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

Phase 2
18 Years
Open (Enrolling)
Colorectal Cancer

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Trial Information

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


- 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.

- Compare the toxicity of these regimens in these patients.

- Correlate gene expression with response rates in patients treated with these regimens.

- Correlate gene expression with toxicity of these regimens in these patients.

- Correlate dihydropyrimidine dehydrogenase, thymidine phosphorylase, and mammalian
excision repair cross complementary protein expression with antitumor response in
patients treated with these regimens.

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

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

PROJECTED ACCRUAL: 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.

Inclusion Criteria


- 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



- 18 and over

Performance status

- ECOG 0-2

Life expectancy

- Not specified


- Absolute neutrophil count ≥ 1,500/mm^3

- Platelet count ≥ 100,000/mm^3


- 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


- 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


- 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


- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for 3 months after study

- Prior non-colorectal malignancies are allowed provided the following criteria are

- 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


Biologic therapy

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


- No prior chemotherapy for metastatic disease

- Adjuvant therapy completed at least 12 months before first evidence of
metastasis allowed

Endocrine therapy

- Not specified


- Not specified


- More than 28 days since prior major surgery

- More than 28 days since prior open biopsy

Type of Study:


Study Design:

Allocation: Randomized, Primary Purpose: Treatment

Outcome Measure:

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

Safety Issue:


Principal Investigator

Neal J. Meropol, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Fox Chase Cancer Center


United States: Federal Government

Study ID:




Start Date:

July 2005

Completion Date:

Related Keywords:

  • Colorectal Cancer
  • recurrent colon cancer
  • stage IV colon cancer
  • recurrent rectal cancer
  • stage IV rectal cancer
  • adenocarcinoma of the colon
  • adenocarcinoma of the rectum
  • Colorectal Neoplasms



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