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Clinical Trials (PDQ®)

Phase II Study of Treatment Selection Based Upon Tumor Thymidylate Synthase Expression in Previously Untreated Patients With Metastatic Colorectal Cancer

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

Alternate Title

Bevacizumab and Oxaliplatin Combined With Irinotecan or Leucovorin and Fluorouracil in Treating Patients With Metastatic or Recurrent Colorectal Cancer

Basic Trial Information

PhaseTypeStatusAgeSponsorProtocol IDs
Phase IITreatmentClosed18 and overNCIECOG-E4203
E4203, NCT00098787

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

Objectives

  1. Compare the response rate (complete and partial), progression-free survival, and overall survival of patients with previously untreated metastatic or locally recurrent colorectal adenocarcinoma with high vs low thymidylate synthase (TS) expression treated with fluorouracil, leucovorin calcium, oxaliplatin, and bevacizumab or irinotecan, oxaliplatin, and bevacizumab.
  2. Compare the toxicity of these regimens in these patients.
  3. Correlate gene expression with response rates in patients treated with these regimens.
  4. Correlate gene expression with toxicity of these regimens in these patients.
  5. Correlate dihydropyrimidine dehydrogenase, thymidine phosphorylase, and mammalian excision repair cross complementary protein expression with antitumor response in patients treated with these regimens.

Entry Criteria

Disease Characteristics:

  • Diagnosis of colorectal adenocarcinoma
    • Metastatic or locally recurrent disease

  • Measurable disease

  • At least 2 formalin-fixed paraffin embedded core needle biopsies OR fine needle aspirate containing a minimum of 3 clusters of malignant cells and fixed tissue from the previous biopsy
    • If no tissue samples are available the patient must be willing to undergo biopsy of a metastatic site

Prior/Concurrent Therapy:

Biologic therapy

  • No concurrent prophylactic filgrastim (G-CSF) or sargramostim (GM-CSF)

Chemotherapy

  • No prior chemotherapy for metastatic disease
    • Adjuvant therapy completed at least 12 months before first evidence of metastasis allowed

Endocrine therapy

  • Not specified

Radiotherapy

  • Not specified

Surgery

  • More than 28 days since prior major surgery
  • More than 28 days since prior open biopsy

Patient Characteristics:

Age

  • 18 and over

Performance status

  • ECOG 0-2

Life expectancy

  • Not specified

Hematopoietic

  • Absolute neutrophil count ≥ 1,500/mm3
  • Platelet count ≥ 100,000/mm3

Hepatic

  • PT (INR) ≤ 1.5 unless patient is receiving full-dose anticoagulants AND the following criteria are met:
    • In-range INR (usually between 2 and 3) AND 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
  • PTT < 1.5 times upper limit of normal (ULN)
  • ALT and AST < 3 times ULN
  • Bilirubin ≤ 1.5 times ULN
  • No hepatic disease that would preclude study therapy

Renal

  • Creatinine ≤ 1.8 mg/dL
  • Meets 1 of the following criteria:
    • Protein negative on urine dipstick
    • Urine protein/creatinine ratio < 1.0
    • Less than 2 g protein on 24-hour urine collection
  • No renal disease that would preclude study therapy

Cardiovascular

  • No arterial thromboembolic events within the past 6 months, including the following:
    • Transient ischemic attack
    • Cerebrovascular accident
    • Unstable angina pectoris
    • Myocardial infarction
  • Patients with a history of hypertension must meet the following criteria:
    • Blood pressure < 150/90 mm Hg
    • Stable regimen of anti-hypertensive therapy
  • No symptomatic arrhythmia
  • No symptomatic congestive heart failure
  • No clinically significant peripheral artery disease
  • No New York Heart Association class III or IV heart disease
  • No other cardiovascular disease that would preclude study therapy

Other

  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception during and for 3 months after study participation
  • Prior non-colorectal malignancies are allowed provided the following criteria are met:
    • No current clinical evidence of persistent or recurrent disease
    • No active therapy for non-colorectal malignancy, including hormonal therapy
  • No serious nonhealing wound, ulcer, or bone fracture within the past 28 days
  • No significant traumatic injury within the past 28 days
  • No neuropathy ≥ grade 2
  • No other nonmalignant systemic disease that would preclude study therapy
  • No ongoing or active infection

Expected Enrollment

246

A total of 117-246 patients (40-72 in arm I, 40-72 in arm II, 37-102 in arm III) will be accrued for this study within 14-23 months.

Outcomes

Primary Outcome(s)

Response rate (complete response [CR] and partial response [PR]) as measured by RECIST

Secondary Outcome(s)

Progression-free survival as measured by time to event at 1 year after closure to accrual
Overall survival as measured by time to event at 1 year after closure to accrual
Toxicity as measured by NCI CTCAE v4.0 at 1 year after closure to accrual

Outline

This is a randomized, multicenter study. Patients are stratified according to thymidylate synthase (TS) expression levels (high vs low or indeterminate). Patients with high TS expression are randomized to 1 of 2 treatment arms (arms I or II). Patients with low or indeterminate TS expression are assigned to arm III.

  • Arm I: Patients receive bevacizumab IV over 30-90 minutes followed by oxaliplatin IV over 2 hours and irinotecan IV over 90 minutes on days 1 and 15.

  • Arm II: Patients receive bevacizumab and oxaliplatin as in arm I, leucovorin calcium IV over 2 hours, and fluorouracil IV over 5 minutes and then continuously over 46 hours on days 1 and 15.

  • Arm III: Patients receive bevacizumab, oxaliplatin, leucovorin calcium, and fluorouracil as in arm II.

In all arms, courses repeat every 28 days in the absence of unacceptable toxicity or disease progression.

Patients are followed up every 3 months for 2 years and then every 6 months for 2 years from the date of study registration.

Trial Contact Information

Trial Lead Organizations

Eastern Cooperative Oncology Group

Neal Meropol, MD, Protocol chair (Contact information may not be current)
Ph: 215-728-2450; 888-369-2427
Jean Grem, MD, Protocol co-chair
Ph: 402-559-6210

Related Information

Featured trial article

Registry Information
Official Title Phase II Study of Treatment Selection Based Upon Tumor Thymidylate Synthase Expression in Previously Untreated Patients With Metastatic Colorectal Cancer
Trial Start Date 2005-07-14
Trial Completion Date 2013-11-30 (estimated)
Registered in ClinicalTrials.gov NCT00098787
Date Submitted to PDQ 2004-10-13
Information Last Verified 2012-04-18
NCI Grant/Contract Number CA21115

Note: The purpose of most clinical trials listed in this database is to test new cancer treatments, or new methods of diagnosing, screening, or preventing cancer. Because all potentially harmful side effects are not known before a trial is conducted, dose and schedule modifications may be required for participants if they develop side effects from the treatment or test. The therapy or test described in this clinical trial is intended for use by clinical oncologists in carefully structured settings, and may not prove to be more effective than standard treatment. A responsible investigator associated with this clinical trial should be consulted before using this protocol.

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