A Study of Bevacizumab (Avastin) in Participants With Newly Diagnosed Locally Advanced Rectal Cancer

Study Overview
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Brief Summary
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This study will assess the efficacy and safety of two different neoadjuvant treatment approaches including bevacizumab in newly diagnosed participants with high risk locally advanced rectal cancer. Participants will be randomized into one of two treatment arms (Arm A or Arm B).

Official Title
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Efficacy and Safety of Two Neoadjuvant Strategies With Bevacizumab in Locally Advanced Resectable Rectal Cancer: A Randomized, Non-Comparative Phase II Study

Conditions
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Rectal Cancer

Intervention / Treatment
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* Drug: Bevacizumab
* Drug: Oxaliplatin
* Drug: Folinic Acid
* Drug: 5-fluorouracil
* Radiation: Preoperative Radiotherapy
* Procedure: Surgery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: histologically confirmed locally advanced rectal cancer; measurable disease; Eastern Cooperative Oncology Group (ECOG) performance status 0-1. Exclusion Criteria: prior treatment with bevacizumab; prior radiotherapy to pelvic region, or previous cytotoxic chemotherapy; previous history of malignancy (other than basal and squamous cell cancer of the skin, or in situ cancer of the cervix); history or evidence of central nervous system (CNS) disease; clinically significant cardiovascular disease; chronic treatment with high dose aspirin (more than [>] 325 milligrams per day [mg/day]) or non-steroidal anti-inflammatory drugs.

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy)<br>In this arm, participants will undergo 3 phases of treatment. During the Phase 1, participants will receive induction chemotherapy with 6 two-week cycles of bevacizumab + Folfox-4 (5-FU + oxaliplatin + folinic acid) for 12 weeks followed by a treatment-free interval of 3 to 4 weeks. The Phase 2 will include 7 weeks of bevacizumab + chemoradiotherapy (intravenous [IV] infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy [5-FU + radiotherapy], with administration of bevacizumab every two weeks [Cycles 1, 3 and 5]) followed by a treatment-free interval of 6 to 8 weeks. The Phase 3 will be surgery involving a radical rectal excision using the total mesorectal excision (TME) technique. | Drug: Bevacizumab<br>* Bevacizumab will be administered at the fixed dose of 5 milligrams per kilogram (mg/kg) as an IV infusion over 30 to 90 minutes.<br>* Other names: Avastin;Drug: Oxaliplatin<br>* Oxaliplatin will be administered at a dose of 85 milligrams per square meter (mg/m^2) as a 2-hour IV infusion.<br>Drug: Folinic Acid<br>* Folinic acid will be administered at a dose of 200 mg/m^2 as a 2-hour infusion.<br>Drug: 5-fluorouracil<br>* 5-fluorouracil will be administered at a dose of 400 mg/m^2 as an IV bolus, then at a dose of 600 mg/m^2 as a continuous infusion for 22 hours in Phase 1, and will be administered at a dose of 225 mg/m^2 as a 24-hour infusion, 5 days a week, for 5 weeks in Phase 2.<br>Radiation: Preoperative Radiotherapy<br>* Radiotherapy will be delivered in fraction of 1.8 gray per day (Gy/day), 5 days a week for 5 weeks, i.e., a total dose of 45 Gy will be administered in 25 fractions over a period of 33 days.<br>Procedure: Surgery<br>* Radical rectal excision based on the TME technique.<br>|
| Experimental: Arm B (Bevacizumab, Chemoradiotherapy)<br>In this arm, participants will receive the Phase 2 and Phase 3 treatments only. The phase 2 will include 7 weeks of bevacizumab + chemoradiotherapy (IV infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy [5-FU + radiotherapy], with administration of bevacizumab every two weeks [Cycles 1, 3 and 5]) followed by a treatment-free interval of 6 to 8 weeks. The phase 3 will be surgery involving a radical rectal excision using the TME technique. | Drug: Bevacizumab<br>* Bevacizumab will be administered at the fixed dose of 5 milligrams per kilogram (mg/kg) as an IV infusion over 30 to 90 minutes.<br>* Other names: Avastin;Drug: 5-fluorouracil<br>* 5-fluorouracil will be administered at a dose of 400 mg/m^2 as an IV bolus, then at a dose of 600 mg/m^2 as a continuous infusion for 22 hours in Phase 1, and will be administered at a dose of 225 mg/m^2 as a 24-hour infusion, 5 days a week, for 5 weeks in Phase 2.<br>Radiation: Preoperative Radiotherapy<br>* Radiotherapy will be delivered in fraction of 1.8 gray per day (Gy/day), 5 days a week for 5 weeks, i.e., a total dose of 45 Gy will be administered in 25 fractions over a period of 33 days.<br>Procedure: Surgery<br>* Radical rectal excision based on the TME technique.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Tumor Sterilization Defined by ypT0-N0 | Tumor sterilization was defined as the absence of residual tumor cells in the resected specimen including lymph nodes (ypT0-N0). The rate of sterilization of the tumoral specimen was assessed after surgery on the surgical specimen by local review. Analyses were performed for participants who have been operated as defined by the protocol (within the study and TME technique) and for all participants who have been operated. Reported is the percentage of participants with tumor sterilization. | After surgery (Arm A: approximately 28-31 weeks after initiation of treatment; Arm B: approximately 13-15 weeks after initiation of treatment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Tumor Down-Staging (ypT0-pT2) | A participant with a downstaging was defined as a participant with T3 (T describes the size of the original [primary] tumor) at inclusion and T2 or T1 or T0 after surgery, or with N+ (N describes lymph nodes involvement) at inclusion and N- after surgery and if T is equal at inclusion and after surgery. The clinical tumor-node-metastasis (cTNM) classification was used at inclusion and the pathological staging tumor and nodes (ypTN) classification after surgery. Reported is the percentage of participants with tumor downstaging of the surgical specimen according to the local review and centralized review. | After surgery (Arm A: approximately 28-31 weeks after initiation of treatment; Arm B: approximately 13-15 weeks after initiation of treatment) | 
| Percentage of Participants With Local and Distant Recurrences | The percentage of participants with a recurrence was described by type of recurrence (local and distant recurrence). | After surgery (Arm A: approximately 28-31 weeks after initiation of treatment; Arm B: approximately 13-15 weeks after initiation of treatment) | 
| Percentage of Participants With Second Cancer, Local or Regional Recurrence, Distant Metastasis, or Death |  | Baseline up to approximately 6 years | 
| Disease-Free Survival (DFS) | The DFS was defined as the time from the first treatment intake to disease recurrence assessed (second primary cancer, local or distant recurrence, distant metastases) or death from any cause. The DFS was analyzed using Kaplan-Meier method. | From first time of the treatment administration to the date of second cancer, local or regional recurrence, distant metastasis or death from any cause (up to approximately 6 years) | 
| Percentage of Participants Who Died |  | Baseline up to approximately 6 years | 
| Overall Survival | The overall survival was defined as the time from the first treatment intake to death from any cause. | From the first treatment administration to the date of death (up to approximately 6 years) | 
| Number of Cycles of Induction Chemotherapy |  | 6 cycles (12 weeks; cycle length = 14 days) | 
| Number of Cycles of Chemotherapy |  | Arm A: Week 16 to Week 23; Arm B: Week 1 to Week 7 | 
| Number of Cycles of Radiotherapy |  | Arm A: Week 16 to Week 23; Arm B: Week 1 to Week 7 | 
| Percentage of Participants With Surgery | The surgery involving a radical rectal excision using the TME technique. | Arm A: approximately 28-31 weeks after initiation of treatment; Arm B: approximately 13-15 weeks after initiation of treatment |