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

Primary Purpose

Colorectal Cancer

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Arsenic trioxide

Fluorouracil

Leucovorin calcium

Plasma levels of elemental arsenic

Peripheral Blood Mononuclear Cells (PBMC) for mRNA analysis

Tumor Biopsy (Fine-Needle Aspiration)

About this trial

This is an interventional treatment trial for Colorectal Cancer focused on measuring recurrent colon cancer, stage IV colon cancer, recurrent rectal cancer, stage IV rectal cancer

Eligibility Criteria

18 Years - 120 Years (Adult, Older Adult)All SexesDoes not accept 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)

Sites / Locations

University of Miami Sylvester Comprehensive Cancer Center - Miami

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Single Arm

Arm Description

Outcomes

Primary Outcome Measures

Maximum tolerated dose

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

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)

Secondary Outcome Measures

Full Information

NCT ID

NCT00449137

First Posted

March 15, 2007

Last Updated

December 14, 2016

Sponsor

University of Miami

1. Study Identification

Unique Protocol Identification Number

NCT00449137

Brief Title

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

2. Study Status

Record Verification Date

December 2016

Overall Recruitment Status

Completed

Study Start Date

June 2005 (undefined)

Primary Completion Date

February 2010 (Actual)

Study Completion Date

December 2010 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Miami

4. Oversight

Data Monitoring Committee

Yes

5. 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Colorectal Cancer

Keywords

recurrent colon cancer, stage IV colon cancer, recurrent rectal cancer, stage IV rectal cancer

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

13 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Single Arm

Arm Type

Experimental

Intervention Type

Drug

Intervention Name(s)

Arsenic trioxide

Other Intervention Name(s)

ATO

Intervention Description

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

Intervention Name(s)

Fluorouracil

Other Intervention Name(s)

5-Fu

Intervention Description

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

Intervention Name(s)

Leucovorin calcium

Intervention Description

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

Other

Intervention Name(s)

Plasma levels of elemental arsenic

Intervention Description

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

Intervention Type

Genetic

Intervention Name(s)

Peripheral Blood Mononuclear Cells (PBMC) for mRNA analysis

Intervention Description

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

Procedure

Intervention Name(s)

Tumor Biopsy (Fine-Needle Aspiration)

Other Intervention Name(s)

FNA

Intervention Description

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

Primary Outcome Measure Information:

Title

Maximum tolerated dose

Description

Time Frame

At study completion

Title

Thymidylate synthase expression

Description

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)

Time Frame

Baseline, Subsequent times

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

120 Years

Accepts Healthy Volunteers

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)

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Bach Ardalan, MD

Organizational Affiliation

University of Miami Sylvester Comprehensive Cancer Center

Official's Role

Study Chair

Facility Information:

Facility Name

University of Miami Sylvester Comprehensive Cancer Center - Miami

City

Miami

State/Province

Florida

ZIP/Postal Code

33136

Country

United States

12. IPD Sharing Statement

Learn more about this trial

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

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