A Study of Avastin (Bevacizumab) Plus Xeloda (Capecitabine) in Patients With Locally Advanced Rectal Cancer.

Study Overview
=================
Brief Summary
-----------------
This open-label study will assess the efficacy and safety of Avastin (bevacizumab) plus Xeloda (capecitabine) in combination with standard technique radiotherapy of the pelvic region in the neo-adjuvant setting in patients with locally advanced primary rectal cancer. Patients will receive 4 courses of Avastin at a dose of 5 mg/kg intravenously (iv) every 2 weeks and for 38 days Xeloda at dose of 825 mg/kg twice daily orally, plus radiation therapy. After surgery, adjuvant treatment with 5-fluorouracil/leucovorin and, at the discretion of the investigator, with Avastin 5 mg/kg iv every 2 weeks for at least 6 months will be given.

Official Title
-----------------
An Open-label Study to Assess the Effect of Combination Treatment With Avastin and Xeloda, Plus Pre-operative Standard Radiotherapy, on Response Rate in Patients With Locally Advanced Rectal Cancer.

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

Intervention / Treatment
-----------------
* Drug: bevacizumab [Avastin]
* Drug: capecitabine [Xeloda]
* Radiation: Radiation therapy
* Procedure: Mesorectal excision
* Drug: bevacizumab [Avastin]
* Drug: 5-fluorouracil
* Drug: leucovorin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adult patients, >=18 years of age Patients with confirmed rectal cancer who are subject to surgery and would benefit from pre-operative combined chemo-radiotherapy Measurable and/or evaluable lesions according to RECIST criteria EOCG performance status 0-1 Exclusion Criteria: Prior radiotherapy or chemotherapy for rectal cancer Untreated brain metastases or spinal cord compression or primary brain tumors Chronic daily treatment with high-dose aspirin (>325 mg/day) or other medications known to predispose to gastrointestinal ulceration Co-existing malignancies, or malignancies diagnosed within the last 5 years, with the exception of basal and squamous cell cancer, or cervical cancer in situ.

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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm<br> | Drug: bevacizumab [Avastin]<br>* 5 mg/kg intravenously every 2 weeks, 4 cycles<br>Drug: capecitabine [Xeloda]<br>* 825 mg/m2 twice daily orally, 38 days<br>Radiation: Radiation therapy<br>* Total dose of 45 Gy over 38 days<br>Procedure: Mesorectal excision<br>* 6-8 weeks after completion of neoadjuvant treatment<br>Drug: bevacizumab [Avastin]<br>* Post-surgery adjuvant treatment at the discretion of the investigator: 5 mg/kg iv every 2 weeks for at least 6 months<br>Drug: 5-fluorouracil<br>* Post-surgery adjuvant therapy: bolus of 400mg/m2 iv plus iv infusion of 600 mg/m2 on Days 1 and 2 of each 2-week cycle for 6 months<br>Drug: leucovorin<br>* Post-surgery adjuvant treatment: 100 mg/m2 iv on Days 1 and 2 of each 2-week cycle for 6 months<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Pathological Complete Response (pCR) | pCR was defined as the absence of viable tumor cells, as determined by standard histologic procedure, in the tumor specimen (including regional lymph nodes) obtained at surgery. In order to minimize evaluation bias, tumor specimens were analyzed by both a central and local pathologist. The number of participants with pathological tumor stage 0 (pT0) and regional lymph nodes stage 0 (pN0) at surgery was determined. pCR was defined as the number of participants with pT0 and pN0 at surgery divided by the total number of participants with pathological tumor stage data collected. | 6 to 8 weeks following completion of neoadjuvant treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants by Primary Tumor (T), Regional Lymph Nodes (N), and Distant Metastasis (M) Clinical Stage at Baseline and at the End of Neo-Adjuvant Treatment (NAT) | The frequencies of clinical tumor stage T (0, 1, 2, 3, 4, or X), regional lymph nodes stage N (0, 1, 2, 3, or 4), and distant metastasis clinical stage M (0, 1, or X) at baseline and at the end of NAT were assessed. The frequencies of pathological tumor stage T and regional lymph nodes stage N at surgery were evaluated. The clinical tumor and lymph node status was assessed by clinical examination, endosonography, and/or rectosigmoidoscopy, and pelvic and abdomen computerized tomography (CT) scan or magnetic resonance imaging (MRI). Response to treatment had to be assessed within 6 weeks after end of treatment by using the same techniques performed at baseline. | Baseline (BL) and end of neoadjuvant treatment (within 6 weeks after the completion of study treatment) | 
| Percentage of Participants Undergoing Sphincter-Saving Surgery by Type of Procedure |  | 6 to 8 weeks after completion of study treatment | 
| Percentage of Participants With Complete Response (CR) at the End of Neoadjuvant Treatment | Percentage of participants with CR was evaluated as the proportion of participants with complete response for the target and non-target lesions, separately, at the end of NAT according to the Response Evaluation Criteria in Solid Tumors (RECIST). CR was defined as disappearance of all target lesions or all non-target lesions and normalization of tumor marker levels. | BL and within 6 weeks after the completion of study treatment | 
| Percentage of Participants With an Overall Response of CR at the End of Neoadjuvant Treatment | Percentage of participants with an overall response of CR was evaluated as the proportion of participants with CR for the target and non-target lesions plus absence of new lesions at the end of NAT according to RECIST. CR was defined as disappearance of all target lesions, all non-target lesions, and normalization of tumor marker levels. | BL and within 6 weeks after the completion of study treatment | 
| Percentage of Participants With New Lesions at the Primary Tumor Site at the End of Neoadjuvant Treatment | The percentage of participants with new lesions located at the primary tumor site were evaluated at the end of NAT. | BL and within 6 weeks after the completion of study treatment | 
| Percentage of Participants With Relapse During Follow-Up | The percentage of participants with local and/or regional relapse during follow-up. New lesions located at rectum or at colon or at lymph node detected at the end of NAT were evaluated as local and/or regional relapse. | BL, within 6 weeks after the completion of neoadjuvant treatment, every 2 weeks for 1 year following surgery, every 3 months thereafter until progression, up to 45 months | 
| Disease-Free Survival (DFS) - Percentage of Participants With an Event | DFS was defined as the time from treatment start date to the date of first progression of disease or date of death due to any cause. | BL, within 6 weeks after the completion of neoadjuvant treatment, every 2 weeks for 1 year following surgery, every 3 months thereafter until progression, up to 45 months | 
| DFS - Time to Event | The time in months from date of start-of-treatment to the date of event defined as the first documented disease progression or death due to any cause. If a participant did not have an event, the time was censored at the date of last adequate tumor assessment. DFS was estimated using the Kaplan-Meier method. | BL, within 6 weeks after the completion of neoadjuvant treatment, every 2 weeks for 1 year following surgery, every 3 months thereafter until progression, up to 45 months | 
| Overall Survival (OS) - Percentage of Participants With an Event | OS was defined as the time from the date of first day of treatment until death due to any cause or the last date the participant was known to be alive. | BL, within 6 weeks after the completion of neoadjuvant treatment, every 2 weeks for 1 year following surgery, every 3 months thereafter until death, up to 45 months | 
| OS - Time to Event | OS was defined as the time from the date of first day of treatment until death due to any cause or the last date the participant was known to be alive. OS was estimated using the Kaplan-Meier method. | BL, within 6 weeks after the completion of neoadjuvant treatment, every 2 weeks for 1 year following surgery, every 3 months thereafter until death, up to 45 months | 
| Time to Disease Progression (TTP) - Percentage of Participants With an Event | TTP was defined as the time from date of treatment start until first documented progression of disease or death due to underlying cancer. | BL, within 6 weeks after the completion of neoadjuvant treatment, every 2 weeks for 1 year following surgery, every 3 months thereafter until death, up to 45 months | 
| TTP - Time to Event | TTP was defined as the time from date of treatment start until first documented progression of disease or death due to underlying cancer. TTP was estimated using the Kaplan-Meier method. | BL, within 6 weeks after the completion of neoadjuvant treatment, every 2 weeks for 1 year following surgery, every 3 months thereafter until death, up to 45 months |