Temozolomide, an oral alkylating agent, has shown activity against
metastatic melanoma. The drug is schedule dependent and is given
daily for 5 days. Altering the schedule may enhance its activity by
depletion of the protein O6-alkylguanine-DNA
alkyltransferase, a major determinant of resistance to temozolomide.
Additionally, we propose to combine temozolomide with interferon alfa
or thalidomide (Thalomid), a new antiangiogenic agent.
We report the preliminary results of an ongoing three-arm phase II
study aiming to assess the efficacy of temozolomide in an 8-hour
schedule against the 24-hour schedule in combination with either
interferon alfa or thalidomide in metastatic melanoma. Patients with
untreated metastatic melanoma were randomized to either arm A (oral
temozolomide at 200 mg/m² every 8 hours for five doses); arm B
(oral temozolomide at 200 mg/m² days 15 and interferon
alfa at 5 million IU/mL² subcutaneously three times a week for 4
weeks); or arm C (oral temozolomide at 150 mg/m² days 15
and oral thalidomide at 100 mg daily for 28 days). Cycles were
repeated every 28 days for up to 1 year. 50 patients have been
randomized to date (18 to arm A, 17 to arm B, and 15 to arm C). The
median age was 55 years (range: 1778 years) and the median
World Health Organization performance status was 1 (range: 02).
Six patients had central nervous system metastases and 37 visceral metastases.
A total of 43 patients were evaluable for response and 47 for
toxicity. The most common side effect was myelosuppression. Grade 3/4
thrombocytopenia occurred in 17 patients (36.1%), with one
treatment-related death due to intracerebral hemorrhage in a patient
with brain metastases. 15 patients presented with grade 3/4
leukopenia (31.9%), more frequent in arms A and B (P = .017),
with associated fever on three occasions. Grade 1/2 diarrhea was more
common in arm B (P = .032). Nonhematologic toxicity was mild
to moderate with similar frequency on the three arms. There were 8
patients with partial responses (16%), 10 with stable disease (20%),
and 24 with progressive disease (48%). The median overall survival
time was 6.5 months and the median response duration was 5.9 months.
CONCLUSION: These results suggest that temozolomide alone or
in combination has activity against metastatic melanoma. Treatment in
all arms appears generally well tolerated with myelosuppression as
the main side effect. Further recruitment is required to identify
differences in efficacy and toxicity.