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Evaluation of Disulfiram Plus Arsenic Trioxide In Patients With Metastatic Melanoma and at Least One Prior Systemic Therapy

Information source: University of California, Irvine
Information obtained from ClinicalTrials.gov on February 07, 2013
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Metastatic Melanoma

Intervention: Disulfiram (Drug); Arsenic trioxide (Drug)

Phase: Phase 1

Status: Recruiting

Sponsored by: University of California, Irvine

Official(s) and/or principal investigator(s):
John P Fruehauf, M.D. PhD, Principal Investigator, Affiliation: Chao Family Comprehensive Cancer Center

Overall contact:
Chao Family Comprehensive Cancer Center, University of California, Irvine, Phone: 1-877-827-7883, Email: ucstudy@uci.edu

Summary

Patients with metastatic melanoma (stage IV), who have progressed after one or more courses of systemic therapy, are recruited to receive Disulfiram plus Arsenic Trioxide. The response rate and toxicity will be evaluated.

PURPOSE:

The purpose of this research study is to find out how well patients respond and how long their responses last when treated with Disulfiram (DSF) and arsenic trioxide, what side effects are caused by DSF and arsenic trioxide, and how often they occur.

Twenty one subjects will be selected to take part of this study. Treatment will be administered in cycles of 12 weeks and the number of cycles a subject participates in will vary based on several factors. Subjects will receive pills orally, two times a day, and continuous bolus infusion over 2-4 hours, daily, Monday-Friday for two weeks followed by a two week rest period. Routine laboratory tests (including blood and urine) and x rays will be done during therapy to check the subject's body's response to treatments.

Clinical Details

Official title: Evaluation of Disulfiram Plus Arsenic Trioxide In Patients With Metastatic Melanoma and at Least One Prior Systemic Therapy (Phase 1b)

Study design: Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Evaluate the tolerability of disulfiram and arsenic trioxide administration as a therapeutic combination

Secondary outcome: Determine the response rate (complete and partial responses) and time to progression

Detailed description: The purpose of this research study is to find out how well patients respond and how long their responses last when treated with Disulfiram (DSF) and arsenic trioxide. As well as what side effects are caused by DSF and arsenic trioxide and how often they occur.

It is our hypothesis that the combination of DSF and arsenic trioxide might demonstrate a synergistic anti-tumor effect, since both agents target GSH metabolism. Arsenic trioxide depletes GSH by conjugation with GSH via glutathione transferase, while DSF oxidizes GSH, thereby creating an increase in intracellular redox stress.

A Phase I study on the safety of DSF in melanoma patients has been performed, At UCI Medical Center (HS#2001-2038) , establishing that the safe dose is equivalent to the FDA approved dose of 500 mg per day. Disulfiram has also previously been given in combination with chemotherapy without significant additional toxicity.

A Phase II study of arsenic trioxide in melanoma from University of Texas' MD Anderson Cancer Center has recently been reported. They treated 20 melanoma patients with arsenic trioxide 0. 25 mg/kg/day for 5 days, followed by a maintenance dose of 0. 35 mg/kg/day twice a week. All patients with melanoma of cutaneous origin and four patients with melanoma of choroidal origin had received prior therapy. The median overall survival duration for patients with melanoma of cutaneous origin was 7. 9 months, and that of patients with melanoma of choroidal origin was not reached at a median follow-up duration of 11. 8 months. Grade 3 toxicity included neutropenia, fatigue, abdominal pain, and arthralgia. Grade 4 toxicity did not occur. It was concluded that single-agent arsenic trioxide was generally well tolerated; however, no tumor regression was observed in this patient population. Kevin B Kim from the MD Anderson Cancer Center recommended that future clinical trials should evaluate arsenic trioxide in combination with other anticancer drugs that may improve its clinical activity in melanoma. Arsenic trioxide has been previously safely administered in combination with conventional chemotherapy.

Clinical studies indicate that these drugs can be given safely to cancer patients and that they can be combined with other drugs. It has been demonstrated that redox regulations in melanoma cells are aberrant and that drugs that interfere with glutathione scavenging of reactive oxygen species, such as Disulfiram and arsenic trioxide, alter melanoma redox status and induce apoptosis.

Disulfiram and Arsenic Trioxide were selected for study based on their ability to alter GSH redox balance. They were chosen because Arsenic trioxide has been reported by several investigators to be synergistic against various solid tumor cell lines in vitro and in vivo when given with buthionine sulfoximine (BSO), another agent that acts similarly to DSF by modulating GSH metabolism; and the effect of Disulfiram (DSF), a member of the dithiocarbamate family, has recently been explored on apoptosis in melanoma cells and as anticipated, DSF caused a 3 to 5-fold increase in apoptosis in all three melanoma cell strains being tested at a very low dose.

Eligibility

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Subjects must have bidimensionally measurable disease. All measurable lesions must be

assessed (by physical examination, CT scan, radionuclide scan or plain X-ray) within 28 days prior to registration. Non-measurable sites must be assessed within 42 days prior to registration. The subject's disease status must be completely assessed and reported.

- All subjects must undergo a CT of abdomen and chest within 28 days prior to

registration.

- All subjects must undergo either a CT or MRI of the brain within 28 days of

registration. Subjects with asymptomatic brain metastasis are eligible for this protocol but their metastasis must be clinically stable and asymptomatic. Subjects with CNS metastasis must have been evaluated by neurosurgery prior to entry to confirm that they are a candidate for this trial. Treatment of symptomatic CNS metastasis that is required before protocol entry.

- Subjects must have progressed based on RECIST criteria after at least one prior

systemic therapy (chemotherapy, biologic/immunotherapy, or a combination regimen) for metastatic disease. This includes development of any new lesion or a 20% increase in the sum of the subject's measurable disease compared to their previous nadir. New CNS metastasis could be the reason for disease progression, but they must be stable clinically and satisfy criteria delineated in section 5. 4. Prior systemic therapy must have been completed at least 28 days before registration.

- Subjects may have received prior biologic or immunotherapy given in an adjuvant

fashion. Prior adjuvant therapy must have been completed at least 28 days prior to registration

- Subjects may have received prior radiation therapy. If all known sites of disease

have been previously radiated, there must be objective evidence of progression for the subject to be eligible. Radiation therapy must have been completed at least 28 days before registration.

- Subjects may have received prior surgery. Prior surgery must have been completed at

least 28 days before registration.

- Performance status must be 0-2 according to Southwest Oncology Group Criteria

Performance Status:

GRADE SCALE

0 Fully active; able to carry on all pre-disease activities without restriction.

1. Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e. g., light housework, office work.

2. Ambulatory and capable of all self care but unable to carry out any work activities. Up and about more than 50% of waking hours.

3. Capable of only limited self care; confined to bed or chair more than 50% of waking hours.

4. Completely disabled. Cannot carry on any self care. Totally confined to bed or chair.

5. Dead

- Subjects must have a normal ECG, without evidence of congestive heart failure.

1. Normal heart rate (less than 100 per minute)

2. Normal sinus rhythm

3. Normal QRS interval

4. Subjects with QT prolongation > 500msec on their ECG will be considered ineligible.

Exclusion Criteria:

- Pregnant or nursing women are not eligible to participate in this trial because

the safe use of this drug in pregnancy has not been established.

- Subjects with severe myocardial disease or coronary occlusion, psychoses, and

hypersensitivity to disulfiram or other thiuram derivatives used in pesticides and rubber vulcanization are excluded from the study.

- Subjects who can not abstain from alcohol intake during the entire duration of

this protocol are not qualified for this study.

Locations and Contacts

Chao Family Comprehensive Cancer Center, University of California, Irvine, Phone: 1-877-827-7883, Email: ucstudy@uci.edu

Chao Family Comprehensive Cancer Center, University of California, Irvine, Orange, California 92868, United States; Recruiting
Phone: 877-827-8839, Email: ucstudy@uci.edu
John P Fruehauf, M.D. PhD, Principal Investigator
Additional Information

Starting date: September 2006
Last updated: October 11, 2010

Page last updated: February 07, 2013

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