Clinical trial NCT00842686: Preoperative Radiotherapy With Capecitabine and Bevacizumab in Locally Advanced Rectal Cancer: CRAB Phase II Study
Official title: Preoperative Radiotherapy With Capecitabine and Bevacizumab in Locally Advanced Rectal Cancer: CRAB Phase II Study
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Locally Advanced Rectal Cancer
Keywords: rectal cancer
capecitabine
bevacizumab
radiotherapy
Lead sponsor: Institute of Oncology Ljubljana
Sponsor class: OTHER
First posted: 2009-02-12
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

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)

Primary outcomes:
measure: Pathological complete remission rate (pCR)
timeFrame: after pathological examination of surgical speciments
Secondary outcomes:
measure: Pathological response rate
timeFrame: Toxicity/safety:during preoperative treatment, early and late postoperative follow up
measure: Rate of sphincter sparing surgical procedure
timeFrame: Toxicity/safety:during preoperative treatment, early and late postoperative follow up
measure: Histopathological R0 resection rate
timeFrame: Toxicity/safety:during preoperative treatment, early and late postoperative follow up
measure: Acute and late toxicity
timeFrame: Toxicity/safety:during preoperative treatment, early and late postoperative follow up
measure: Loco-regional failure rate
timeFrame: Toxicity/safety:during preoperative treatment, early and late postoperative follow up
measure: Disease-free survival
timeFrame: Toxicity/safety:during preoperative treatment, early and late postoperative follow up
measure: Overall survival
timeFrame: Toxicity/safety:during preoperative treatment, early and late postoperative follow up
measure: Quality of life
timeFrame: Toxicity/safety:during preoperative treatment, early and late postoperative follow up
Other outcomes:
Locations:
city: Ljubljana
country: Slovenia
facility: Onstitute of Oncology, Zaloška 2
Study officials:
affiliation: Institute of Oncology, Ljubljana, Slovenia
name: Vaneja Velenik, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Camma C, Giunta M, Fiorica F, Pagliaro L, Craxi A, Cottone M. Preoperative radiotherapy for resectable rectal cancer: A meta-analysis. JAMA. 2000 Aug 23-30;284(8):1008-15. doi: 10.1001/jama.284.8.1008.
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.
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.
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.
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.
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.
citation: 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. doi: 10.1016/j.ijrobp.2007.02.001.