First-in-human study of pelcitoclax (APG-1252) in combination with paclitaxel in patients (pts) with relapsed/refractory small-cell lung cancer (R/R SCLC).

e20612 Background: Targeting BCL-2/BCL-xL proteins is considered an important approach for anticancer drug development. Investigational pelcitoclax (APG-1252) as a single agent is a novel BCL-2/BCL-xL dual inhibitor, which has demonstrated synergistic antitumor activity in combination with chemotherapy preclinically through targeting both BCL-xL and MCL-1 pathways. The phase I study of pelcitoclax suggested promising antitumor activity and a favorable safety profile. Methods: The primary aim of this study was to determine the safety and preliminary efficacy of pelcitoclax combined with paclitaxel in patients with R/R SCLC. Patients received pelcitoclax 160 mg or 240 mg IV infusion on Days 1, 8, and 15 plus paclitaxel 80 mg/m 2 on Days 1 and 8 of a 21-day cycle. The primary endpoint of phase Ib was to characterize the safety and tolerability of the combination. The primary endpoint of phase 2 was the objective response rate (ORR) of pelcitoclax at the RP2D plus paclitaxel using RECIST v1.1. Results: On December 20, 2021, 28 pts (median age, 63 [range, 37-77] years) were enrolled. The median (range) duration of treatment was 84 (7-259) days. The RP2D of pelcitoclax was determined to be 240 mg. A total of 26 pts experienced any grade treatment-related adverse events (TRAEs), including anemia (32.1%); ALT or AST elevation (28.6% each); neutropenia (25%); fatigue, leukopenia, or thrombocytopenia (21.4% each); peripheral neuropathy, nausea, or alopecia (17.9% each); peripheral sensory neuropathy or decreased appetite (14.3% each); and lymphopenia, hyponatremia, or dizziness (10.7% each). A total of 15 pts had at least one ≥ grade 3-4 TRAE, and 11 (39.3%) had serious AEs. No dose-limiting toxicity was reported. A total of 5 of 20 evaluable pts (4 pts in the 240 mg cohort and 1 in the 160 mg cohort) reported PR (ORR 25%), with a median response duration of 83 days. The pharmacokinetics profile showed that pelcitoclax systemic exposure increased between 160 and 240 mg, with an average terminal half-life of 3.7 to 7.4 hours and without any drug-drug interaction. Conclusions: Pelcitoclax was well tolerated at doses of up to 240 mg/week. Treatment with pelcitoclax 240 mg and paclitaxel 80 mg/m 2 demonstrated modest antitumor activity in pts with R/R SCLC. Further clinical exploration, preferably in selected patient populations with relevant biomarkers, is warranted to fully elucidate the clinical activity of pelcitoclax. Clinical trial information: NCT04210037.