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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.

2005 Background: The standard of care treatment for newly diagnosed GBM is maximal safe surgical resection followed by two DNA damaging agents, RT and TMZ. Cellular response to DNA damage involves checkpoints that halt the cell cycle to allow DNA repair. AZD1775 is an oral small molecular inhibitor of a nuclear tyrosine kinase Wee1, a key regulator of the G2/M checkpoint. Abrogation of the G2/M checkpoint prevents repair and pushes cells into mitosis with unrepaired DNA damage. AZD1775 was shown to enhance TMZ and RT effects in preclinical models. Methods: 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. The dose finding portion is comprised of two arms, one with AZD1775 given Monday through Friday during concurrent RT/TMZ and a second arm given with adjuvant TMZ qd x 5d/28d cycle. Each arm had standard 3+3 design. 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. Results: 51 patients enrolled in the dose finding arms. For the concurrent arm, the MTD was 200 mg. At 275 mg one patient had grade 3 fatigue and another had grade 4 thrombocytopenia and neutropenia. Two of 6 total patients enrolled at 200 mg experienced DLTs (grade 4 neutropenia and grade 3 ALT elevation). The MTD for the adjuvant arm was 425 mg as 1 of 6 patients had DLT (grade 4 decrease in ANC). At 500 mg, 2 of 3 patients experienced intolerable diarrhea despite prophylaxis. Enrollment in the combination cohort is completed and evaluation of safety is underway. The 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: The MTD for AZD1775 in combination with RT/TMZ is 200 mg qd M-F with concurrent RT/TMZ and 425 mg qd x 5d/28d cycle in combination with adjuvant TMZ. IDD and PK/PD analysis is ongoing to inform the decision to proceed to phase II testing. Clinical trial information: NCT01849146.