Phase I trial of polifeprosan 20 with carmustine implant plus continuous infusion of intravenous O6-benzylguanine in adults with recurrent malignant glioma: new approaches to brain tumor therapy CNS consortium trial

Abstract

Purpose: This phase I trial was designed to (1) establish the dose of O6-benzylguanine (O6-BG) administered intravenously as a continuous infusion that suppresses O6-alkylguanine-DNA alkyltransferase (AGT) levels in brain tumors, (2) evaluate the safety of extending continuous-infusion O6-BG at the optimal dose with intracranially implanted carmustine wafers, and (3) measure the pharmacokinetics of O6-BG and its metabolite.

Patients and methods: The first patient cohort (group A) received 120 mg/m2 of O6-BG over 1 hour followed by a continuous infusion for 2 days at escalating doses presurgery. Tumor samples were evaluated for AGT levels. The continuous-infusion dose that resulted in undetectable AGT levels in 11 or more of 14 patients was used in the second patient cohort. Group B received the optimal dose of O6-BG for 2, 4, 7, or 14 days after surgical implantation of the carmustine wafers. The study end point was dose-limiting toxicity (DLT).

Results: Thirty-eight patients were accrued. In group A, 12 of 13 patients had AGT activity levels of less than 10 fmol/mg protein with a continuous-infusion O6-BG dose of 30 mg/m2/d. Group B patients were enrolled onto 2-, 4-, 7-, and 14-day continuous-infusion cohorts. One DLT of grade 3 elevation in ALT was seen. Other non-DLTs included ataxia and headache. For up to 14 days, steady-state levels of O6-BG were 0.1 to 0.4 micromol/L, and levels for O6-benzyl-8-oxoguanine were 0.7 to 1.3 micromol/L.

Conclusion: Systemically administered O6-BG can be coadministered with intracranially implanted carmustine wafers, without added toxicity. Future trials are required to determine if the inhibition of tumor AGT levels results in increased efficacy.

Conflict of interest statement

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: N/A Leadership: N/A Stock: N/A Honoraria: N/A Research Funds: N/A Testimony: N/A Other: M. Eileen Dolan, KERYX Biopharmaceuticals; Jon Weingart, MGI PHARMA

Figures

Fig 1

Mean (±standard deviation) of O6-benzylguanine (O6-BG; ) and O6-benzyl-8-oxoguanine (8-oxoBG; ) plasma concentration in group A patients. A total of 14 patients were treated with 120 mg/m2 O6-BG over 1 hour followed immediately by a continuous infusion of 30 mg/m2/d O6-BG for 48 hours presurgery.

Fig 2

A total of 26 patients were treated with 120 mg/m2 of O6-benzylguanine (O6-BG) over 1 hour, administered at least 1 hour presurgery, and followed immediately by a 30 mg/m2/d of continuous-infusion O6-BG beginning on the day of surgery. The length of the infusion increased up to14 days. Concentrations of O6-benzyl-8-oxoguanine (8-oxoBG; ) and O6-BG ( ) were evaluated before the O6-BG bolus, day of surgery, and various days postsurgery.