Clinical trial NCT00449137: Arsenic Trioxide, Fluorouracil, and Leucovorin in Treating Patients With Stage IV Colorectal Cancer That Has Relapsed or Not Responded to Treatment
Official title: A Phase I Study of 5-FU (Plus Leucovorin) and Arsenic Trioxide for Patients With Refractory/Relapsed Metastatic Colorectal Carcinoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Colorectal Cancer
Keywords: recurrent colon cancer
stage IV colon cancer
recurrent rectal cancer
stage IV rectal cancer
Lead sponsor: University of Miami
Sponsor class: OTHER
First posted: 2007-03-19
Enrollment: 13
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: RATIONALE: Drugs used in chemotherapy, such as fluorouracil and leucovorin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Arsenic trioxide may help fluorouracil and leucovorin work better by making tumor cells more sensitive to the drugs. Giving arsenic trioxide together with fluorouracil and leucovorin may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of arsenic trioxide and fluorouracil when given together with leucovorin in treating patients with stage IV colorectal cancer that has relapsed or not responded to treatment.

Detailed description: OBJECTIVES:

* 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.

Eligibility criteria: DISEASE CHARACTERISTICS:

* 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 bevacizumab)
* Bidimensionally measurable disease
* Must have tumor amenable to biopsy and be willing to undergo fine-needle aspiration
* No CNS metastases

PATIENT CHARACTERISTICS:

* 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

PRIOR CONCURRENT THERAPY:

* 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)

Primary outcomes:
measure: Maximum tolerated dose
timeFrame: At study completion
measure: Thymidylate synthase expression
timeFrame: Baseline, Subsequent times
Secondary outcomes:
Other outcomes:
Locations:
city: Miami
country: United States
facility: University of Miami Sylvester Comprehensive Cancer Center - Miami
state: Florida
Study officials:
affiliation: University of Miami Sylvester Comprehensive Cancer Center
name: Bach Ardalan, MD
role: STUDY_CHAIR
References: