Side Effects to FOLFOXIRI + Tocotrienol/Placebo as First Line Treatment of Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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Treatment with FOLFOXIRI (5-fluorouracil, oxaliplatin, irinotecan) can be effective, but it has serious side effects, which may require hospitalization. The purpose of this study is to investigate whether the addition of tocotrienol can reduce the side effects to FOLFOXIRI otherwise leading to hospitalization.

Official Title
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A Randomized Investigation of Side Effects to FOLFOXIRI in Combination With Tocotrienol or Placebo as First Line Treatment of Metastatic Colorectal Cancer

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: Irinotecan 165 mg/m2 iv
* Drug: Oxaliplatin 85 mg/m2 iv
* Drug: Calcium folinate 200 mg/m2 iv
* Drug: 5-fluorouracil 3200 mg/m2
* Dietary Supplement: Tocotrienol
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically verified colorectal adenocarcinoma. Patients to receive first line treatment of metastatic disease, including potentially resectable or non-resectable disease > 6 months without recurrence after end of adjuvant chemotherapy for radically treated stage II or III colorectal cancer Disease evaluable according to RECIST 1.1, but not necessarily measurable disease. Age 18-75 years Performance status (PS) 0-1. If age 71-75, then PS 0 Life expectancy > 3 months Organ and bone marrow function as follows: Neutrophil count ≥ 1.5 x 10^9/L Thrombocytes ≥ 100 x 10^9/L Total bilirubin ≤ 1.5 x upper level of normal (ULN) Alanine transaminase (ALAT) ≤ 2.5 x ULN (or≤ 5 x ULN in case of liver metastases) Fertile women must present negative pregnancy test. Male (with a female fertile partner) as well as female patients must use secure contraceptives during and 6 months after end of treatment. Orally and written informed consent to treatment and biobank Exclusion Criteria: Primarily resectable metastases Chemotherapy, radiotherapy or immunotherapy within 4 weeks Known neuropathy ≥ grade 2 Serious competitive medical condition Other concurrent malignant disease other than non-melanoma skin cancer Previous serious and unexpected reactions to 5-fluorouracil, calcium folinate, oxaliplatin, irinotecan or capecitabine. Hypersensitivity to one or more of the active substances or auxilliary agents

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Chemotherapy plus tocotrienol<br>Every 2 weeks: irinotecan 165 mg/m2 iv, oxaliplatin 85 mg/m2 iv, calcium folinate 200 mg/m2 iv, and 5-fluorouracil 3200 mg/m2 as a 46 hour infusion. Daily: Tocotrienol 300 mg x 3 daily | Drug: Irinotecan 165 mg/m2 iv<br>* Max. 4 months<br>Drug: Oxaliplatin 85 mg/m2 iv<br>* Max. 4 months<br>Drug: Calcium folinate 200 mg/m2 iv<br>* Max. 6 months<br>Drug: 5-fluorouracil 3200 mg/m2<br>* Max. 6 months<br>Dietary Supplement: Tocotrienol<br>* Max. 2 years or at the discretion of the investigator<br>|
| Placebo Comparator: Chemotherapy plus placebo<br>Every 2 weeks: irinotecan 165 mg/m2 iv, oxaliplatin 85 mg/m2 iv, calcium folinate 200 mg/m2 iv, and 5-fluorouracil 3200 mg/m2 as a 46 hour infusion. Daily: Placebo x 3 daily | Drug: Irinotecan 165 mg/m2 iv<br>* Max. 4 months<br>Drug: Oxaliplatin 85 mg/m2 iv<br>* Max. 4 months<br>Drug: Calcium folinate 200 mg/m2 iv<br>* Max. 6 months<br>Drug: 5-fluorouracil 3200 mg/m2<br>* Max. 6 months<br>Drug: Placebo<br>* Max. 2 years or at the discretion of the investigator<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first serious adverse event |  | 6 months after the last patient has finished chemotherapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of non-planned hospitalizations calculated from date of first treatment until 1 month after completed chemotherapy |  | 6 months after the last patient has finished chemotherapy | 
| Duration of non-planned hospitalizations calculated from date of first treatment until 1 month after completed chemotherapy |  | 6 months after the last patient has finished chemotherapy | 
| Death during treatment calculated from date of first treatment until 1 month after completed chemotherapy |  | 6 months after the last patient has finished chemotherapy | 
| Response rate |  | 6 months after the last patient has finished chemotherapy | 
| Progression free survival |  | 6 months after the last patient has finished chemotherapy | 
| Overall survival |  | 6 months after the last patient has finished chemotherapy | 
| Number of patients with treatment related adverse events as assessed by CTCAE v.4.0 |  | 6 months after the last patient has finished chemotherapy | 
| Quality of life as measured by combined questionnaire consisting of EORTC QLQ-C30 and CR29 |  | 6 months after the last patient has finished chemotherapy | 
| Resection rate |  | 6 months after the last patient has finished chemotherapy |