Preoperative Radiotherapy With Capecitabine and Bevacizumab in Locally Advanced Rectal Cancer: CRAB Phase II Study - Full Text View

Purpose

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.

Condition	Intervention	Phase
Locally Advanced Rectal Cancer	Drug: bevacizumab, capecitabine	Phase 2

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Preoperative Radiotherapy With Capecitabine and Bevacizumab in Locally Advanced Rectal Cancer: CRAB Phase II Study

Resource links provided by NLM:

MedlinePlus related topics: Cancer

Drug Information available for: Capecitabine Bevacizumab

U.S. FDA Resources

Further study details as provided by Institute of Oncology Ljubljana:

Primary Outcome Measures:

Pathological complete remission rate (pCR) [ Time Frame: after pathological examination of surgical speciments ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Pathological response rate [ Time Frame: Toxicity/safety:during preoperative treatment, early and late postoperative follow up ] [ Designated as safety issue: Yes ]
Rate of sphincter sparing surgical procedure [ Time Frame: Toxicity/safety:during preoperative treatment, early and late postoperative follow up ] [ Designated as safety issue: Yes ]
Histopathological R0 resection rate [ Time Frame: Toxicity/safety:during preoperative treatment, early and late postoperative follow up ] [ Designated as safety issue: Yes ]
Acute and late toxicity [ Time Frame: Toxicity/safety:during preoperative treatment, early and late postoperative follow up ] [ Designated as safety issue: Yes ]
Loco-regional failure rate [ Time Frame: Toxicity/safety:during preoperative treatment, early and late postoperative follow up ] [ Designated as safety issue: Yes ]
Disease-free survival [ Time Frame: Toxicity/safety:during preoperative treatment, early and late postoperative follow up ] [ Designated as safety issue: Yes ]
Overall survival [ Time Frame: Toxicity/safety:during preoperative treatment, early and late postoperative follow up ] [ Designated as safety issue: Yes ]
Quality of life [ Time Frame: Toxicity/safety:during preoperative treatment, early and late postoperative follow up ] [ Designated as safety issue: Yes ]

Estimated Enrollment:	60
Study Start Date:	January 2009
Estimated Study Completion Date:	August 2014
Primary Completion Date:	August 2010 (Final data collection date for primary outcome measure)

Intervention Details:

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)

Other Names:

Avastin
Xeloda
radiation

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

Eligibility

Ages Eligible for Study:	18 Years to 80 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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)

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00842686

Locations

Slovenia
Onstitute of Oncology, Zaloška 2
Ljubljana, Slovenia, 1000

Sponsors and Collaborators

Institute of Oncology Ljubljana

Investigators

Principal Investigator:

Vaneja Velenik, MD, PhD

Institute of Oncology, Ljubljana, Slovenia

More Information

Publications:

Cammà C, Giunta M, Fiorica F, Pagliaro L, Craxì A, Cottone M. Preoperative radiotherapy for resectable rectal cancer: A meta-analysis. JAMA. 2000 Aug 23-30;284(8):1008-15.

Sauer R, Becker H, Hohenberger W, Rödel 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.

Dunst J, Reese T, Sutter T, Zühlke H, Hinke A, Kölling-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.

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.

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. Review.

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. No abstract available.

Czito BG, Bendell JC, Willett CG, Morse MA, Blobe GC, Tyler DS, Thomas J, Ludwig KA, Mantyh CR, Ashton J, Yu D, Hurwitz HI. Bevacizumab, oxaliplatin, and capecitabine with radiation therapy in rectal cancer: Phase I trial results. Int J Radiat Oncol Biol Phys. 2007 Jun 1;68(2):472-8.

Responsible Party:	Velenik Vaneja, MD, PhD, Institute of Oncolg Ljubljana, Slovenia
ClinicalTrials.gov Identifier:	NCT00842686 History of Changes
Other Study ID Numbers:	ML21901
Study First Received:	February 11, 2009
Last Updated:	March 23, 2012
Health Authority:	Slovenia: Agency for Medicinal Products - Ministry of Health Slovenia: Ethics Committee

Keywords provided by Institute of Oncology Ljubljana:

rectal cancer
capecitabine
bevacizumab
radiotherapy

Additional relevant MeSH terms:

Rectal Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Rectal Diseases
Capecitabine
Fluorouracil
Bevacizumab

Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors

ClinicalTrials.gov processed this record on May 19, 2013