Neoadjuvant Bevacizumab, Capecitabine and Radiation Therapy With or Without Oxaliplatin Locally Advanced Rectal Cancer

Study Overview
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Brief Summary
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Phase II clinical trial, open-label, randomized, two arms, multicentre (possibly multinational). Academic, investigator initiated. To assess the activity of bevacizumab (AvastinTM) in combination with capecitabine (XelodaTM) and radiation therapy with or without oxaliplatin (EloxatinTM) in the pre-operative treatment of locally advanced rectal cancer, followed by TME (total mesorectal excision).

Detailed Description
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See Synopsis

Official Title
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A Randomized Phase II Study of Bevacizumab, Capecitabine and Radiation Therapy With or Without Oxaliplatin in the Preoperative Treatment of Locally Advanced Rectal Cancer

Conditions
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Locally Advanced Rectal Cancer

Intervention / Treatment
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* Drug: Oxaliplatin
* Drug: Bevacizumab
* Drug: Capecitabine
* Radiation: radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adenocarcinoma of rectum measurable (RECIST), locally advanced (defined by MRI - Tumour beyond mesorectal fascia (T4) or Tumour ≤ 2 mm from mesorectal fascia or T3 tumour < 5 cm from anal verge Patient is at least 18 years of age Good organ function Exclusion Criteria: Evidence of distant metastases Contraindication for bevacizumab Pregnant or breastfeeding women.

Ages Eligible for Study
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Minimum Age: 18 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 |
| --- | --- |
| Active Comparator: AXE (ARM 1)<br>Oxaliplatin, Bevacizumab and Capecitabine concurrently with radiotherapy. | Drug: Oxaliplatin<br>* Administered on days 15,22,29,36 en 43; 50 mg/m2<br>* Other names: Eloxatin;Drug: Bevacizumab<br>* Administered on days 1,15,29 and 43 ; 5mg/kg<br>* Other names: Avastin;Drug: Capecitabine<br>* 825 mg/m2 ; 25 days - 5days per week, concurrent with radiotherapy<br>* Other names: Xeloda;Radiation: radiotherapy<br>* Total dose 45Gy<br>|
| Active Comparator: AX (ARM 2)<br>Bevacizumab and Capecitabine concurrently with radiotherapy | Drug: Bevacizumab<br>* Administered on days 1,15,29 and 43 ; 5mg/kg<br>* Other names: Avastin;Drug: Capecitabine<br>* 825 mg/m2 ; 25 days - 5days per week, concurrent with radiotherapy<br>* Other names: Xeloda;Radiation: radiotherapy<br>* Total dose 45Gy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathologic Response at Surgery. Overview of Complete Pathologic Responses, Good and Little Tumour Regression Rates at Surgery. | Dworak tumour regression grades (TRG) were used to assess pathologic response: TRG0=no regression. TRG1=dominant tumor mass with obvious fibrosis and/or vasculopathy; TRG2=dominant fibrotic changes with few tumour cells or groups; TRG3=very few (difficult to find microscopically) tumour cells in fibrotic tissue with or without mucus substance. TRG4=no intact viable tumour cells, only fibrotic mass or presence of mucin lakes without associated malignant cells (total tumour regression). Pathologic assessments of tumour response post chemoradiotherapy as provided by investigators (read by local pathologists on operative specimens) were reviewed centrally for all pts for whom surgical materials were available (centrally reviewed set). The diagnosis of independent central reviewers primed. Pathologic complete response rates (TRG4) are reported (%). Good (TRG3 and TRG4 together) and little (TRG 0,1 and 2) tumour regression rates are summarized. For these 2 last rows, % add to 100. | 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Histopathologic R0 and Negative CRM Resection | Histopathologic R0 resection rate was defined as margins histologically negative for tumour involvement after resection. The circumferential resection margin (CRM) is considered to be involved if microscopic tumour is present <1mm from or at the inked circumferential or radial resection margin. Data on quality of mesorectal excision were expected but not collected consistently. | 4 months | 
| Number of Participants With Pathologic Complete Response at Surgery. Number of Participants With Good or Little Pathological Tumour Regression at Surgery. | Dworak tumour regression grades (TRG) were used to assess pathologic response: TRG0=no regression. TRG1=dominant tumor mass with obvious fibrosis and/or vasculopathy; TRG2=dominant fibrotic changes with few tumour cells or groups; TRG3=very few (difficult to find microscopically) tumour cells in fibrotic tissue with or without mucus substance. TRG4=no intact viable tumour cells, only fibrotic mass or presence of mucin lakes without associated malignant cells (total tumour regression). Pathologic assessments of tumour response post chemoradiotherapy as provided by investigators (read by local pathologists on operative specimens) were reviewed centrally for all pts for whom surgical materials were available (centrally reviewed set). The diagnosis of independent central reviewers primed. Pathologic complete response rates (TRG4) are reported (%). Good (TRG3 and TRG4 together) and little (TRG 0,1 and 2) tumour regression rates are summarized. For these 2 last rows, % add to 100. | 4 months | 
| Clinical Response Rate | Baseline tumour measurements were performed within 4 weeks prior to treatment start (RECIST). The same methods of assessment (CT and/or MRI) were used for each measurable lesion at baseline and during follow-up. Complete Response (CR) is disappearance of all clinical and radiological evidence of tumour (both target and non-target lesions). Partial Response (PR) is at least a 30% decrease in the sum of LD of target lesions, taking as reference the baseline sum of tumour longest diameters (LD). Stable Disease (SD) is steady state of disease. Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Progressive Disease (PD) is at least a 20% increase in the sum of LD of measured lesions taking as references the smallest sum LD recorded since the treatment started. Appearance of new lesions constitutes PD. In exceptional circumstances, unequivocal progression of non-target lesions was considered evidence of PD. | 3 months | 
| Types and Numbers of Adverse Events - General Overview | Adverse events graded as per NCI CTCAE (US National Cancer Institute Common Terminology Criteria for Adverse Events) version 3.0. All Serious Adverse Events occurrences are reported and counts are summarized here; all Adverse Events (all grades) related and not related to study treatment are reported and summarized here; all severe laboratory events (hematology and biochemistry Gr 3 and higher) are reported and summarized here; all severe postoperative complications (Gr 3 and higher) occurred within the first month post surgery are reported and summarized here. See section Adverse events for details. | continuous up to 1 year | 
| Recurrence Rates and Disease Free Survival | Counts and proportions of patients experiencing recurrence of disease (local and distant). | up to 5 years | 
| Death Rates and Overall Survival | Counts and proportions of patients deceased (post-study). | up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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bevacizumab, capecitabine, radiation therapy, oxaliplatin, multimodality treatments, TME (total mesorectal excision), Axe Beam, rectal cancer, neoadjuvant, pathological complete response, postoperative complications