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

Sponsored by:	University of California, Irvine
Information provided by:	University of California, Irvine
ClinicalTrials.gov Identifier:	NCT00571116

Purpose

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.

Condition	Intervention	Phase
Metastatic Melanoma	Drug: Disulfiram Drug: Arsenic trioxide	Phase I

MedlinePlus related topics: Arsenic Cancer Melanoma

Drug Information available for: Arsenic trioxide Disulfiram

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Non-Randomized, Open Label, Uncontrolled, Single Group Assignment, Safety/Efficacy Study
Official Title:	Evaluation of Disulfiram Plus Arsenic Trioxide In Patients With Metastatic Melanoma and at Least One Prior Systemic Therapy (Phase 1b)

Further study details as provided by University of California, Irvine:

Primary Outcome Measures:

Evaluate the tolerability of disulfiram and arsenic trioxide administration as a therapeutic combination [ Time Frame: 5 years ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Determine the response rate (complete and partial responses) and time to progression [ Time Frame: 5 years ] [ Designated as safety issue: Yes ]

Estimated Enrollment:	21
Study Start Date:	September 2006
Estimated Study Completion Date:	December 2011
Estimated Primary Completion Date:	December 2009 (Final data collection date for primary outcome measure)

Intervention Details:

pills orally, two times a day

Arsenic trioxide by bolus infusion (through a vein in the arm) daily Monday through Friday at the infusion center, alternating two weeks on and two weeks off for the entire cycle

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

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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.

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.
Ambulatory and capable of all self care but unable to carry out any work activities. Up and about more than 50% of waking hours.
Capable of only limited self care; confined to bed or chair more than 50% of waking hours.
Completely disabled. Cannot carry on any self care. Totally confined to bed or chair.
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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00571116

Contacts

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

Locations

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

Sponsors and Collaborators

University of California, Irvine

Investigators

Principal Investigator:

John P Fruehauf, M.D. PhD

Chao Family Comprehensive Cancer Center

More Information

Responsible Party:	University of California, Irvine Medical Center ( John P. Fruehauf, M.D., PhD )
Study ID Numbers:	UCI 06-08
Study First Received:	December 6, 2007
Last Updated:	January 5, 2009
ClinicalTrials.gov Identifier:	NCT00571116
Health Authority:	United States: Institutional Review Board

Keywords provided by University of California, Irvine:

Metastatic Melanoma
Disulfiram
Arsenic Trioxide
Metastatic Melanoma and at Least One Prior Systemic Therapy

Study placed in the following topic categories:

Disulfiram
Neuroectodermal Tumors
Nevus, Pigmented
Neoplasms, Germ Cell and Embryonal
Arsenic trioxide

Neuroepithelioma
Nevus
Ethanol
Neuroendocrine Tumors
Melanoma

Additional relevant MeSH terms:

Neoplasms
Neoplasms by Histologic Type
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Therapeutic Uses
Neoplasms, Nerve Tissue

Enzyme Inhibitors
Nevi and Melanomas
Central Nervous System Agents
Pharmacologic Actions
Alcohol Deterrents

ClinicalTrials.gov processed this record on January 13, 2009