Positive phase II study in the treatment of advanced malignant melanoma with fotemustine

Abstract

To date, dacarbazine (DTIC) has been the most effective drug in the treatment of advanced metastatic melanoma, achieving response rates of up to 28% (mean, 21%). Multidrug responses were generally no better than those obtained using monotherapy. A quite promising clinical trial was conducted using the new nitrosourea fotemustine. A total of 19 patients presenting with advanced malignant melanoma (clinical stage IV according to the 1987 UICC classification system) underwent treatment involving a more rapid infusion of the drug and a reduction in the rest period from 5 to 3 weeks. This monotherapy with fotemustine yielded two complete responses and seven partial responses; in addition, four patients showed no change and six cases progressed after the induction cycle (median duration of response to date, 7.6 months, including four cases that have not relapsed). Fotemustine was well tolerated by the patients, with the only mild side effects being thrombocytopenia, leukocytopenia and easily controlled nausea/vomiting. Preclinical studies performed previously indicated that fotemustine inhibits enzymes involved in the ribonucleotide reduction pathway (i.e. DNA synthesis), whereby responding patients (n = 3) appeared to favor the thioredoxin reductase/thioredoxin electron transfer to ribonucleotide reductase, whereas non-responders (n = 4) expressed the alternate glutathione reductase/glutaredoxin mechanism. The 47% response rate obtained in these studies vs the 24% reported previously for fotemustine may reflect variations in enzymes in the ribonucleotide reduction pathway in different patients. However, the efficacy of fotemustine against advanced melanoma warrants more extensive trials of this drug, especially since the quality of life of the patients during and after chemotherapy was not severely affected.

Fotemustine as second-line treatment for recurrent or progressive glioblastoma after concomitant and/or adjuvant temozolomide: a phase II trial of Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO)

“…We decided to modify the fotemustine dose recommended in a prior phase I trial [ 14 ] and in other studies on glioma or melanoma patients [ 1 , 15 , 19 , 20 , 25 ], as grade 4 thrombocytopenia was observed after induction therapy in the first three patients and this life-threatening toxicity was considered unacceptable in the palliative setting of salvage therapy of GBM patients. This is consistent with the previous observation that hematological toxicity is increased by prior chemotherapy [ 24 ].…”

The History and Future of Chemotherapy for Melanoma

“…20-22 Fotemustine, a nitrosourea available in Europe, may be the most active, with response rates over multiple clinical trials averaging 22%. 23-26 In addition, although nitrosoureas are lipid-soluble and cross the blood-brain barrier, only fotemustine was found to have a 25% response rate for cerebral metastasis. 24 In a phase III clinical trial of fotemustine (100 mg/m 2 weekly for 3 weeks) versus DTIC (250 mg/m 2 /day for 5 days every 4 weeks), the response rate for fotemustine was 15.2% versus 6.8% for DTIC.…”

Persistent thrombocytopenia during melanoma treatment with fotemustine

“…Six studies report the data for fotemustine given as monotherapy to patients with metastatic melanoma. The main toxicity was haematological with delayed and reversible leucocytopenia and/or thrombocytopenia [1,2,[4][5][6][7].…”