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

Alternate Title

Oxaliplatin, Fluorouracil, and Leucovorin With or Without PTK787/ZK 222584 in Treating Patients With Refractory or Recurrent Metastatic Colon or Rectal Cancer

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase III Treatment Closed 18 and over NCI, Pharmaceutical / Industry UCLA-0304011 NOVARTIS-CPTK787-0133/304946, NCT00068679

Objectives

Primary

1. Compare the overall survival of patients with refractory or recurrent metastatic adenocarcinoma of the colon or rectum treated with oxaliplatin, fluorouracil, and leucovorin calcium with or without PTK787/ZK 222584.

Secondary

1. Compare the progression-free survival of patients treated with these regimens.
2. Compare the time to progression and time to treatment failure in patients treated with these regimens.
3. Compare the objective tumor response rate (complete and partial) in patients treated with these regimens.
4. Compare the time to first deterioration in WHO performance status in patients treated with these regimens.
5. Compare the time to first definitive weight loss greater than 5% in patients treated with these regimens.
6. Determine the pharmacokinetics of PTK787/ZK 222584 in these patients.
7. Compare the tolerability and safety profile of these regimens in these patients.

Entry Criteria

Disease Characteristics:

• Histologically or cytologically confirmed adenocarcinoma of the colon or rectum
  • Metastatic disease



• Previously treated with 1 and only 1 first-line chemotherapy regimen for metastatic disease comprising irinotecan and a fluoropyrimidine
  • Progressive disease during OR within 6 months after the last dose of prior first-line therapy
    • Therapy must not have been discontinued due to toxic effects



• Measurable disease



• No prior or concurrent CNS disease (i.e., primary brain tumor, malignant seizures, CNS metastases, or carcinomatous meningitis)



• No pleural effusion or ascites causing grade 2 or greater dyspnea

Prior/Concurrent Therapy:

Biologic therapy

• More than 2 weeks since prior biologic therapy or immunotherapy and recovered
• No prior anti-vascular endothelial growth factor agents
• No other concurrent biologic therapy

Chemotherapy

• See Disease Characteristics
• More than 3 weeks since prior chemotherapy and recovered
• Prior adjuvant fluoropyrimidine allowed
• No prior oxaliplatin
• No prior adjuvant irinotecan
• No other concurrent chemotherapy

Endocrine therapy

• Not specified

Radiotherapy

• Recovered from prior radiotherapy
• More than 4 weeks since prior full-field radiotherapy*
• More than 2 weeks since prior limited-field radiotherapy*
• No concurrent radiotherapy

 [Note: *The site of prior radiotherapy should have evidence of progressive disease if it is the only site of disease]

Surgery

• Recovered from prior surgery
• More than 4 weeks since prior major surgery (i.e., laparotomy)
• More than 2 weeks since prior minor surgery
• Prior insertion of a vascular access device allowed

Other

• More than 4 weeks since prior investigational drugs
• No other concurrent investigational agents
• No concurrent therapeutic warfarin or similar oral anticoagulants that are metabolized by the cytochrome P450 system
• No concurrent grapefruit or grapefruit juice
• No concurrent oral cryotherapy (e.g., ice for mucositis prophylaxis) during oxaliplatin administration
• Concurrent heparin allowed

Patient Characteristics:

Age

• 18 and over

Performance status

• WHO 0-2

Life expectancy

• At least 12 weeks

Hematopoietic

• Absolute neutrophil count at least 1,500/mm³
• Platelet count at least 100,000/mm³
• Hemoglobin at least 9 g/dL (transfusion allowed)

Hepatic

• Bilirubin no greater than 1.5 times upper limit of normal (ULN)
• AST and ALT no greater than 3.0 times ULN (5 times ULN if liver metastases are present)
• No acute or chronic liver disease (i.e., hepatitis or cirrhosis)

Renal

• Creatinine no greater than 1.5 times ULN
• No proteinuria by dipstick
  • If 1+ protein on the dipstick, total urine protein must be no greater than 500 mg AND creatinine clearance at least 50 mL/min
• No chronic renal disease

Cardiovascular

• No uncontrolled high blood pressure
• No history of labile hypertension
• No history of poor compliance with an antihypertensive regimen
• No unstable angina pectoris
• No symptomatic congestive heart failure
• No myocardial infarction within the past 6 months
• No serious uncontrolled cardiac arrhythmia

Pulmonary

• No interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the lung

Gastrointestinal

• No impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of PTK787/ZK 222584, including any of the following:
  • Ulcerative disease
  • Uncontrolled nausea
  • Vomiting
  • Diarrhea
  • Malabsorption syndrome
  • Bowel obstruction
  • Inability to swallow tablets

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective barrier contraception
• No known dihydropyrimidine dehydrogenase deficiency
• No known allergy or hypersensitivity to platinum-containing drugs
• No peripheral sensory neuropathy with functional impairment (grade 2 or greater)
• No other primary malignancy within the past 5 years except inactive basal cell or squamous cell skin cancer
• No other concurrent severe and/or uncontrolled medical condition that would preclude study participation

Expected Enrollment

A total of 830 patients (415 per treatment arm) will be accrued for this study within 18 months.

Outline

This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to WHO performance status (0 vs 1 or 2) and lactic dehydrogenase level (no greater than 1.5 times upper limit of normal [ULN] vs greater than 1.5 times ULN). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oxaliplatin IV over 2 hours on day 1 and leucovorin calcium IV over 2 hours and fluorouracil IV continuously over 22 hours on days 1 and 2. Patients also receive oral PTK787/ZK 222584 once daily on days 1-14.



• Arm II: Patients receive oxaliplatin, fluorouracil, and leucovorin calcium as in arm I and an oral placebo once daily on days 1-14.

In both arms, courses repeat every 2 weeks in the absence of disease progression or unacceptable toxicity.

Patients are followed monthly for survival.

Trial Contact Information

Trial Lead Organizations

Jonsson Comprehensive Cancer Center at UCLA

Joel Hecht, MD, Principal investigator		Ph: 310-206-4303; 888-798-0719

Registry Information
Official Title		A Randomized, Double-Blind, Placebo-Controlled, Phase III Study of Oxaliplatin/5-Fluorouracil/Leucovorin with PTK787/ZK 222584 or Placebo in Patients with Previously Treated Metastatic Adenocarcinoma of the Colon or Rectum
Trial Start Date		2003-06-16
Registered in ClinicalTrials.gov		NCT00068679
Date Submitted to PDQ		2003-08-04
Information Last Verified		2004-11-30
NCI Grant/Contract Number		P30-CA16042