A Phase I Open-label Study of the Safety, Tolerability, and Pharmacokinetics of NHWD-870 HCl in Patients with Lymphoma and Other Advanced Solid Tumors.

INTRODUCTION

NHWD-870 HCl is a next-generation oral BET inhibitor (US Patent 10,428,071 B2). We conducted a Phase I dose‑escalation study.

METHODS

This multicenter, open-label, phase I study used a Bayesian optimal interval (BOIN) dose-escalation design. NHWD-870 HCl was administered once daily on an intermittent schedule (5 days on/2 days off) at doses ranging from 0.5 to 3.5 mg. The primary endpoints were safety, cycle 1 Dose-Limiting Toxicities (DLTs), the maximum tolerated dose (MTD), and the recommended phase II dose (RP2D). Secondary endpoints included Objective Response Rate (ORR), Disease Control Rate (DCR), and pharmacokinetics (PK).

RESULTS

Thirty-one patients received NHWD-870 HCl. Overall, 93.5% (29/31) experienced at least one adverse event (AE), and 83.9% (26/31) experienced at least one treatment-related AE (TRAE). The most common TRAEs were thrombocytopenia (45.2%; grade ≥3, 25.8%), anemia (41.9%; grade ≥3, 12.9%), and increased blood bilirubin (32.3%; grade ≥3, 3.2%). Treatment-related Serious Adverse Events (SAEs) occurred in 4 patients (12.9%; thrombocytopenia, n=3; wound bleeding, n=1), and no treatment-related deaths were reported. Twenty-four patients were evaluable for DLTs, and all 3 DLTs occurred at the 2.75 mg dose level, corresponding to a cycle 1 DLT rate of 30.0%, which was within the BOIN target interval (0.18- 0.42). However, considering the concentration-dependent thrombocytopenia, the occurrence of grade 4 thrombocytopenia at 2.75 mg (2 events), the higher discontinuation rate, and the lessthan-dose-proportional increase in exposure at 2.75 mg, the RP2D was determined to be 2.0 mg on a 5-days-on/2-days-off schedule. Among the 29 response-evaluable patients, the ORR was 3.45%, and the DCR was 69.0%. Durable stable disease was observed in selected patients, including approximately 21 months in melanoma and more than 26 months in NUT carcinoma. PK analyses showed rapid absorption (median Tmax, approximately 1-2 h) and less-than-doseproportional increases in Cmax and AUC over the 0.5-2.75 mg dose range; the mean terminal half-life was approximately 11-16 h, with mild accumulation.

DISCUSSION: NHWD-870 HCl showed manageable, predominantly hematologic toxicity, with thrombocytopenia demonstrating clear dose- and exposure-related trends. Although the cycle 1 DLT rate at 2.75 mg was consistent with the BOIN target interval, the occurrence of grade 4 thrombocytopenia, the higher frequency of treatment interruptions and discontinuations, and the subproportional increase in exposure supported selection of 2.0 mg (5 days on/2 days off) as the RP2D. Although the ORR was low, the durable disease control observed in BET-dependent tumors, including NUT carcinoma and DLBCL, supports further biomarker-driven studies.

CONCLUSION

NHWD-870 HCl demonstrated manageable, mainly hematologic toxicity and preliminary antitumor activity, supporting further clinical evaluation, particularly in NUT carcinoma and DLBCL.