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

NCT04430985 | Withdrawn Phase 2

• 2 other identifiers: GI 19492019-004397-26
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

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%.

Conditions

Metastatic Colorectal Cancer

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (5)

• 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)

• Objective response rate

  Evaluation by CT-scan after 8 cycles (each cycle is 14 days) of treatment (i.e after 16 weeks)

• 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)

• Overall survival

  Survival follow-up is planned for at least 3 years from treatment start

• Safety and tolerability of the treatment

  During the 16 weeks of treatment and 100 days thereafter (up to 31 weeks)

Other Outcomes (2)

• Exploratory analysis of immunological response in tumor tissue

  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

  Blood samples are drawn at baseline through study completion (up to 3 years)

Study Arms (1)

FOLFOX + Immunotherapy

EXPERIMENTAL

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; Drug: 5-Fluorouracil; Drug: Leucovorin; Drug: Nivolumab; Device: Ipilimumab

Interventions

Oxaliplatin DRUG

Day 1 in cycle 1-4: 100 mg/m2 intrahepatic administration Day 1 in cycle 5-8: oxaliplatin 85 mg/m2 i.v.

FOLFOX + Immunotherapy

5-Fluorouracil DRUG

Day 1 each cycle: 400 mg/m2 i.v. bolus, 2400 mg/m2 i.v.over 46 hrs

FOLFOX + Immunotherapy

Leucovorin DRUG

Day 1 each cycle: 400 mg/m2 i.v.

FOLFOX + Immunotherapy

Nivolumab DRUG

Day 3 in cycle 3 to 8: 3 mg/kg i.v.

FOLFOX + Immunotherapy

Ipilimumab DEVICE

Day 3 in cycle 3 and 6: 1 mg/kg i.v.

FOLFOX + Immunotherapy

Eligibility Criteria

• Age: 18 Years - 79 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Dorte Nielsen: lead
• Danish Cancer Society: collaborator

Study Sites (1)

Herlev University Hospital, Department of Oncology

Herlev, 2730, Denmark

Location

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Oxaliplatin; Fluorouracil; Leucovorin; Nivolumab

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Coordination Complexes; Organic Chemicals; Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Coenzymes; Enzymes and Coenzymes; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Ole Larsen, MD, PhD

  Herlev Hospital, Department of Oncology

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor Dorte Nielsen, MD, PhD, DMSc

Study Record Dates

• First Submitted: June 8, 2020
• First Posted: June 16, 2020
• Study Start: September 30, 2020
• Primary Completion: September 6, 2021
• Study Completion: September 6, 2021
• Last Updated: October 27, 2021

Record last verified: 2021-10

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1)