Arsenic Trioxide, Fluorouracil, and Leucovorin in Treating Patients With Stage IV Colorectal Cancer That Has Relapsed or Not Responded to Treatment

Sponsor

University of Miami (Other)

Overall Status

Completed

CT.gov ID

NCT00449137

Collaborator

(none)

Enrollment

Location

Arm

Duration (Months)

0.2

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer	Drug: Arsenic trioxide Drug: Fluorouracil Drug: Leucovorin calcium Other: Plasma levels of elemental arsenic Genetic: Peripheral Blood Mononuclear Cells (PBMC) for mRNA analysis Procedure: Tumor Biopsy (Fine-Needle Aspiration)	Phase 1

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

13 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Jun 1, 2005

Actual Primary Completion Date :

Feb 1, 2010

Actual Study Completion Date :

Dec 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Single Arm	Drug: Arsenic trioxide ATO will be administered at dose levels determined by the dose escalation scheme (section 4.2). Intra-venous (IV) infusion of ATO (mg/kg body weight) over 1-4 hours will be administered for 5 consecutive days (day 1 to day 5) during the first week, twice a week on weeks 2 and 3 (days 8, 11, 15, and 18), and only one day (day 22) of week 4. Treatment will continue for a maximum of 8 cycles, provided that the patient tolerates treatment and there is evidence of clinical benefit. Other Names: ATO Drug: Fluorouracil Escalate 5-FU, starting at dose 1600 mg/m2. On day 8, 15, and 22 the assigned dose of 5 FU plus 500 mg/m2 of leucovorin will be administered over 24 hours intravenous infusion following the administration of arsenic trioxide. Treatment will continue for a maximum of 8 cycles, provided that the patient tolerates treatment and there is evidence of clinical benefit. Other Names: 5-Fu Drug: Leucovorin calcium On day 8, 15, and 22 the assigned dose of 5 FU plus 500 mg/m2 of leucovorin will be administered over 24 hours intravenous infusion following the administration of arsenic trioxide. Treatment will continue for a maximum of 8 cycles, provided that the patient tolerates treatment and there is evidence of clinical benefit. Other: Plasma levels of elemental arsenic Pre-Treatment and and one hour post ATO on days 1, 5, 8, 11,15, 18, and 22 Genetic: Peripheral Blood Mononuclear Cells (PBMC) for mRNA analysis Peripheral blood samples (PAXgene Blood RNA tube, Qiagen, USA) will be obtained up to 2 weeks prior to start of treatment (same day as the first FNA) and one hour post ATO on days 1, 5, 8, 11,15, 18, and 22. Along with FNA an additional blood sample will be obtained on day 23 of every odd treatment cycle. Procedure: Tumor Biopsy (Fine-Needle Aspiration) Pre-Treatment, Day 23 of Cycles 1, 3, 5, 7 Other Names: FNA

Arm

Intervention/Treatment

Experimental: Single Arm

Drug: Arsenic trioxide

ATO will be administered at dose levels determined by the dose escalation scheme (section 4.2). Intra-venous (IV) infusion of ATO (mg/kg body weight) over 1-4 hours will be administered for 5 consecutive days (day 1 to day 5) during the first week, twice a week on weeks 2 and 3 (days 8, 11, 15, and 18), and only one day (day 22) of week 4. Treatment will continue for a maximum of 8 cycles, provided that the patient tolerates treatment and there is evidence of clinical benefit.

Other Names:

ATO

Drug: Fluorouracil

Escalate 5-FU, starting at dose 1600 mg/m2. On day 8, 15, and 22 the assigned dose of 5 FU plus 500 mg/m2 of leucovorin will be administered over 24 hours intravenous infusion following the administration of arsenic trioxide. Treatment will continue for a maximum of 8 cycles, provided that the patient tolerates treatment and there is evidence of clinical benefit.

Other Names:

5-Fu

Drug: Leucovorin calcium

On day 8, 15, and 22 the assigned dose of 5 FU plus 500 mg/m2 of leucovorin will be administered over 24 hours intravenous infusion following the administration of arsenic trioxide. Treatment will continue for a maximum of 8 cycles, provided that the patient tolerates treatment and there is evidence of clinical benefit.

Other: Plasma levels of elemental arsenic

Pre-Treatment and and one hour post ATO on days 1, 5, 8, 11,15, 18, and 22

Genetic: Peripheral Blood Mononuclear Cells (PBMC) for mRNA analysis

Peripheral blood samples (PAXgene Blood RNA tube, Qiagen, USA) will be obtained up to 2 weeks prior to start of treatment (same day as the first FNA) and one hour post ATO on days 1, 5, 8, 11,15, 18, and 22. Along with FNA an additional blood sample will be obtained on day 23 of every odd treatment cycle.

Procedure: Tumor Biopsy (Fine-Needle Aspiration)

Pre-Treatment, Day 23 of Cycles 1, 3, 5, 7

Other Names:

FNA

Outcome Measures

Primary Outcome Measures

Maximum tolerated dose [At study completion]
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.
Thymidylate synthase expression [Baseline, Subsequent times]
We will characterize TS levels in study patients at baseline and at subsequent times following initiation of treatment by descriptive statistics (minimum, maximum, average, standard deviation)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 120 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)