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Preoperative Radiotherapy With Capecitabine and Bevacizumab in Locally Advanced Rectal Cancer: CRAB Phase II Study (CRAB)

Primary Purpose

Locally Advanced Rectal Cancer

Status
Unknown status
Phase
Phase 2
Locations
Slovenia
Study Type
Interventional
Intervention
bevacizumab, capecitabine
Sponsored by
Institute of Oncology Ljubljana
About
Eligibility
Locations
Outcomes
Full info

About this trial

This is an interventional treatment trial for Locally Advanced Rectal Cancer focused on measuring rectal cancer, capecitabine, bevacizumab, radiotherapy

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Male or female patients with histologically proven adenocarcinoma of the rectum (tumour located below the peritoneum), T3/4 or any node positive disease (clinical stage according the TNM classification system)
  • No evidence of metastatic disease.
  • The disease must be considered either resectable at the time of entry or thought to become resectable after preoperative chemoradiation.
  • Age 18 - 80 years
  • WHO Performance Status 0-2
  • No prior radiotherapy, chemotherapy or any targeting therapy for rectal cancer
  • Adequate hematological, hepatic and renal function Ability to swallow tablets
  • Signed informed consent
  • Patients must be willing and able to comply with the protocol for duration of the study

Exclusion Criteria:

  • Malignancy of the rectum other than adenocarcinoma
  • Any unrested synchronous colon cancer
  • Other co-existing malignancy or malignancy within the past 5 years, with the exception of adequately treated in situ carcinoma of the cervix or basal cell carcinoma of the skin
  • Significant heart disease (uncontrolled hypertension despite of medication (> 150/100 mmHg), NYHA class III or IV heart disease,unstable angina or myocardial infarction within the past 1 year prior the study entry, history of significant ventricular arrhythmia requiring treatment)
  • Serious, non-healing wound, ulcer or bone fracture
  • Evidence of active peptic ulcer or upper GI bleeding
  • Evidence of bleeding diathesis or coagulopathy
  • Chronic daily treatment with high-dose aspirin(>325mg/day)
  • Current or recent (>10 days) use of full-dose of parenteral anticoagulants or thrombolytic agents for therapeutic purpose
  • Patients receiving a concomitant treatment with drugs interacting with capecitabine such as flucitosine, phenytoin, or warfarin
  • Known dihydropyrimidine dehydrogenase (DPD)deficiency
  • Major surgery within 4 weeks prior to study treatment starts, or lack of complete recovery from the effects of major surgery or open biopsy
  • Known hypersensitivity to biological drugs
  • Treatment with any investigational drug within 30 days before beginning treatment with the study drug
  • Pregnant or lactating patient
  • Females with a positive or no pregnancy test unless childbearing potential can be otherwise excluded (amenorrheic for at least 2 years,hysterectomy or oophorectomy)

Sites / Locations

  • Onstitute of Oncology, Zaloška 2

Outcomes

Primary Outcome Measures

Pathological complete remission rate (pCR)

Secondary Outcome Measures

Pathological response rate
Rate of sphincter sparing surgical procedure
Histopathological R0 resection rate
Acute and late toxicity
Loco-regional failure rate
Disease-free survival
Overall survival
Quality of life

Full Information

First Posted
February 11, 2009
Last Updated
March 23, 2012
Sponsor
Institute of Oncology Ljubljana
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1. Study Identification

Unique Protocol Identification Number
NCT00842686
Brief Title
Preoperative Radiotherapy With Capecitabine and Bevacizumab in Locally Advanced Rectal Cancer: CRAB Phase II Study
Acronym
CRAB
Official Title
Preoperative Radiotherapy With Capecitabine and Bevacizumab in Locally Advanced Rectal Cancer: CRAB Phase II Study
Study Type
Interventional

2. Study Status

Record Verification Date
March 2012
Overall Recruitment Status
Unknown status
Study Start Date
January 2009 (undefined)
Primary Completion Date
August 2010 (Actual)
Study Completion Date
August 2014 (Anticipated)

3. Sponsor/Collaborators

Name of the Sponsor
Institute of Oncology Ljubljana

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The use of preoperative chemoradiation and adjuvant chemotherapy with 5-FU based chemotherapy reduced local recurrence rate to less than 10%, but has only had limited effect on overall survival due to the constantly high (more than 30%) rate of distant metastasis. However, it has been shown that complete eradication of the primary tumour observed in the histopathological specimen (pathological complete response, pCR) correlates with a favourable overall prognosis so obtaining a pCR might be beneficial. The aim of the study is to investigate whether the addition of bevacizumab to preoperative fluoropyrimidinebased chemoradiation improves pathological complete remission rate in locally advanced rectal cancer with acceptable toxicity. Secondary objectives are to evaluate pathological downstaging rate, histopathological R0 resection rate,sphincter preservation rate, perioperative surgical complication rate, local control, DFS, OS, late toxicity and quality of life.
Detailed Description
radiotherapy: 45 Gy to the pelvis (25x 1.8 Gy on days 1-33, excluding weekends) plus 5.4 Gy on days 36-38 as a boost to the primary tumour (3 fractions of 1.8 Gy).Three- dimensional CT planing and a four field box technique with high energy photons (15 MV) will be used. All fields will be treated daily. Multileaf collimators will be used to shape individual radiation fields. Patients will be irradiated in a prone position with a full bladder and by using belly board to minimize exposure of the small bowel. capecitabine 825 mg/m² p.o. twice daily on days 1-38 (including weekends), bevacizumab: at dose 5 mg/kg on days -14, 2, 16,30. Radical surgery (TME): to be undertaken ideally 6-8 weeks following completion of chemoradiation. Postoperative treatment (in patients achieving histopathological R0 or R1 resection):capecitabine 1250 mg/m² p.o. twice daily for 14 consecutive days every three weeks; 4 cycles (R0)or 6 cycles (R1) beginning 6-8 weeks after surgery

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Locally Advanced Rectal Cancer
Keywords
rectal cancer, capecitabine, bevacizumab, radiotherapy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
60 (Anticipated)

8. Arms, Groups, and Interventions

Intervention Type
Drug
Intervention Name(s)
bevacizumab, capecitabine
Other Intervention Name(s)
Avastin, Xeloda, radiation
Intervention Description
bevacizumab 5mg/kg days -15,1,15,29 capecitabine 1250 mg/square m/day during radiotherapy radiotherapy 50,4 Gy (1,8 Gy per fraction)
Primary Outcome Measure Information:
Title
Pathological complete remission rate (pCR)
Time Frame
after pathological examination of surgical speciments
Secondary Outcome Measure Information:
Title
Pathological response rate
Time Frame
Toxicity/safety:during preoperative treatment, early and late postoperative follow up
Title
Rate of sphincter sparing surgical procedure
Time Frame
Toxicity/safety:during preoperative treatment, early and late postoperative follow up
Title
Histopathological R0 resection rate
Time Frame
Toxicity/safety:during preoperative treatment, early and late postoperative follow up
Title
Acute and late toxicity
Time Frame
Toxicity/safety:during preoperative treatment, early and late postoperative follow up
Title
Loco-regional failure rate
Time Frame
Toxicity/safety:during preoperative treatment, early and late postoperative follow up
Title
Disease-free survival
Time Frame
Toxicity/safety:during preoperative treatment, early and late postoperative follow up
Title
Overall survival
Time Frame
Toxicity/safety:during preoperative treatment, early and late postoperative follow up
Title
Quality of life
Time Frame
Toxicity/safety:during preoperative treatment, early and late postoperative follow up

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male or female patients with histologically proven adenocarcinoma of the rectum (tumour located below the peritoneum), T3/4 or any node positive disease (clinical stage according the TNM classification system) No evidence of metastatic disease. The disease must be considered either resectable at the time of entry or thought to become resectable after preoperative chemoradiation. Age 18 - 80 years WHO Performance Status 0-2 No prior radiotherapy, chemotherapy or any targeting therapy for rectal cancer Adequate hematological, hepatic and renal function Ability to swallow tablets Signed informed consent Patients must be willing and able to comply with the protocol for duration of the study Exclusion Criteria: Malignancy of the rectum other than adenocarcinoma Any unrested synchronous colon cancer Other co-existing malignancy or malignancy within the past 5 years, with the exception of adequately treated in situ carcinoma of the cervix or basal cell carcinoma of the skin Significant heart disease (uncontrolled hypertension despite of medication (> 150/100 mmHg), NYHA class III or IV heart disease,unstable angina or myocardial infarction within the past 1 year prior the study entry, history of significant ventricular arrhythmia requiring treatment) Serious, non-healing wound, ulcer or bone fracture Evidence of active peptic ulcer or upper GI bleeding Evidence of bleeding diathesis or coagulopathy Chronic daily treatment with high-dose aspirin(>325mg/day) Current or recent (>10 days) use of full-dose of parenteral anticoagulants or thrombolytic agents for therapeutic purpose Patients receiving a concomitant treatment with drugs interacting with capecitabine such as flucitosine, phenytoin, or warfarin Known dihydropyrimidine dehydrogenase (DPD)deficiency Major surgery within 4 weeks prior to study treatment starts, or lack of complete recovery from the effects of major surgery or open biopsy Known hypersensitivity to biological drugs Treatment with any investigational drug within 30 days before beginning treatment with the study drug Pregnant or lactating patient Females with a positive or no pregnancy test unless childbearing potential can be otherwise excluded (amenorrheic for at least 2 years,hysterectomy or oophorectomy)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Vaneja Velenik, MD, PhD
Organizational Affiliation
Institute of Oncology, Ljubljana, Slovenia
Official's Role
Principal Investigator
Facility Information:
Facility Name
Onstitute of Oncology, Zaloška 2
City
Ljubljana
ZIP/Postal Code
1000
Country
Slovenia

12. IPD Sharing Statement

Citations:
PubMed Identifier
10944647
Citation
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Results Reference
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PubMed Identifier
15496622
Citation
Sauer R, Becker H, Hohenberger W, Rodel C, Wittekind C, Fietkau R, Martus P, Tschmelitsch J, Hager E, Hess CF, Karstens JH, Liersch T, Schmidberger H, Raab R; German Rectal Cancer Study Group. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004 Oct 21;351(17):1731-40. doi: 10.1056/NEJMoa040694.
Results Reference
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PubMed Identifier
12351595
Citation
Dunst J, Reese T, Sutter T, Zuhlke H, Hinke A, Kolling-Schlebusch K, Frings S. Phase I trial evaluating the concurrent combination of radiotherapy and capecitabine in rectal cancer. J Clin Oncol. 2002 Oct 1;20(19):3983-91. doi: 10.1200/JCO.2002.02.049.
Results Reference
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PubMed Identifier
17042060
Citation
Velenik V, Anderluh F, Oblak I, Strojan P, Zakotnik B. Capecitabine as a radiosensitizing agent in neoadjuvant treatment of locally advanced resectable rectal cancer: prospective phase II trial. Croat Med J. 2006 Oct;47(5):693-700.
Results Reference
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PubMed Identifier
17827451
Citation
Duda DG, Jain RK, Willett CG. Antiangiogenics: the potential role of integrating this novel treatment modality with chemoradiation for solid cancers. J Clin Oncol. 2007 Sep 10;25(26):4033-42. doi: 10.1200/JCO.2007.11.3985.
Results Reference
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PubMed Identifier
16258121
Citation
Willett CG, Boucher Y, Duda DG, di Tomaso E, Munn LL, Tong RT, Kozin SV, Petit L, Jain RK, Chung DC, Sahani DV, Kalva SP, Cohen KS, Scadden DT, Fischman AJ, Clark JW, Ryan DP, Zhu AX, Blaszkowsky LS, Shellito PC, Mino-Kenudson M, Lauwers GY. Surrogate markers for antiangiogenic therapy and dose-limiting toxicities for bevacizumab with radiation and chemotherapy: continued experience of a phase I trial in rectal cancer patients. J Clin Oncol. 2005 Nov 1;23(31):8136-9. doi: 10.1200/JCO.2005.02.5635. No abstract available.
Results Reference
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Results Reference
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Preoperative Radiotherapy With Capecitabine and Bevacizumab in Locally Advanced Rectal Cancer: CRAB Phase II Study

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