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

Alternate Title

Combination Chemotherapy and Bevacizumab in Treating Patients With Locally Advanced, Metastatic, or Recurrent Colorectal Cancer

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase III Treatment Completed 18 and over NCI SWOG-S0303 S0303, ECOG-S0303, NCT00070122

Objectives

1. Compare overall survival in patients with locally advanced, metastatic, or recurrent colorectal cancer treated with fluorouracil, leucovorin calcium, oxaliplatin, and bevacizumab vs capecitabine, oxaliplatin, and bevacizumab.
2. Compare progression-free survival and time to treatment failure in patients treated with these regimens.
3. Compare the response of patients with measurable disease treated with these regimens.
4. Compare toxicity rates of these regimens in these patients.
5. Compare patient-reported functional status and convenience of therapy in patients treated with these regimens.
6. Correlate germline polymorphisms of DNA repair (e.g., ERCC-1, XRCC1, GST-P1, XPD, and ribonucleotide reductase), target enzymes (e.g., thymidylate synthase, dihydropyrimidine dehydrogenase, and thymidine phosphorylase), angiogenesis (e.g., vascular endothelial growth factor), and growth factors (e.g., epithelial growth factor receptor) with survival, progression-free survival, and toxicity from chemotherapy in patients treated with these regimens.
7. Correlate tumor mRNA expression levels of similar DNA repair enzymes as well as enzymes involved in angiogenesis with survival and progression-free survival in patients treated with these regimens.
8. Correlate tumor mRNA expression levels of similar target enzymes before treatment with survival, progression-free survival, and toxicity in patients treated with these regimens.

Entry Criteria

Disease Characteristics:

• Histologically or cytologically confirmed locally advanced, recurrent, or metastatic colorectal adenocarcinoma
  • Not curable by surgery or amenable to radiotherapy with curative intent
  • Previously resected colorectal cancer with new evidence of metastasis does not require separate histologic or cytologic confirmation unless one of the following is true:
    • More than 5 years has elapsed between primary surgery and development of metastatic disease
    • Primary tumor was T1-T2, N0, M0



• Site of primary lesion must be or have been in the large bowel as determined by endoscopy, radiology, or surgery



• Measurable or evaluable disease



• No known brain or leptomeningeal disease

Prior/Concurrent Therapy:

Biologic therapy

• No prior bevacizumab

Chemotherapy

• No prior oxaliplatin
• No prior chemotherapy for advanced colorectal cancer
  • Prior adjuvant therapy for resected stage II-III disease allowed provided at least 12 months have elapsed between completion of therapy and diagnosis of recurrent disease

Endocrine therapy

• Not specified

Radiotherapy

• At least 28 days since prior radiotherapy and recovered

Surgery

• See Disease Characteristics
• More than 28 days since prior major surgical procedure or open biopsy
• More than 7 days since prior fine needle aspiration or core biopsy
• No concurrent major surgery

Other

• More than 10 days since prior full-dose aspirin (325 mg)
• No concurrent antiplatelet agents (e.g., dipyridamole, ticlopidine, clopidogrel, or cilostazol)
• No other concurrent investigational agents
• No concurrent therapeutic anticoagulation
  • Prophylactic anticoagulation of central venous lines allowed
  • Low-dose prophylactic enoxaparin or heparin allowed
• No concurrent cimetidine
• No concurrent sorivudine or its related analogs (e.g., brivudine)
• No concurrent use of a cold cap or iced mouth rinses

Patient Characteristics:

Age

• 18 and over

Performance status

• Zubrod 0-2

Life expectancy

• Not specified

Hematopoietic

• No history of hemorrhagic or thrombotic disorders
• Absolute neutrophil count greater than 1,500/mm³
• Platelet count greater than 100,000/mm³

Hepatic

• Bilirubin no greater than 2.0 times upper limit of normal (ULN)
• SGOT no greater than 2.5 times ULN (5 times ULN for patients with liver involvement)
• Alkaline phosphatase no greater than 2.5 times ULN (5 times ULN for patients with liver involvement or 10 times ULN for patients with bone involvement)
• INR no greater than 1.5
• PTT no greater than ULN

Renal

• Creatinine no greater than 1.5 times ULN
• Creatinine clearance at least 50 mL/min
• Proteinuria less than 1+*

  OR

• Protein less than 500mg/24 hours*

 [Note: *Proteinuria caused by ureteral stents and not due to nephropathy allowed]

Cardiovascular

• No uncontrolled hypertension
  • Hypertension must be well-controlled (i.e., less than 160/90) and on a stable regimen of antihypertensive therapy
• No unstable angina
• No symptomatic congestive heart failure
• No myocardial infarction within the past 6 months
• No serious uncontrolled cardiac arrhythmia
• No New York Heart Association class III or IV heart disease

Pulmonary

• No symptomatic pulmonary fibrosis

Other

• Not pregnant or nursing
• Fertile patients must use effective contraception
• No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, or adequately treated stage I or II cancer currently in complete remission
• No active or uncontrolled severe infection
• No contraindication to oral medications (e.g., severe dysphagia)
  • G-tubes or J-tubes allowed
• No peripheral neuropathy greater than grade 1
• No serious non-healing wound, ulcer, or bone fracture
• No significant traumatic injury within the past 28 days
• No other severe acute or chronic medical condition or laboratory abnormality that would preclude study participation
• No psychiatric condition that would preclude study participation

Expected Enrollment

A total of 2,200 patients (1,100 per treatment arm) will be accrued for this study within 3 years.

Outline

This is a randomized, multicenter study. Patients are stratified according to Zubrod performance status (0 or 1 vs 2) and prior adjuvant therapy (yes vs no). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV continuously over 46-48 hours beginning on day 1. Patients are further randomized to receive bevacizumab or placebo* IV over 30-90 minutes on day 1. Courses repeat every 2 weeks in the absence of disease progression or unacceptable toxicity.

   [Note: *As of 11/15/04, placebo is no longer part of treatment plan; all patients receive bevacizumab.]




• Arm II: Patients receive oxaliplatin IV over 2 hours on day 1 and oral capecitabine on days 1-15. Patients are further randomized to receive bevacizumab or placebo* as in arm I. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.

   [Note: *As of 11/15/04, placebo is no longer part of treatment plan; all patients receive bevacizumab.]

Patients are followed every 3 months until disease progression. After disease progression, patients are followed every 6 months for 2 years and then annually for up to 4 years after study entry.

Trial Contact Information

Trial Lead Organizations

Southwest Oncology Group

Charles Blanke, MD, FACP, Study coordinator		Ph: 503-494-1556; 800-494-1234
Heinz-Josef Lenz, MD, Study coordinator		Ph: 323-865-3955; 800-865-0102 Email: lenz_h@ccnt.usc.edu

Registry Information
Official Title		A Phase III Trial Of Modified FOLFOX6 Versus CAPOX, With Bevacizumab (NSC-704865) Or Placebo, As First-Line Therapy In Patients With Previously Untreated Advanced Colorectal Cancer
Trial Start Date		2004-04-01
Registered in ClinicalTrials.gov		NCT00070122
Date Submitted to PDQ		2003-08-14
Information Last Verified		2004-08-16
NCI Grant/Contract Number		CA32102

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