ACTR-14. PHASE I STUDY OF AZD1775 WITH RADIATION THERAPY (RT) AND TEMOZOLOMIDE (TMZ) IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA (GBM) AND EVALUATION OF INTRATUMORAL DRUG DISTRIBUTION (IDD) IN PATIENTS WITH RECURRENT GBM

ABSTRACT: Abstract AZD1775 is an oral small molecular inhibitor of the G2/M checkpoint regulator Wee1. The Adult Brain Tumor Consortium 1202 trial (NCT01849146) is a phase I, open label, multicenter dose-finding study of AZD1775 in combination with standard RT and TMZ followed by an IDD study for patients undergoing surgery for recurrent GBM. Dose of AZD1775 was increased in a 3 + 3 design M-F during concurrent RT/TMZ and x 5d/28d cycle with adjuvant TMZ in separate cohorts. A combination cohort with both concurrent and adjuvant AZD1775 at MTD and analysis of PK/PD and IDD at MTD in patients undergoing surgery for recurrent GBM followed. MTD was 200 mg for concurrent with 2/6 patients experiencing DLTs (grade 4 neutropenia, grade 3 ALT elevation). MTD for the adjuvant cohort was 425 mg with 1/6 patients experiencing DLT (grade 4 decrease in ANC). 6/12 patients experienced DLTs when cohorts were combined, however, five during the concurrent phase. Three patients had grade ?3 ALT/AST elevation, one had grade 3 afib, and one had grade 4 neutropenia/thrombocytopenia, grade 3 dehydration/fatigue/muscle weakness. A sixth patient had grade 4 neutropenia in the first adjuvant cycle. Following amendment, an additional 6 patients were enrolled with 150 mg (concurrent) and 425 mg (adjuvant) combination and are in the observation period with one DLT currently. Drug concentration in contrast enhancing and non-enhancing brain tumor was 4–8 x and 0.5–2.6 x greater than plasma, respectively for patients on IDD portion. CONCLUSIONS AZD1775 in combination with RT/TMZ at 200 mg qd M-F with concurrent RT/TMZ and 425 mg qd x 5d/28d cycle in combination with adjuvant TMZ had unacceptable DLT rate in the concurrent phase. A cohort with 150 mg concurrent/425 mg adjuvant has competed accrual with acceptable rates of toxicity currently in observation. AZD1775 has good penetration to non-enhancing and enhancing tumor areas.

SUBMITTER: Alexander B 

PROVIDER: S-EPMC6216169 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature