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

Sponsor

Dorte Nielsen (Other)

Overall Status

Withdrawn

CT.gov ID

NCT04430985

Collaborator

Danish Cancer Society (Other)

Enrollment

Location

Arm

11.2

Actual Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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%.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Colorectal Cancer	Drug: Oxaliplatin Drug: 5-Fluorouracil Drug: Leucovorin Drug: Nivolumab Device: Ipilimumab	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Sep 30, 2020

Actual Primary Completion Date :

Sep 6, 2021

Actual Study Completion Date :

Sep 6, 2021

Arms and Interventions

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.

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.

Outcome Measures

Primary Outcome Measures

Disease-free Survival at 3 years [3 years from start of treatment within the trial]
Proportion of patients without signs of disease 3 years after treatment start

Secondary Outcome Measures

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

Other Outcome Measures

Exploratory analysis of immunological response in tumor tissue [Tumor tissue samples taken at baseline and week 16]
Composition of immune infiltrates in order to define the immune cell subsets present within FFPE tumor tissue before and after exposure to therapy.
Explorative analysis of biomarkers predictive of response to the combination of nivolumab, ipilimumab in combination with FOLFOX [Blood samples are drawn at baseline through study completion (up to 3 years)]
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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 79 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.