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Phase II study of Cloretazine for the treatment of adults with recurrent glioblastoma multiforme¹

Duke University Medical Center, Brain Tumor Center, Department of Surgery (M.A.B., K.P., A.D., D.A.R., S.S., A.H.F., H.S.F., J.J.V.), Department of Medicine (J.N.R., J.A.Q.), Department of Pathology (D.D.B.), and Cancer Center Biostatistics (J.E.H.), Durham, NC 27710; Vion Pharmaceuticals (A.C.), New Haven, CT 06511; and Cedars Sinai Medical Center-Maxine Dunitz Neurosurgical Institute, Department of Surgery (M.A.B.), Los Angeles, CA 90025; USA

² Address Correspondence to James J. Vredenburgh, M.D., Brain Tumor Center, Duke University Medical Center, Box 3624, Durham, NC 27710, USa (vrede001{at}mc.duke.edu).

Cloretazine (VNP40101M) is a newly synthesized alkylating agent belonging to a novel class of alkylating agents called 1,2-bis(sulfonyl)hydrazines. Agents that belong to this class do not produce vinylating and chloroethylating species, and hence this class of alkylating agents is thought to have minimal systemic toxicity. Cloretazine produces two short-lived active species: 1,2-bis(methylsulfonyl)-1-(2-chloroethyl) hydrazine (a chloroethylating species) and a thiophilic carbamoylating methylisocyanate species. The chloroethylating species preferentially produces lesions at the O⁶ position of guanine. The methylisocyanate species may inhibit O⁶-alkylguanine-DNA alkyltransferase, an important mechanism of resistance against alkylating agents. The purpose of this study was to determine the efficacy and tolerability of Cloretazine in patients with recurrent glioblastoma multiforme. The basis for the determination of efficacy was the proportion of patients alive without evidence of disease progression six months after initiation of treatment. Patients with recurrent glioblastoma multiforme received Cloretazine (300 mg/m²) intravenously every six weeks. Radiographic response, survival data, and toxicity were assessed. Thirty-two patients were enrolled. Median age was 56 years; 24 patients (75%) were men. At six months, two patients were alive and progression free, so the six-month progression-free survival (PFS) was 6%. The median PFS was 6.3 weeks. There were no objective radiographic responses. Twelve patients had stable disease for at least one cycle, but only two patients received more than three cycles. Nine patients experienced grade 4 thrombocytopenia and three patients experienced grade 4 neutropenia. Cloretazine administered every six weeks was relatively well tolerated, although this schedule has insignificant activity for patients with recurrent glioblastoma multiforme.

Key Words: Cloretazine • glioblastoma multiforme

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