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Phase I Trial of VNP40101M (Cloretazine) in Children with Recurrent Brain Tumors: A Pediatric Brain Tumor Consortium Study

Authors' Affiliations: ¹ The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina; ² Dana-Farber Cancer Institute and Children's Hospital, and ³ Children's Hospital of Boston, Boston, Massachusetts; ⁴ Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital; ⁵ Operations and Biostatistics Center, Pediatric Brain Tumor Consortium, Memphis, Tennessee; ⁶ Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; ⁷ Children's Memorial Hospital, Chicago, Illinois; ⁸ Children's National Medical Center, Washington, District of Columbia; ⁹ Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania; ¹⁰ Texas Children's Cancer Center/Baylor College of Medicine, Houston, Texas; ¹¹ Vion Pharmaceuticals, New Haven, Connecticut; and ¹² Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio

Requests for reprints: Sridharan Gururangan, MRCP(UK), The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Box 3624, Durham, NC 27710. Phone: 919-668-6288; Fax: 919-668-2485; E-mail: gurur002{at}mc.duke.edu.

Purpose: VNP40101M (Cloretazine), a novel DNA alkylating agent, was evaluated in a phase I study in children with recurrent brain tumors.

Experimental Design: VNP40101M was given i.v. daily for 5 consecutive days every 6 weeks for up to eight cycles. Dose escalation was done independently in patients stratified based on intensity of prior therapy (moderately pretreated, stratum I; heavily pretreated, stratum II). Correlative studies included pharmacokinetics and measurement of O⁶-alkylguanine-DNA alkyl transferase levels in peripheral blood mononuclear cells before and after treatment.

Results: Forty-one eligible patients (stratum I, 19; stratum II, 22) were enrolled on this study. The dose-limiting toxicity in 35 evaluable patients was myelosuppression, which occurred in 4 of 16 patients in stratum I and 3 of 19 patients in stratum II. Pharmacokinetic studies showed a median terminal half-life of 30 min (range, 14-39.5). The maximum tolerated dose in stratum I and II were 45 and 30 mg/m²/d daily for 5 days every 6 weeks, respectively. Peripheral blood mononuclear cells alkylguanine alkyl transferase levels did not decrease significantly after VNP40101M treatment. Central imaging review confirmed that three patients had stable disease for a median of 45 weeks (range, 37-61+) after therapy.

Conclusions: The recommended dose of VNP40101M for phase II studies in children with brain tumors is 45 mg/m²/d in moderately pretreated and 30 mg/m²/d in heavily pretreated patients when administered for 5 consecutive days every 6 weeks.