Hospital, Department of Oncology

Study record dates

Study Major Dates

• Study Start (Actual): September 30, 2020
• Primary Completion (Actual): September 6, 2021
• Study Completion (Actual): September 6, 2021

Study Registration Dates

• First Submitted: June 8, 2020
• First Submitted That Met QC Criteria: June 11, 2020
• First Posted (Actual): June 16, 2020

Study Record Updates

• Last Update Posted (Actual): October 27, 2021
• Last Update Submitted That Met QC Criteria: October 19, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Antineoplastic Agents, Immunological; Micronutrients; Vitamins; Immune Checkpoint Inhibitors; Antidotes; Vitamin B Complex; Fluorouracil; Oxaliplatin; Nivolumab; Leucovorin; Ipilimumab
• Other Study ID Numbers: GI 1949; 2019-004397-26 (EudraCT Number)

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