A First-in-Human Phase I Study of LOXO-338, an Oral Selective Bcl-2 Inhibitor, in Patients With Advanced Hematologic Malignancies.

Background: LOXO-338 is a novel, orally bioavailable small-molecule inhibitor of Bcl-2, designed to achieve selectivity for Bcl-2 over Bcl-xL, thus avoiding dose-limiting thrombocytopenia associated with Bcl-xL inhibition. This first-in-human, open-label, Phase 1 study investigated LOXO-338 in patients with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or B-cell non-Hodgkin lymphoma (NHL) (NCT05024045).

Patients and methods: Patients with histologically confirmed advanced B-cell malignancies who had received ≥ 2 prior therapies were enrolled in Phase 1 dose escalation (interval 3 + 3 design). LOXO-338 was administered orally as 50 to 300 mg once-daily dose until discontinuation due to progressive disease or unacceptable toxicity. The primary objective was to determine the maximum tolerated dose (MTD)/recommended Phase 2 dose of LOXO-338. Secondary objectives included safety, tolerability, pharmacokinetics, and preliminary antitumor activity.

Results: In total, 27 patients with CLL/SLL (n = 10) or NHL (n = 17) were treated. No dose-limiting toxicities occurred and the MTD was not reached. Treatment-emergent adverse events occurred in 23 patients (85%); anemia (22%) and fatigue (22%) were the most prevalent. Treatment-related adverse events (TRAEs) occurred in 15% and were mostly grade 1 (11%) or 2 (4%); grade ≥ 3 or serious TRAEs were not reported. Tumor lysis syndrome was not observed. The overall response rate was 19% (95% CI: 6.3, 38.1) and disease control rate was 67% (95% CI: 46, 83.5). LOXO-338 was orally bioavailable with dose-dependent increases in exposure.

Conclusion: LOXO-338 was well tolerated with a favorable safety profile in previously treated patients with advanced hematologic malignancies. Preliminary efficacy was observed in this heavily pretreated population supporting further investigation.