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

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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.

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