Official Title: “Evaluation of Disulfiram in Patients With Metastatic Melanoma and at Least One Prior Systemic Therapy, Phase I/II”

Melanoma remains a malignancy that is largely resistant to chemotherapy. Metastatic disease responds poorly to the treatments used today with only 2 out of 30 drugs tested, DTIC and nitrosoureas, showing response rates greater than 10%, and complete responses are rare.

DTIC-based regimen has been recognized as a standard chemotherapy for advanced melanoma, and temozolomide demonstrated efficacy equal to that of DTIC and is an oral alternative agent that also crosses the blood brain barrier. Randomized phase III trials have shown no survival benefit of adding other agents (cisplatin, BCNU, and tamoxifen). Biochemotherapy is being developed extensively with moderate improvement in the responsive rate (approximately 50%) and is under evaluation in randomized trial to identify whether there is survival benefit to this strategy, compared with chemotherapy alone. Recently, a randomized phase III study comparing chemotherapy (cisplatin, dacarbazine, and tamoxifen) with biochemotherapy (the same chemotherapy regimen plus high-dose IL-2 and interferon alfa) have shown 44% response rate for biochemotherapy vs. 27% for chemotherapy. However, the tendency toward an increased response rate in patients who received biochemotherapy did not translate into an increase in overall survival, and there was, in fact, a trend for a survival advantage in patients receiving chemotherapy alone (median survival: 10.7 vs 15.8 months). New agents (or combinations) need to be developed for this refractory malignancy.

Disulfiram (DSF), an agent used to treat alcoholism for the past few decades, has been shown to induce apoptosis in thymocytes. The hypothetical mechanism is that DSF chelates copper and creates an intracellular oxidative stress by oxidizing glutathione and establishing a recycling situation.

It has been demonstrated that redox regulations in melanoma cells are aberrant and metal chelators (such as dithiocarbamate) alter the redox status and induce apoptosis in melanoma cells. We have recently explored the effect of disulfiram (DSF), a member of the dithiocarbamate family, on apoptosis in melanoma cells and as we anticipated, DSF caused a 3 to 5-fold increase in apoptosis in all three melanoma cell strains being tested at a very low dose (25-50ng/ml). The same dose of DSF did not have significant apoptotic effect on melanocytes. We are currently studying the mechanisms by which DSF induces apoptosis in melanoma cells.

The advantages of using DSF in this phase I/II trial are the following:

DSF has been used as a drug for many years for the treatment of alcoholism. It's mechanism, pharmacokinetics, toxicity/tolerable dose are well known, and this drug is relatively non-toxic by itself at therapeutic dose. Doses of greater than 3000mg/m2 can cause reversible confusion.

Acute overdose in the absence of ethanol is an infrequent event. It rarely occurs in children, or adult for suicidal purpose. Combined toxicity (with metronidazole or isoniazid), or unmasking of underlying psychoses in patients stressed by the withdrawal of alcohol may occur.

Adults may have clinical signs after acute ingestion of about 3 grams of DSF, and death may occur with ingestion of 10 to 30 grams. Brewer (1993) reported a case of an adult who ingested 600 mg daily for over 6 years and experienced no significant side effects other than slight drowsiness. Single doses of up to 6 grams/day have been reported in adults without adverse effect. A phase I study using combination of disulfiram with cisplatin was reported by Stewart DJ et al in 1987. The dose of DSF ranged from 1000 mg/m2 to 3000 mg/m2 (PO), and reversible confusion was the dose-limiting toxicity at a disulfiram dose of 3000 mg/m2 administered 1 hr before the end of a 2-hr cisplatin infusion. A randomized phase II study of cisplatin alone (100 mg/m2) versus cisplatin plus disulfiram (2000 mg/m2, PO) have shown enhancing gastrointestinal and ototoxicities (ECOG 2-3), and no difference in nephrotoxicity between two groups.

Symptoms of overdose commonly involved the CNS system, which include lethargy, drowsiness, ataxia, movement disorders, psychoses, seizure and coma.

DSF can be taken orally; therefore, it is convenient to administer.

DSF can penetrate the blood-brain barrier (unlike dacarbazine and many other chemotherapy agents); therefore, it might have an active effect on CNS metastasis.

This study is designed to include women and minorities, but is not designed to measure differences of intervention effect.

Study Type: Interventional

Study Design: Treatment, Non-Randomized, Open Label, Uncontrolled, Single Group Assignment, Efficacy Study

Intervention(s) in this Clinical Trial

• Drug: Disulfiram

Primary Measures

• Determine the response rate
• Evaluate the toxicity of disulfiram administration

Inclusion Criteria:

• Subjects must be between the ages of 18 and 80.
• Patient must have pathologically proven and surgically incurable malignant melanoma, which is Stage IV.
• Patient 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 patient's disease status must be completely assessed and reported.
• All patients must undergo a CT of abdomen and chest within 28 days prior to registration.
• All patients must undergo either a CT or MRI of the brain within 28 days of registration. Patients with or without brain metastasis are both recruited for this protocol.
• Patients must have received at least one prior systemic therapy (chemotherapy, biologic/immunotherapy, or a combination regimen) for metastatic disease. Prior systemic therapy must have been completed at least 28 days before registration.
• Patients 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
• Patients 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 patient to be eligible. Radiation therapy must have been completed at least 28 days before registration.
• Patients 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 Zubrod Criteria.
• If day 28 or 42 falls on a weekend or holiday, the limit may be extended to the next working day.
• Patients must be informed of the investigational nature of this study and sign and give written informed consent in accordance with institutional and federal guidelines.

Exclusion Criteria:

• Patients 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.
• Patients who can not abstain from alcohol intake during the entire duration of this protocol are not qualified for this study.
• Patients requiring ongoing therapy with other investigational drugs are excluded.
• 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.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 80 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: University of California, Irvine

Overall Clinical Trial Officials and Contacts

John Fruehauf, MD Principal Investigator Chao Family Comprehensive Cancer Center  

Information obtained from ClinicalTrials.gov on October 07, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00256230

Study ID Number: UCI 01-01

ClinicalTrials.gov Identifier: NCT00256230

Health Authority: United States: Institutional Review Board