Phase II Trial of Dacarbazine and Thalidomide for the Treatment of Metastatic Melanoma

Abstract

Objective: This phase II study evaluated the efficacy and tolerability of dacarbazine in combination with thalidomide in metastatic melanoma patients. Methods: Chemotherapy-naïve patients with histologically confirmed, measurable metastatic melanoma with no evidence of brain metastases and adequate hematologic and organ function received dacarbazine (1,000 mg/m² i.v. every 3 weeks) and thalidomide (starting dose of 200 mg/day orally at night, escalated every 3 weeks) as tolerated. The primary endpoint was objective tumor response, evaluated after every 3 cycles of treatment. Fifteen patients, age range 29–77 years, were accrued for this study. All had stage IV disease (1 M1a, 5 M1b, 9 M1c). Nine patients had had no prior adjuvant therapy, 6 had received prior immunotherapy. The median number of cycles was 5 (range 1–18), with 8 patients receiving ≥3 cycles. The median thalidomide dose administered was 200 mg/day with a maximum tolerated dose of 400 mg/day. Results: Of the 13 patients evaluable for response, 1 patient had a partial response, 3 patients had stable disease and 9 patients had progressive disease. No complete responses were seen. Two patients were not evaluable for response: 1 withdrew due to toxicity and 1 died of unrelated causes. Grade III neutropenia, thrombocytopenia and nausea were attributed to dacarbazine. Grade III/IV constipation, peripheral neuropathy, fatigue, edema and rash were attributed to thalidomide. Conclusion: The addition of thalidomide to dacarbazine in metastatic melanoma yielded activity insufficient to proceed with additional trials of this combination. Thalidomide dose escalation beyond 200 mg/day was limited by unacceptable toxicity. Therefore, this combination does not warrant further investigation.

Role of Angiogenesis and Microenvironment in Melanoma Progression

“…Authors conclude that this combination of Thalidomide and Temozolomide does not appear to have a clinical benefit that exceeds Dacarbazine alone and they not recommend it further for phase III trials or for standard community use. Similar results have been obtained when Thalidomide has been associated to Dacarbazine in the treatment of patients with advanced melanoma (Ott et al, 2009). Of the 13 patients evaluable for response of that enrolled in this phase II trial, 1 patient had a partial response, 3 patients had stable disease and 9 patients had progressive disease.…”

“…However, the high incidence of life-threatening events, particularly thrombosis, that are unacceptable in the adjuvant setting, render the up-front antithrombotic prophylaxis necessary for further evaluation of this combination. Many studies are also focused on the effects of Thalidomide on advanced melanoma in combination with Interferon alpha 2 b (Hutchins et al, 2007;Vaishampayan et al, 2007), Temozolomide (Quirt et al, 2007;Atkins et al, 2008), and Dacarbazine (Ott et al, 2009) with encouraging results. The combination of Pegylated Interferon and Thalidomide was evaluated in a phase II trial (Vaishampayan et al, 2007).…”

Clinical Studies on the Treatment of Cancer Cachexia with Megestrol Acetate plus Thalidomide

“…At present, this drug is approved for multiple myeloma and currently used experimentally to treat various cancers, dermatological, neurological and inflammatory diseases [6,7,8]. The clinical use of thalidomide in CACS is still controversial despite some researches indicating that orally administered thalidomide could improve CACS symptoms and patient quality of life (QoL) [9,10].…”

Enrollment in Clinical Trials Correlates with Improved Survival in Metastatic Melanoma

“…Approximately 50% (91) of the patients in our study participated in therapeutic clinical trials and 15% (27) were enrolled in more than one study during the course of their stage IV disease [26,27,28,29,30,31,32,33]. It is interesting to note that stage IV patients who participated in clinical trials survived twice as long as those who did not.…”