Tocotrienol and Bevacizumab in Metastatic Colorectal Cancer

Study Overview
=================
Brief Summary
-----------------
This double blind, randomized phase II trial will investigate whether the addition of tocotrienol will improve the effect and lower the toxicity of standard chemotherapy and bevacizumab. Half of the patients will receive tocotrienol and the other half placebo. Treatment is planned for a period of maximum six months and will be discontinued earlier in case of progression or unacceptable toxicity.

Official Title
-----------------
Tocotrienol and Bevacizumab in Metastatic Colorectal Cancer. A Randomized Phase II Marker Trial

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

Intervention / Treatment
-----------------
* Drug: Fluorouracil
* Drug: Calcium folinate
* Drug: Oxaliplatin
* Drug: Bevacizumab
* Drug: Capecitabine
* Dietary Supplement: Tocotrienol
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histopathologically verified adenocarcinoma of the colon or rectum Metastatic disease Planned treatment with FOLFOX or capecitabine combined with bevacizumab Evaluable disease according to RECIST 1.1 Performance status 0-2 Expected survival ≥ 3 months Patient acceptance to collection of blood samples for translational research Age ≥ 18 years Contraception during and 6 months after last dose for women of childbearing potential (less than one year amenorrhea and not undergone hysterectomy, bilateral salpingectomy or bilateral oophorectomy) and for male patients with a fertile partner. Hormonal contraception, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized partner, or sexual abstinence is accepted. Adequate bone marrow function, liver function, and renal function (within 7 days prior to inclusion): WBC ≥ 3.0 x 109/l or neutrophils (ANC) ≥ 1.5 x 10^9/l Platelet count ≥ 100 x 10^9/l Hemoglobin ≥ 6.0 mmol/l Serum bilirubin ≤ 2.0 x ULN Serum transaminase ≤ 2.5 x ULN Serum creatinine ≤ 1.5 ULN Urine dipstick for protein ≤ 2+, if the dipstick shows protein ≥ 2+, 24 hour urine testing must be performed and show protein contents ≤ 1g. Written and orally informed consent Exclusion Criteria: Other active malignant disease within 5 years prior to inclusion in the study. Other experimental therapy within 28 days prior to treatment initiation. Underlying medical disease not adequately treated. Surgery, including open biopsy, within 4 weeks prior to first dose of bevacizumab. Cerebral vascular attack, transient ischemic attack or subarachnoid hemorrhage within six months before start of treatment Bleeding tumor Pregnant or breastfeeding women Fertile patients not willing to use effective methods of contraception during treatment and for six months after end of treatment. Hypersensitivity to one or more active substances or auxiliary substances

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

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

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

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

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A, standard treatment + tocotrienol<br>Fluorouracil + calcium folinate + oxaliplatin + bevacizumab + tocotrienol OR capecitabine + bevacizumab + tocotrienol | Drug: Fluorouracil<br>* 2800 mg/m2 iv<br>Drug: Calcium folinate<br>* 400 mg/m2 iv<br>Drug: Oxaliplatin<br>* 85 mg/m2 iv<br>Drug: Bevacizumab<br>* 5 mg/kg OR 7.5 mg/kg iv<br>Drug: Capecitabine<br>* 2000 mg/m2 orally daily for two weeks<br>Dietary Supplement: Tocotrienol<br>* 300 mg orally x 3 daily<br>|
| Placebo Comparator: Arm B, standard treatment + placebo<br>Fluorouracil + calcium folinate + oxaliplatin + bevacizumab + placebo OR capecitabine + bevacizumab + placebo | Drug: Fluorouracil<br>* 2800 mg/m2 iv<br>Drug: Calcium folinate<br>* 400 mg/m2 iv<br>Drug: Oxaliplatin<br>* 85 mg/m2 iv<br>Drug: Bevacizumab<br>* 5 mg/kg OR 7.5 mg/kg iv<br>Drug: Capecitabine<br>* 2000 mg/m2 orally daily for two weeks<br>Other: Placebo<br>* Placebo orally x 3 daily<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The rate of progression free patients at six months |  | Six months after enrollment of the last patient | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first serious adverse event according to CTCAE 5.0 | CTCAE=Common Terminology Criteria for Adverse Events | Six months after enrollment of the last patient | 
| Response rate as measured by RECIST 1.1 | RECIST=Response evaluation criteria in solid tumors | Six months after enrollment of the last patient | 
| Overall survival |  | 12 months after enrollment of the last patient | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Colorectal cancer, Tocotrienol, Natural killer cells, Circulating tumor DNA