Aziridinylbenzoquinone (AZQ) in the treatment of recurrent pediatric brain and other malignant solid tumors

Abstract

To assess the response rates and toxicity of AZQ in children with recurrent brain and other malignant solid tumors, a phase II study was implemented by the Pediatric Oncology Group. Eligible patients received AZQ 18 mg/M2/week i.v. for 4 doses followed by a 2 week rest period. Each dose was given over four hours (1/3 over the initial 20 minutes). After the first year, the dosage was reduced to 13 mg/M2 due to myelotoxicity resulting in treatment delays. No objective responses were observed in 73 evaluable children with various non-central nervous system tumors. Of the 91 patients with brain tumors, there were 4 CR's and 2 PR's in patients with astrocytoma, ependymoma, glioblastoma multiforme, oligodendroglioma, brain stem glioma and intracranial yolk sac tumor (median duration, 10 months; range, 2-20+ months). Three of 4 CR's were achieved with a dosage of 18 mg/M2/week. An additional 13 children with brain tumors experienced stable or improved disease (duration, 2-36 + months; median 7.5 months). The principal toxicity was myelosuppression which was cumulative but there were also 3 allergic reactions to AZQ. We conclude that for selected brain tumors, the rates of objective response and stable disease plus the duration of responses support further assessment of AZQ in combination with other agents. Furthermore, the 18 mg/M2 dosage may provide better responses.

Clinical applications of quinone-containing alkylating agents

“…Diaziquone has also been extensively evaluated in pediatric tumors. It produced a 10% response rate in recurrent pediatric brain tumors (174,175), but had little effect in other solid tumors (174) or acute leukemias (176). In addition, because diaziquone shows little non-hematopoietic toxicity, it has been investigated for inclusion into bone marrow transplant preparative regimens (177).…”

Clinical management of brain stem glioma

“…A recent literature review of single agent phase 2 studies that have included patients with brain stem gliomas has identified trials of cisplatin,46-48 carboplatin,49-52iproplatin,50 oral etoposide,53 54cyclophosphamide,55 ifosfamide,561-(s-chlorethyll)-3-(2.6, dioxo-3-piperdyl)-1-nitrosourea (PCNU),57 thiotepa,58methotrexate,59 topotecan,60 β interferon,61 temozolomide,62 and aridylbenzoquinone 63. Conventional response criteria would require a 30% “partial response” rate (table 2) to establish that the drug had activity.…”