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

NCT ID: NCT00449137

Last Updated: 2016-12-15

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 13 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2005-06-30
• Study Completion Date: 2010-12-31

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.

Conditions

Colorectal Cancer

Keywords

recurrent colon cancer; stage IV colon cancer; recurrent rectal cancer; stage IV rectal cancer

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Single Arm

Group Type: EXPERIMENTAL

Arsenic trioxide

Intervention Type: DRUG

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.

Fluorouracil

Intervention Type: DRUG

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.

Leucovorin calcium

Intervention Type: DRUG

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.

Plasma levels of elemental arsenic

Intervention Type: OTHER

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

Peripheral Blood Mononuclear Cells (PBMC) for mRNA analysis

Intervention Type: GENETIC

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.

Tumor Biopsy (Fine-Needle Aspiration)

Intervention Type: PROCEDURE

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

Interventions

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.

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: DRUG

Plasma levels of elemental arsenic

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

Intervention Type: OTHER

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.

Intervention Type: GENETIC

Tumor Biopsy (Fine-Needle Aspiration)

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

Intervention Type: PROCEDURE

Other Intervention Names

ATO; 5-Fu; FNA

Eligibility Criteria

Inclusion 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)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 120 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Miami

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Bach Ardalan, MD

Role: STUDY_CHAIR

University of Miami Sylvester Comprehensive Cancer Center

Locations

University of Miami Sylvester Comprehensive Cancer Center - Miami

Miami, Florida, United States

Countries

United States

Other Identifiers

SCCC-2004162

Identifier Type: -

Identifier Source: secondary_id

20050801

Identifier Type: -

Identifier Source: org_study_id