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

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.

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.