Phase I/II study of BIBW 2992 with or without daily temozolomide in the treatment of patients with recurrent malignant glioma.
Abstract:
Background: BIBW 2992 is a novel, potent, orally bioavailable irreversible inhibitor of epidermal growth factor receptor EGFR/HER1 and HER2 receptor tyrosine kinases, as well as the constitutively active EGFRvIII mutant, which has demonstrated a high level of in vitro resistance to reversible EGFR inhibitors. Protracted (metronomic) temozolomide (TMZ) regimens may overcome MGMT resistance. Methods: The primary objective of the phase I part of the trial (reported here) was to determine the maximum tolerated dose (MTD) of continuous, daily BIBW 2992 following dose escalation from 20 mg/dose to a maximum of 50 mg/dose in combination with daily 75 mg/m2 TMZ administered for 21 days, followed by 7 days off (TMZ 21/7) among patients with recurrent malignant glioma. A standard "3+3" dose-escalation design was employed. Patients were treated either until occurrence of dose-limiting adverse events (DLAEs) or disease progression. Results: In total, 32 patients were treated (20 mg/ dose, n=6; 40 mg/dose, n=8; 50 mg/dose, n=18) and the BIBW 2992 MTD was 50 mg/dose. DLAEs reported in cycle 1 included a grade 4 intracranial hemorrhage in a patient on enoxaparin sodium injections (Levonox), as well as grade 3 hypokalemia (n=1) and grade 3 diarrhea (n=1). The percentage of patients with DLAEs, any adverse events, related adverse events, adverse events leading to discontinuation, CTCAE grade 3/4 events and serious adverse events was consistently higher in the 50 mg dose cohort (BIBW 2992) compared to the 40 mg and 20 mg dose cohorts. Across all dose cohorts, patients were treated for between 6 and 276 days. Most patients were treated for one or two cycles. Average treatment duration was longer in the 20 mg/dose and 40 mg/dose cohorts compared to the 50 mg/dose cohort. Conclusions: Although the MTD of BIBW 2992 in combination with daily TMZ was observed at 50 mg, the proposed recommended dose for phase II was 40 mg BIBW 2992 in combination with daily 75 mg/m2 TMZ administered for 21 days, followed by 7 days off.
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