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

Study Overview
=================
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%.

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

Conditions
-----------------
Metastatic Colorectal Cancer

Intervention / Treatment
-----------------
* Drug: Oxaliplatin
* Drug: 5-Fluorouracil
* Drug: Leucovorin
* Drug: Nivolumab
* Device: Ipilimumab


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 79 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FOLFOX + Immunotherapy<br>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<br>* Day 1 in cycle 1-4: 100 mg/m2 intrahepatic administration Day 1 in cycle 5-8: oxaliplatin 85 mg/m2 i.v.<br>Drug: 5-Fluorouracil<br>* Day 1 each cycle: 400 mg/m2 i.v. bolus, 2400 mg/m2 i.v.over 46 hrs<br>Drug: Leucovorin<br>* Day 1 each cycle: 400 mg/m2 i.v.<br>Drug: Nivolumab<br>* Day 3 in cycle 3 to 8: 3 mg/kg i.v.<br>Device: Ipilimumab<br>* Day 3 in cycle 3 and 6: 1 mg/kg i.v.<br>|

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) |