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A Phase I Study of 5-FU (Plus Leucovorin) and Arsenic Trioxide for Patients With Refractory/Relapsed Metastatic Colorectal Carcinoma

Phase 1
18 Years
Not Enrolling
Colorectal Cancer

Thank you

Trial Information

A Phase I Study of 5-FU (Plus Leucovorin) and Arsenic Trioxide for Patients With Refractory/Relapsed Metastatic Colorectal Carcinoma


- Determine the maximum tolerated dose and best dose combination of fluorouracil and
arsenic trioxide when given together with leucovorin calcium in patients with relapsed
or refractory stage IV colorectal cancer.

- Determine if arsenic trioxide down regulates the expression of thymidylate synthase in
tumor and in peripheral blood mononuclear cells in these patients.

OUTLINE: This is a dose-escalation study of fluorouracil and arsenic trioxide.

Patients receive arsenic trioxide IV over 1-4 hours on days 1-5, 8, 11, 15, 18, and 22 and
fluorouracil IV over 24 hours and leucovorin calcium IV over 24 hours on days 8, 15, and 22.
Treatment repeats every 5 weeks for up to 8 courses in the absence of disease progression or
unacceptable toxicity.

Cohorts of 1-6 patients receive escalating doses of fluorouracil and arsenic trioxide until
the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding
that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6
patients are treated at the MTD.

Patients undergo peripheral blood mononuclear cell (PBMC) collection and fine-needle tumor
aspiration periodically to determine the effects of arsenic trioxide on thymidylate synthase
expression in the tumor and in PBMCs.

After completion of study treatment, patients are followed periodically for 3 years.

PROJECTED ACCRUAL: A total of 20 patients will be accrued for this study.

Inclusion Criteria


- Histologically confirmed colorectal cancer

- Stage IV disease (i.e., any T, any N, M1 disease)

- Relapsed or refractory disease

- Disease progressed after ≥ 2 different fluorouracil-containing chemotherapy
regimens (e.g., irinotecan hydrochloride or oxaliplatin with or without

- Bidimensionally measurable disease

- Must have tumor amenable to biopsy and be willing to undergo fine-needle aspiration

- No CNS metastases


- ECOG performance status 0-2

- Life expectancy > 2 months

- Platelet count > 100,000/mm^3

- WBC ≥ 3,000/mm^3

- Creatinine ≤ 1.5 times upper limit of normal

- Bilirubin ≤ 2 times normal

- SGOT ≤ 5 times normal

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for at least 4 months
after completion of study treatment

- No preexisting peripheral neuropathy ≥ grade 2

- Ejection fraction ≥ 30%

- Baseline QT interval < 500 msec

- No serious underlying medical illness or active infection

- No underlying medical condition that could be aggravated by the treatment

- No life-threatening disease unrelated to colorectal cancer

- No other malignancy within the past 5 years unless currently disease-free and all
therapy for the malignancy has been completed

- No preexisting neurological disorder (i.e., seizure disorder) ≥ grade 3

- No cardiac disease, including any of the following:

- Recurrent supraventricular arrhythmia

- Any type of sustained ventricular arrhythmia or conduction block (e.g., grade II
or III atrioventricular block or left bundle branch block)

- Uncontrolled ischemic heart disease

- History of nonsustained ventricular tachycardia

- Prolonged PR intervals (i.e., 1st degree heart block)

- No known hypersensitivity to arsenic trioxide or fluorouracil

- No history of allergic reactions attributed to compounds of similar biologic
composition to arsenic trioxide or fluorouracil


- See Disease Characteristics

- Recovered from all treatment-related toxicity

- At least 4 weeks since prior chemotherapy or radiotherapy and recovered

- More than 4 weeks since prior investigational drug

- No other concurrent investigational or commercial anticancer agent or therapy

- Concurrent local radiotherapy allowed for symptom relief (e.g., significant onset of
pain after enrollment, but before beginning study therapy)

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose

Outcome Description:

The objective of this phase I study is to determine a phase II dose of combination of 5-FU and ATO that can be safely used for the treatment of 5-FU resistant colon cancer. Following the dose escalation/de-escalation procedure described in section 4.2, the recommended phase II dose of the combination 5-FU with ATO will be established as the maximum tolerated dose (MTD), defined as the highest dose level combination at which <=1 out of 6 patients experiencing DLT.

Outcome Time Frame:

At study completion

Safety Issue:


Principal Investigator

Bach Ardalan, MD

Investigator Role:

Study Chair

Investigator Affiliation:

University of Miami Sylvester Comprehensive Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

June 2005

Completion Date:

December 2010

Related Keywords:

  • Colorectal Cancer
  • recurrent colon cancer
  • stage IV colon cancer
  • recurrent rectal cancer
  • stage IV rectal cancer
  • Colorectal Neoplasms



University of Miami Sylvester Comprehensive Cancer Center - MiamiMiami, Florida  33136