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

NCT00449137 | Completed Phase 1 DMC

• 2 other identifiers: 20050801SCCC-2004162
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 1

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.

Conditions

Colorectal Cancer

Keywords

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

Outcome Measures

Primary Outcomes (2)

• 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.

  At study completion

• 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)

  Baseline, Subsequent times

Study Arms (1)

Single Arm

EXPERIMENTAL

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)

Interventions

Arsenic trioxide 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.

Also known as: ATO

Single Arm

Fluorouracil 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.

Also known as: 5-Fu

Single Arm

Leucovorin calcium 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.

Single Arm

Plasma levels of elemental arsenic OTHER

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

Single Arm

Peripheral Blood Mononuclear Cells (PBMC) for mRNA analysis 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.

Single Arm

Tumor Biopsy (Fine-Needle Aspiration) PROCEDURE

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

Also known as: FNA

Single Arm

Eligibility Criteria

• Age: 18 Years - 120 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

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)

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• University of Miami: lead

Study Sites (1)

University of Miami Sylvester Comprehensive Cancer Center - Miami

Miami, Florida, 33136, United States

Location

MeSH Terms

Conditions

Colorectal Neoplasms; Colonic Neoplasms; Rectal Neoplasms

Interventions

Arsenic Trioxide; Fluorouracil; Leucovorin; Biopsy, Fine-Needle

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Arsenicals; Inorganic Chemicals; Oxides; Oxygen Compounds; Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Coenzymes; Enzymes and Coenzymes; Biopsy, Needle; Biopsy; Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Specimen Handling; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Punctures; Investigative Techniques

Study Officials

• Bach Ardalan, MD

  University of Miami Sylvester Comprehensive Cancer Center

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 15, 2007
• First Posted: March 19, 2007
• Study Start: June 1, 2005
• Primary Completion: February 1, 2010
• Study Completion: December 1, 2010
• Last Updated: December 15, 2016

Record last verified: 2016-12

Locations

US (1)