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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.

BACKGROUND: Others and we have shown additional checkpoint molecules are expressed in GBM and preclinical studies have shown that combining anti-Lag-3 and anti-CD137 with anti-PD-1 can induce effective antitumor immune responses. METHODS: The Adult Brain Tumor Consortium (ABTC) 1501 trial is a phase I, open label, multicenter, multi-arm dose-finding/safety study of anti-LAG-3 (BMS-986016) or anti-CD137 (BMS-663513) alone and in combination with anti-PD-1 in patients with first time recurrent GBM. The primary objective was to define MTD for the mono and combination treatments with a secondary objective of OS. Using a sequential allocation, we started with doses of 80mg for anti-LAG-3 and 8mg flat for anti-CD137. Anti-PD-1 was given at a flat dose of 240 mg in the combination treatment arms. Using a 3 + 3 design our target DLT rate was < 33%. RESULTS: To date 30 patients were enrolled into the trial with median age at 56, median KPS of 90. Median treatment cycle was 3 and 43% tumors were MGMT methylated. Recruitment of the monotherapy Anti-LAG-3 and anti-CD137 arms were completed. We observed no DLT at the highest dose for Anti-LAG-3 at 800mg and only one DLT (a grade 3 elevated serum ALT at end of cycle 2) with anti-CD137 at the top dose of anti-CD137 at 8mg flat. In addition, three out of 12 patients developed elevated ALT at end of cycle 2 that was considered possibly related to anti-CD137. Another two patients had grade 1 elevated ALTs. Six patients are currently enrolled into a combination cohort of Anti-LAG-3 at160mg +anti-PD-1with no observed DLT and the combination arm of anti-CD137 with anti-PD-1 is open to accrual. CONCLUSIONS: The safe monotherapy dose is 800mg for anti-LAG-3 and 8mg flat for anti-CD137. Both Anti-LAG-3 and anti-CD137 in combination with antiPD-1 cohorts and an intratumoral surgical anti-CD137 cohort are open for accrual.