Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Related Information
Registry Information

Alternate Title

Combination Chemotherapy With or Without Bevacizumab in Treating Patients Who Have Had Surgery for Stage II or Stage III Rectal Cancer (Groups I and II Closed to Accrual as of 4/29/2009)

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Biomarker/Laboratory analysis, Treatment	Closed	18 and over	NCI	ECOG-E5204 E5204, NSABP-ECOG-E5204, NCCTG-ECOG-E5204, NCT00303628

Special Category: NCI Web site featured trial, NCI - CMS pilot project trial

Objectives

Primary

1. Compare the overall survival of patients who have undergone prior surgery and neoadjuvant chemoradiotherapy for clinical stage II or III rectal cancer treated with adjuvant oxaliplatin, leucovorin calcium, fluorouracil with vs without postoperative bevacizumab.

Secondary

1. Evaluate tolerance of treatment, patterns of failure, and disease-free survival in patients treated with these regimens.
2. Assess long-term rectal function using the Patient Bowel Function/Uniscale questionnaire and the Functional Assessment of Cancer (FACT)-Diarrhea subscale in patients treated with these regimens.
3. Validate the FACT-Diarrhea subscale.
4. Assess long-term symptoms of oxaliplatin-related neurotoxicity using the FACT/GOG-Neurotoxicity subscale in patients treated with these regimens.
5. Correlate TS, DPD and TP expression (key targets for fluorouracil); retention of chromosome 18q alleles and microsatellite instability (MSI) with TGFβ1RII mutation (markers for fluorouracil efficacy); ERCC1, ERCC2, and XPF expression (participants in repair of adducts from oxaliplatin); and p53 gene mutation and possibly other molecular markers pertinent to vascular endothelial growth factor in tumor tissue specimens with treatment efficacy in these patients.
6. Correlate tumor molecular prognostic markers (chromosome 18q allelic loss and MSI) with survival in patients treated with this regimen.

Entry Criteria

Disease Characteristics:

• Histologically confirmed adenocarcinoma of the rectum meeting 1 of the following clinical (e.g., before neoadjuvant therapy) or pathologic staging criteria:
  • T3, N+, M0
  • T3, N0, M0
  • T4, N0, M0
  • Any T, N1-2, M0
  • T4, N0-2, M0 disease must meet 1 of the following criteria:
    • Clinically fixed tumor on rectal examination with tumor adherent to the pelvic sidewall or sacrum
    • Hydronephrosis on CT scan or IVP
    • Ureteric or bladder invasion as documented by cystoscopy and cytology or biopsy
    • Invasion into prostate
    • Vaginal or uterine involvement



• Must have undergone complete tumor resection ≥ 28 days ago and able to begin treatment by day 56
  • No evidence of metastatic disease on the surgical/intraoperative examination



• Must have undergone concurrent neoadjuvant chemoradiotherapy*
  • Must have undergone prior radiotherapy at a dose of 40-55.8 Gy** AND received 1 of the following chemotherapy regimens:
    • Continuous infusion of fluorouracil with or without oxaliplatin
    • Fluorouracil and leucovorin calcium
    • Capecitabine with or without oxaliplatin
    • Capecitabine with or without oxaliplatin OR a continuous infusion of fluorouracil with or without oxaliplatin received on protocol NSABP-R-04

   [Note: *Neoadjuvant chemoradiotherapy received on protocol NSABP-R-04 allowed provided it met these criteria]

   [Note: **Intensity-modulated radiotherapy allowed]




• No evidence of metastatic disease confirmed by CT scan, MRI, or ultrasound of the liver or chest CT scan or chest x-ray within the past 6 months



• No evidence of tumor outside of the pelvis, including liver metastases, peritoneal seeding, or metastatic inguinal lymphadenopathy

Prior/Concurrent Therapy:

• See Disease Characteristics
• No other prior chemotherapy or pelvic radiotherapy except as neoadjuvant treatment for current diagnosis of rectal cancer
• No prior invasive procedure, including either of the following:
  • Major surgical procedure or open biopsy within the past 28 days
  • Core biopsy or other minor procedure, except placement of a vascular access device, within the past 7 days
• No concurrent major surgery
• Concurrent participation on protocol NSABP-R-04 allowed

Patient Characteristics:

• ECOG performance status 0-1
• Platelet count ≥ 100,000/mm³
• Absolute granulocyte count ≥ 1,500/mm³
• Bilirubin normal (unless chronic grade 1 bilirubin elevation due to Gilbert's disease or similar syndrome due to slow conjugation of bilirubin)
• Alkaline phosphatase (AP) < 2.5 times upper limit of normal (ULN) and AST < 1.5 times ULN
• Hepatitis B and C negative (for patients with AP > normal) unless previously vaccinated
• Serum creatinine ≤ 1.5 times ULN
• Urine protein:creatinine (UPC) ratio < 1.0 OR urine protein < 1 g on 24-hour urine collection
• INR ≤ 1.5
  • INR > 1.5 allowed provided patient is on full-dose anticoagulants AND meets all of the following criteria:
    • In-range INR (i.e., between 2 and 3) on a stable dose of warfarin or low molecular weight heparin
    • No active bleeding or pathological condition that is associated with a high risk of bleeding
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for at least 3 months after study treatment
• No other previous or concurrent malignancy except nonmelanoma skin cancer, breast cancer in situ, carcinoma in situ of the cervix, or previously treated nonpelvic cancer that has been disease-free for > 5 years
  • Patients with a history of breast cancer (without evidence of disease) who remain on hormonal therapy for > 5 years are eligible
• No active bleeding not related to the primary rectal tumor within the past 6 months
• No active inflammatory bowel disease or other serious medical illness which might limit the ability of the patient to receive protocol therapy
• No active gastroduodenal ulcer determined by endoscopy
• No serious or nonhealing wound, skin ulcer, or bone fracture
• No clinically significant peripheral sensory or motor neuropathy ≥ grade 2
• No nonmalignant systemic disease (e.g., cardiovascular, renal, or hepatic) that would preclude study treatment including, but not limited to, any of the following:
  • New York Heart Association class III or IV congestive heart failure
  • Concurrent symptomatic arrhythmia
• No transient ischemic attack or cerebrovascular accident
• No arterial thromboembolic event, unstable angina, or myocardial infarction within the past 12 months
• No significant peripheral vascular disease
• No psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude study requirements
• Patients with a history of hypertension must have blood pressure < 150/90 mm Hg AND be on a stable regimen of antihypertensive therapy
• No significant traumatic injury within the past 28 days
• No known allergy to platinum compounds

Expected Enrollment

A total of 2,100 patients will be accrued for this study.

Outcomes

Overall survival

Tolerability
Patterns of failure (local/regional and distant recurrence)
Disease-free survival

Outline

This is a randomized study. Patients are stratified according to ECOG performance status (0 vs 1), clinical staging (high risk [T3, N+, M0 or T4, any N, M0] vs low risk [T1-2, N+, M0 or T3, N0, M0]), prior pre-operative oxaliplatin (yes vs no), and prior radiotherapy dose (40-50 Gy vs > 50-55.8 Gy pre-operatively). Patients are randomized to 1 of 2 treatment arms.

• Arm I (closed to accrual as of 4/29/2009): Patients receive oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV on day 1 followed by fluorouracil IV continuously over 46 hours on days 1 and 2. Treatment repeats every 2 weeks for up to 12 courses* in the absence of disease progression or unacceptable toxicity.



• Arm II (closed to accrual as of 4/29/2009): Patients receive bevacizumab** IV over 30-90 minutes on day 1. Patients also receive oxaliplatin, leucovorin calcium, and fluorouracil as in arm I*.

   [Note: **Patients no longer receive bevacizumab as of 4/29/2009)]

 [Note: *Patients who received prior neoadjuvant oxaliplatin including patients on protocol NSABP-R-04 receive up to 9 courses of treatment followed by leucovorin calcium IV and fluorouracil IV with (arm II) or without (arm I) bevacizumab for up to 3 courses.]

Patients complete 10-15 minute questionnaires about bowel function 4 times during study treatment.

After completion of study treatment, patients are followed periodically for approximately 10 years.

Trial Contact Information

Trial Lead Organizations

Eastern Cooperative Oncology Group

Al Benson, MD, FACP, Protocol chair		Ph: 312-695-6180
Neal Meropol, MD, Protocol co-chair		Ph: 215-728-2450; 888-369-2427

National Surgical Adjuvant Breast and Bowel Project

Nicholas Petrelli, MD, Protocol chair		Ph: 302-623-4500 Email: npetrelli@christianacare.org

North Central Cancer Treatment Group

Frank Sinicrope, MD, Protocol chair		Ph: 507-538-7623 Email: cancerclinicaltrials@mayo.edu

NCIC-Clinical Trials Group

J. D. Brierley, MD, Protocol chair		Ph: 416-946-2124 Email: james.brierly@rmp.uhn.on.ca

Related Information

PDQ® clinical trial NSABP-R-04
Featured trial article

Registry Information
Official Title		Intergroup Randomized Phase III Study of Postoperative Oxaliplatin, 5-Fluorouracil and Leucovorin vs Oxaliplatin, 5-Fluorouracil, Leucovorin and Bevacizumab for Patients With Stage II or III Rectal Cancer Receiving Pre-Operative Chemoradiation
Trial Start Date		2006-02-17
Trial Completion Date		2020-05-01 (estimated)
Registered in ClinicalTrials.gov		NCT00303628
Date Submitted to PDQ		2006-01-30
Information Last Verified		2009-04-30
NCI Grant/Contract Number		CA21115

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