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

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

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).

Study Overview

• Status: Completed
• Conditions: Locally Advanced Rectal Cancer
• Intervention / Treatment: Drug: Oxaliplatin; Drug: Bevacizumab; Drug: Capecitabine; Radiation: radiotherapy

Detailed Description

See Synopsis

• Study Type: Interventional
• Enrollment (Actual): 84
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Aalst, Belgium, 9300
    • Onze Lieve Vrouwziekenhuis
  • Antwerp, Belgium, ZNA Middelheim
    • ZNA Middelheim
  • Brugge, Belgium, 8310
    • AZ St- Lucas
  • Brussels, Belgium, 1070
    • Erasme hospital
  • Brussels, Belgium, 1200
    • Cliniques Universitaires St Luc
  • Kortrijk, Belgium, 8500
    • AZ Groeninge
  • Liege, Belgium, 4000
    • C.H.U. Sart-Tilman
  • Namur, Belgium, 5000
    • Clinique Sainte Elisabeth
  • Roeselare, Belgium, 8800
    • H. Hartziekenhuis

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: AXE (ARM 1); Oxaliplatin, Bevacizumab and Capecitabine concurrently with radiotherapy.	Drug: Oxaliplatin; Administered on days 15,22,29,36 en 43; 50 mg/m2; Other Names: Eloxatin; Drug: Bevacizumab; Administered on days 1,15,29 and 43 ; 5mg/kg; Other Names: Avastin; Drug: Capecitabine; 825 mg/m2 ; 25 days - 5days per week, concurrent with radiotherapy; Other Names: Xeloda; Radiation: radiotherapy; Total dose 45Gy
Active Comparator: AX (ARM 2); Bevacizumab and Capecitabine concurrently with radiotherapy	Drug: Bevacizumab; Administered on days 1,15,29 and 43 ; 5mg/kg; Other Names: Avastin; Drug: Capecitabine; 825 mg/m2 ; 25 days - 5days per week, concurrent with radiotherapy; Other Names: Xeloda; Radiation: radiotherapy; Total dose 45Gy

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Universitaire Ziekenhuizen KU Leuven
• Investigators: Principal Investigator: Eric Van Cutsem, Prof. Dr., UZ Leuven

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2009
• Primary Completion (Actual): March 1, 2014
• Study Completion (Actual): March 1, 2019

Study Registration Dates

• First Submitted: January 23, 2009
• First Submitted That Met QC Criteria: January 23, 2009
• First Posted (Estimate): January 26, 2009

Study Record Updates

• Last Update Posted (Actual): July 10, 2019
• Last Update Submitted That Met QC Criteria: July 9, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: capecitabine; neoadjuvant; oxaliplatin; bevacizumab; rectal cancer; radiation therapy; postoperative complications; pathological complete response; TME (total mesorectal excision); multimodality treatments; Axe Beam
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Rectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Capecitabine; Oxaliplatin; Bevacizumab
• Other Study ID Numbers: s51104 - ML5194; 2007-007177-23 (EudraCT Number); MO19051 (Other Grant/Funding Number: UZ Leuven with support from Roche and Sanofi)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO