| Abstract: |
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. © 2025 Elsevier Inc. |
| Keywords: |
adult; clinical article; human tissue; treatment outcome; aged; aged, 80 and over; middle aged; unclassified drug; clinical trial; drug tolerability; fatigue; neutropenia; advanced cancer; area under the curve; diarrhea; drug dose reduction; drug safety; monotherapy; recommended drug dose; side effect; treatment duration; antineoplastic agents; antineoplastic agent; protein bcl 2; apoptosis; mantle cell lymphoma; multiple cycle treatment; neutrophil count; anemia; nausea; thrombocytopenia; cohort analysis; herpes zoster; waldenstroem macroglobulinemia; antineoplastic activity; pathology; histology; asthenia; coughing; dizziness; drug dose escalation; fever; rash; aspartate aminotransferase; b cell lymphoma; hematologic malignancy; hematologic neoplasms; multicenter study; erythema; drug clearance; pleura effusion; open study; drug bioavailability; maximum plasma concentration; time to maximum plasma concentration; drug blood level; maximum tolerated dose; phase 1 clinical trial; intestine obstruction; drug half life; drug therapy; disease control; administration, oral; chronic lymphatic leukemia; marginal zone lymphoma; proto-oncogene proteins c-bcl-2; leukemia, lymphocytic, chronic, b-cell; protein inhibitor; hematologic disease; skin infection; drug exposure; upper respiratory tract infection; night sweat; nose obstruction; cellulitis; ecchymosis; oral drug administration; neck pain; chronic lymphocytic leukemia; decreased appetite; overall response rate; bcl-xl; chemoimmunotherapy; small lymphocytic lymphoma; very elderly; humans; human; male; female; article; volume of distribution; b cell chronic lymphocytic leukemia; preliminary data; bruton tyrosine kinase inhibitor; coronavirus disease 2019; covid-19 pneumonia; first in human study; b-cell non–hodgkin lymphoma; loxo 338
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