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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
University of Miami Sylvester Comprehensive Cancer Center
ClinicalTrials.gov Identifier:
NCT00449137
First received: March 15, 2007
Last updated: July 25, 2014
Last verified: August 2013
  Purpose

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 Intervention 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

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by University of Miami Sylvester Comprehensive Cancer Center:

Primary Outcome Measures:
  • Maximum tolerated dose [ Time Frame: At study completion ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Baseline, Subsequent times ] [ Designated as safety issue: No ]
    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)


Enrollment: 13
Study Start Date: June 2005
Study Completion Date: December 2010
Primary Completion Date: February 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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 Name: 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 Name: FNA

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00449137

Locations
United States, Florida
University of Miami Sylvester Comprehensive Cancer Center - Miami
Miami, Florida, United States, 33136
Sponsors and Collaborators
University of Miami Sylvester Comprehensive Cancer Center
Investigators
Study Chair: Bach Ardalan, MD University of Miami Sylvester Comprehensive Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: University of Miami Sylvester Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT00449137     History of Changes
Other Study ID Numbers: UMIAMI-20050801, SCCC-2004162
Study First Received: March 15, 2007
Last Updated: July 25, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by University of Miami Sylvester Comprehensive Cancer Center:
recurrent colon cancer
stage IV colon cancer
recurrent rectal cancer
stage IV rectal cancer

Additional relevant MeSH terms:
Colorectal Neoplasms
Colonic Diseases
Digestive System Diseases
Digestive System Neoplasms
Gastrointestinal Diseases
Gastrointestinal Neoplasms
Intestinal Diseases
Intestinal Neoplasms
Neoplasms
Neoplasms by Site
Rectal Diseases
Arsenic trioxide
Fluorouracil
Levoleucovorin
Antidotes
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Protective Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on October 21, 2014