Combination of Cetuximab, Capecitabine, and Oxaliplatin With or Without Bevacizumab

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine the objective response rate of patients with previously untreated metastatic colorectal cancer treated with the combination of cetuximab, capecitabine, and oxaliplatin with out without bevacizumab.

Detailed Description
-----------------
Research has shown that the more drug treatments patients with cancer of the colon or rectum receive, the longer they live. One uses the drugs capecitabine and oxaliplatin which all patients on this study will receive. Bevacizumab is an antibody which blocks blood flow to tumors and increases how long patients with colorectal cancer live. However, it can increase the risk of stroke and heart attack. Bevacizumab is currently a standard part of treatment for colorectal cancer. Cetuximab is an antibody which blocks a protein called EGFR which shrinks colorectal cancer. It may be helpful with initial chemotherapy and with bevacizumab. One goal of this study is to find out the response rate (chance of tumor shrinking) with two treatments for colorectal cancer. All patients will get capecitabine, oxaliplatin and cetuximab. Half will receive bevacizumab. All drugs in this study are approved to treat colorectal cancer. This research study is being done to find the best, safest way to combine these therapies.

Official Title
-----------------
Phase II Study of the Combination of Cetuximab, Capecitabine, and Oxaliplatin With Out Without Bevacizumab as Initial Therapy for Metastatic Colorectal Cancer

Conditions
-----------------
Colorectal Neoplasms

Intervention / Treatment
-----------------
* Drug: bevacizumab
* Drug: cetuximab
* Drug: Oxaliplatin
* Drug: Capecitabine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: measurable metastatic adenocarcinoma of the colon or rectum no prior systemic therapy for metastatic disease adjuvant therapy must have been completed >/=12 months prior to recurrence, prior radiotherapy permitted but must have been completed > 6 months prior to study entry must have tumor tissue available for EGFR and thymidine phosphorylase evaluation ECOG PS 0-1 age >/= 18 adequate organ function: WBC>/=3,000, ANC >/=1,500, platelets>/= 100,000, total bilirubin </= 1.5X ULN, AST&ALT </= 2.5X ULN, create clearance >/= 50mL/min negative pregnancy test w/in 72 hours of treatment for women of child bearing potential ability to understand and willing to sign written ICF able to swallow and absorb oral medication Exclusion Criteria: medical or psychiatric condition which would potentially pose risk to patient by participation (i.e. but not limited to:uncontrolled hypertension, MI w/in 6 months,CNS disease, pregnancy or nursing) history of neoplasm (other than non-metastatic skin cancer or carcinoma in situ of cervix) w/in 5 years surgical procedure (not including closed biopsy or access port placement), open biopsy, significant traumatic injury w/in 28 days of registration or anticipation of need for surgical procedure while on study, fine needle aspiration or core biopsy w/in 7 days of registration urine protein:creatinine ration >/=1.0 at screening evidence of bleeding diathesis or coagulopathy (in absence of anticoagulation) prior severe infusion reaction to MAB or allergic reaction to capecitabine or oxaliplatin underlying neuropathy >/= grade 2 TIA or CVA w/in 6 months

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cetuximab, Oxaliplatin, Capecitabine, Bevacizumab<br>Cetuximab 400 mg/m2 IV initial dose (cycle 1 day 1 only), then 250mg/m2 IV weekly of each 21 day cycle; Oxaliplatin 130mg/m2 IV day 1 of each 21 day cycle; Capecitabine 850mg/m2 PO every 12 hours days 1-14 of each 21 day cycle; Bevacizumab 7.5mg/kg IV day 1 of each 21 day cycle | Drug: bevacizumab<br>* Bevacizumab 7.5mg/kg IV day 1 of each 21 day cycle<br>* Other names: Avastin;Drug: cetuximab<br>* Cetuximab 400mg/m2 IV initial dose (cycle 1 day 1 only), then 250mg/m2 IV weekly each 21 day cycle<br>* Other names: Erbitux;Drug: Oxaliplatin<br>* Oxaliplatin 130mg/m2 IV day 1 every 21 days<br>* Other names: Eloxatin;Drug: Capecitabine<br>* Capecitabine 850mg/m2 PO every 12 hours days 1-14 of each 21 day cycle<br>* Other names: Xeloda;|
| Active Comparator: Cetuximab, Oxaliplatin, Capecitabine<br>Cetuximab 400 mg/m2 IV initial dose (cycle 1 day 1 only), then 250mg/m2 IV weekly of each 21 day cycle; Oxaliplatin 130mg/m2 IV day 1 of each 21 day cycle; Capecitabine 850mg/m2 PO every 12 hours days 1-14 of each 21 day cycle | Drug: cetuximab<br>* Cetuximab 400mg/m2 IV initial dose (cycle 1 day 1 only), then 250mg/m2 IV weekly each 21 day cycle<br>* Other names: Erbitux;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | Objective response rate calculated by the proportion of overall response: CR+PR. Patients were categorized by one of the following (1-4 per RECISTv1.0 criteria on CT, MRI, x-ray; 4-9 considered failure to respond/disease progression): complete response (CR): Disappearance of all lesions partial response (PR): >=30% decrease in the sum of the longest diameter of target lesions (SoL); from baseline SoL stable disease (SD): Neither PR, PD, or CR progressive disease (PD): >=20% increase in the SoL; from smallest SoL. Or appearance of new lesion early death from malignant disease early death from toxicity early death from other cause 9) unknown (not assessable, insufficient data) | every 6-9 weeks; from date of first study drug dose until off treatment date (median of 8 cycles; range <1-19) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression (TTP) | Per Response Evaluation Criteria In Solid Tumors (RECISTv1.0) assessed by CT, MRI, x-ray scan: Complete response (CR): Disappearance of all lesions Partial response (PR): >=30% decrease in the sum of the longest diameter of target lesions (SoL); from baseline SoL Stable disease (SD): Neither PR, PD, or CR Progressive disease (PD): >=20% increase in the SoL; from smallest SoL. Or appearance of new lesion | every 6-9 weeks; from dose of first study drug to event | 
| Overall Survival | Follow-up for survival to be done at 3 month intervals for 2 years, then 6 month intervals for up to 5 years from study registration | From dose of first study drug to last timepoint known to be alive (median follow-up for all patients was 25.9 months) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
metastatic, colorectal, cancer, initial therapy