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

Primary Purpose

Metastatic Colorectal Cancer

Status
Withdrawn
Phase
Phase 2
Locations
Denmark
Study Type
Interventional
Intervention
Oxaliplatin
5-Fluorouracil
Leucovorin
Nivolumab
Ipilimumab
Sponsored by
Dorte Nielsen
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Metastatic Colorectal Cancer

Eligibility Criteria

18 Years - 79 Years (Adult, Older Adult)All SexesDoes not accept 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.

Sites / Locations

  • Herlev University Hospital, Department of Oncology

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

FOLFOX + Immunotherapy

Arm Description

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)

Outcomes

Primary Outcome Measures

Disease-free Survival at 3 years
Proportion of patients without signs of disease 3 years after treatment start

Secondary Outcome Measures

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
Objective response rate
Proportion of patients with complete or partial response according to RECIST v1.1
Progression free survival
Time from start of treatment to progression of disease or death
Overall survival
Time from start of treatment to death
Safety and tolerability of the treatment
Incidence of treatment related Adverse Events

Full Information

First Posted
June 8, 2020
Last Updated
October 19, 2021
Sponsor
Dorte Nielsen
Collaborators
Danish Cancer Society
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1. Study Identification

Unique Protocol Identification Number
NCT04430985
Brief Title
FOLFOX + Immunotherapy With Intrahepatic Oxaliplatin for Patients With Metastatic Colorectal Cancer
Acronym
IMMUNOX
Official Title
FOLFOX + Immunotherapy With Intrahepatic Administration of Oxaliplatin for Patients With Multiple Non-resectable Liver Metastasis From Colorectal Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
October 2021
Overall Recruitment Status
Withdrawn
Why Stopped
Problems identifying eligble patients
Study Start Date
September 30, 2020 (Actual)
Primary Completion Date
September 6, 2021 (Actual)
Study Completion Date
September 6, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Dorte Nielsen
Collaborators
Danish Cancer Society

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. 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%.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Metastatic Colorectal Cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
0 (Actual)

8. Arms, Groups, and Interventions

Arm Title
FOLFOX + Immunotherapy
Arm Type
Experimental
Arm Description
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)
Intervention Type
Drug
Intervention Name(s)
Oxaliplatin
Intervention Description
Day 1 in cycle 1-4: 100 mg/m2 intrahepatic administration Day 1 in cycle 5-8: oxaliplatin 85 mg/m2 i.v.
Intervention Type
Drug
Intervention Name(s)
5-Fluorouracil
Intervention Description
Day 1 each cycle: 400 mg/m2 i.v. bolus, 2400 mg/m2 i.v.over 46 hrs
Intervention Type
Drug
Intervention Name(s)
Leucovorin
Intervention Description
Day 1 each cycle: 400 mg/m2 i.v.
Intervention Type
Drug
Intervention Name(s)
Nivolumab
Intervention Description
Day 3 in cycle 3 to 8: 3 mg/kg i.v.
Intervention Type
Device
Intervention Name(s)
Ipilimumab
Intervention Description
Day 3 in cycle 3 and 6: 1 mg/kg i.v.
Primary Outcome Measure Information:
Title
Disease-free Survival at 3 years
Description
Proportion of patients without signs of disease 3 years after treatment start
Time Frame
3 years from start of treatment within the trial
Secondary Outcome Measure Information:
Title
Patients becoming eligible for resection of liver metastasis
Description
Number of patients with reduction of tumor burden to an extent that they become eligible for resection/radio frequency ablation of liver metastasis
Time Frame
Evaluation of resectability after 8 cycles (each cycle is 14 days) of treatment (i.e after 16 weeks)
Title
Objective response rate
Description
Proportion of patients with complete or partial response according to RECIST v1.1
Time Frame
Evaluation by CT-scan after 8 cycles (each cycle is 14 days) of treatment (i.e after 16 weeks)
Title
Progression free survival
Description
Time from start of treatment to progression of disease or death
Time Frame
Evaluation by CT-scan after 8 cycles of treatment each cycle is 14 days) and every 3 months thereafter until progression (max 3 years)
Title
Overall survival
Description
Time from start of treatment to death
Time Frame
Survival follow-up is planned for at least 3 years from treatment start
Title
Safety and tolerability of the treatment
Description
Incidence of treatment related Adverse Events
Time Frame
During the 16 weeks of treatment and 100 days thereafter (up to 31 weeks)
Other Pre-specified Outcome Measures:
Title
Exploratory analysis of immunological response in tumor tissue
Description
Composition of immune infiltrates in order to define the immune cell subsets present within FFPE tumor tissue before and after exposure to therapy.
Time Frame
Tumor tissue samples taken at baseline and week 16
Title
Explorative analysis of biomarkers predictive of response to the combination of nivolumab, ipilimumab in combination with FOLFOX
Description
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
Time Frame
Blood samples are drawn at baseline through study completion (up to 3 years)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
79 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ole Larsen, MD, PhD
Organizational Affiliation
Herlev Hospital, Department of Oncology
Official's Role
Principal Investigator
Facility Information:
Facility Name
Herlev University Hospital, Department of Oncology
City
Herlev
ZIP/Postal Code
2730
Country
Denmark

12. IPD Sharing Statement

Plan to Share IPD
No

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

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