Background: CSF-1R signaling regulates the function of tumor-associated macrophages (TAMs) which are poor prognostic indicators in several cancers. In animal models, including intracranial GBM, M-CSF/CSF-1 blockade may reduce TAM recruitment to the tumor microenvironment, inhibit tumor growth, and overcome resistance to PD-1 inhibitors. BLZ945, a highly selective brain penetrant CSF-1R kinase inhibitor, is being explored as single agent and with the anti-PD-1 mAb, spartalizumab. Here we present dose-escalation results from a Phase I/II, open-label study of BLZ945 ± spartalizumab (NCT02829723). Methods: Pts aged ≥18 years with advanced/metastatic solid tumors including GBM, received BLZ945 Q1W (300 mg-1600 mg QD and 600 mg BID), 7d on/7d off (150 mg-300 mg QD), or 4d on/10d off (300 mg-1200 mg QD and 600 mg BID); or BLZ945 Q1W (150 mg-1400 mg QD, 600 mg-800 mg BID) or 4d on/10d off (300 mg-1200 mg QD) + spartalizumab (400 mg IV, Q4W). Phase I objective was to characterize safety, tolerability, antitumor activity and pharmacokinetics (PK) of BLZ945 ± spartalizumab and determine the MTDs and/or RP2Ds using an adaptive Bayesian logistic regression model with overdose control, and considering overall safety including control of ALT/AST, PK, and clinical efficacy. Results: We report 146 pts receiving BLZ945 (77 pts) or the combination (69 pts), 57/43% M/F, median age 57.5 years. DLTs occurred in 7/77 pts in the BLZ945 arm (increases in amylase, lipase, AST, ALP, worsening of elevated amylase, sudden death) and 7/69 pts in the combination arm (increases in amylase, AST, ALT, dizziness, hyperuricemia). Treatment-related AEs (TRAEs) (≥20%) were AST increase (35%), nausea (29%) and vomiting (23%) in the BLZ945 arm and AST increase (38%), ALT increase (25%), vomiting (23%), and nausea (20%) in the combination arm. Gr ≥3 TRAEs were reported in 19/77 (25%) pts in the BLZ945 arm and 23/69 (33%) pts in the combination arm. Median duration of exposure (DOE) was 8 weeks for BLZ945 alone (1.0-66.6) and for the combination (2.1-85.0). BLZ945 half-life was 15hr-24hr, exposure increases were less than dose proportional after 600/700 mg. BLZ945 did not affect spartalizumab PK and vice versa. Overall response assessment (RECIST 1.1) showed a partial response in 1 pt with HNSCC in the combination arm; stable disease was observed in 21/61 (34%) and 22/49 (45%) pts in the BLZ945 and combination arms, respectively. In evaluable pts with relapsed/refractory GBM (n=18: 7 BLZ945 arm, 11 combination arm), 2 partial responses were reported per RANO (1 per arm). Among treated pts with GBM (n=24), the median DOE was 8 weeks, with 7/24 (29%) pts on treatment for >16 weeks. Conclusions: BLZ945 ± spartalizumab showed an acceptable safety pattern; RP2D was declared as 1200 mg (4d on/10d off) for single-agent BLZ945, the MTD was 700 mg (4d on/10d off) for BLZ945 + spartalizumab. Encouraging preliminary antitumor activity was observed in pts with GBM.

Citation Format: Chia-Chi Lin, Marta Gil-Martin, Todd M. Bauer, Aung Naing, Darren Wan-Teck Lim, John Sarantopoulos, Ravit Geva, Yuichi Ando, Liqiong Fan, Somesh Choudhury, Pei-Jung Tu, Cornelia Quadt, Armando Santoro. Phase I study of BLZ945 alone and with spartalizumab (PDR001) in patients (pts) with advanced solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT171.