Final report of the french multicenter phase II study of the nitrosourea fotemustine in 153 evaluable patients with disseminated malignant melanoma including patients with cerebral metastases

Abstract

One hundred sixty-nine patients with histologic evidence of disseminated malignant melanoma, including patients with cerebral metastases, were entered into a Phase II study of the nitrosourea fotemustine. The treatment regimen consisted of a 100 mg/m2 1 hour IV infusion every week for 3 consecutive weeks, followed by a 4- to 5-week rest period (induction therapy). In responding or stabilized patients, maintenance therapy consisted of 100 mg/m2 every 3 weeks until the disease progressed. One hundred fifty-three patients were evaluable for response. Three complete responses and 34 partial responses were observed (according to the World Health Organization criteria), leading to an objective response rate of 24.2% (95% confidence interval: 17.4% to 31.0%). Responses were also documented on cerebral (25.0%), visceral (19.2%), or nonvisceral (31.8%) metastatic sites. The median duration of response was 22 weeks (range, 7 to 80 weeks). The objective response rate in previously untreated patients was 30.7% (19 of 62 patients). The main toxicity was hematologic with delayed and reversible leukopenia and/or thrombopenia. The objective response rate observed (especially in untreated patients), the activity on cerebral metastases, and the small amount of extra-hematologic toxicity encountered suggest that fotemustine is an effective drug in disseminated malignant melanoma.

Sequential administration of varying doses of dacarbazine and fotemustine in advanced malignant melanoma

“…However, the two cases of interstitial pneumonitis in our study received a cumulative dosage of < 400 mg m-2 of fotemustine suggesting that the synergy between DTIC and fotemustine (as used in the schedule here) may be responsible for the acute pulmonary event, possibly related to greater cytotoxicity in normal lung cells following depletion of the endogenous ATase. A recent phase II study of fotemustine alone in 153 patients with disseminated melanoma was not associated with any pulmonary toxicity and similar finding was reported in another 38 patients with gliomas treated with fotemustine alone (Jacquillat et al, 1990;Frenay et al, 1991). Lung tissue has a relatively low ATase activity in comparison with other tissues (Grafstrom et al, 1984;Gerson et al, 1986) and as a result they may be more sensitive to the cytotoxic effects of DNA alkylation.…”

“…bolus or daily injections over 5 days, have produced an overall response rate of about 20% (Comis 1976;Mastrangelo et al, 1982;Geeraerts & Nathanson, 1986;Balch et al, 1989) 800 mg m-2 with dactinomycin (Hochster et al, 1985) or 250 mg m-2 daily for 5 days with dactinomycin (Robidoux et al, 1982) gave response rates of 23%, 22% and 15% respectively. Fotemustine alone gave a response rate of about 24% (Jacquillat et al, 1990). Therefore the overall response rate of 30% achieved with the current study would support the use of a combination of DTIC and fotemustine, although, because of the absence of a direct comparison, no conclusions about the scheduling can be reached.…”

“…Therefore in an attempt to improve the clinical response rate of DTIC, fotemustine was administered at 4h after DTIC administration, the time which was shown to be associated with maximal ATase depletion in the peripheral blood lymphocytes. Fotemustine is a new drug containing a phosphonoalanine carrier grafted to the nitrosourea radical and it has shown promising clinical efficacy (Jacquillat et al, 1990). The present study evaluates and compares the clinical results of using three different doses of DTIC (400, 500 and 800 mg m2) with fotemustine (100 mg m-2).…”

Temozolomide in advanced malignant melanoma with small brain metastases

“…The response rates of brain metastases to fotemustine as single agent in Phase II studies ranged between 8% and 28%. [21][22][23][24] However, in a recent, large, Phase III study that compared fotemustine with dacarbazine in patients with metastatic melanoma, the response of brain metastases was 5.9% after treatment with fotemustine versus 0% after dacarbazine. 21 Anecdotal responses also were reported after other cytotoxic regimens, predominantly in patients with favorable characteristics like solitary, small, or asymptomatic brain metastases.…”

A Phase I/II study of lomustine and temozolomide in patients with cerebral metastases from malignant melanoma

“…Trials of a related compound, fotemustine, have reported response rates of 5 -25% in melanoma metastatic to the brain (Jacquillat et al, 1990;Mornex et al, 2003;Avril et al, 2004) and fotemustine has also been given in combination with dacarbazine Merimsky et al, 1992;Lee et al, 1993;Chang et al, 1994;Comella et al, 1997;Richard et al, 1998;Seeber et al, 1998) and with temozolomide (Marzolini et al, 1998;Gander et al, 1999). These drug combinations are generally well tolerated although unexpected pulmonary toxicity was reported in two studies of the combination of dacarbazine and fotemustine (Gerard et al, 1993;Lee et al, 1993).…”