First-in-human study of TQB3617, a BET inhibitor in patients with relapsed/refractory hematologic malignancies.

3094 Background: TQB3617 is a first-in-class, oral, small molecular inhibitor of the bromodomain and extra terminal (BET) protein family. This is an open-label, Phase I study investigated TQB3617 monotherapy to treat advanced malignant tumors (NCT05110807). Here, we report the primary results of TQB3617 in patients with (pts/w) hematologic malignancies. Methods: This is a modified 3 + 3 design and dose escalation study. Aged ≥18 years old, ECOG PS score of 0~2, and pts/w advanced malignancy tumor who had failed standard treatment or were unable to receive standard treatment or had no effective treatment were enrolled. The doses of TQB3617 were 0.05mg, 0.1mg, 0.15mg, 0.2mg, 0.25mg and 0.3mg. TQB3617 was administered with a daily schedule in 28 day-cycles (28/28), or 14 days on drug/7 days off schedule in 21 day-cycles (14/21). The primary outcomes were the recommended Phase 2 dose (RP2D) or the maximum tolerated dose (MTD), secondary end points were pharmacokinetics (PK) and preliminary antitumor activity. Results: By November 9, 2023, 36 pts/w hematologic malignancies were enrolled, 32 lymphomas, 2 myelofibrosis (MF), 2 other hematologic malignancies. The median age was 53 years, 23 patients were male. The ECOG PS score of 28 patients was 1. Median number of prior therapies was 3 (IQR 1-7). The number of patients enrolled per dose level and schedule was one at 0.05 mg 28/28, eleven at 0.1 mg 28/28, eight at 0.15 mg 28/28, five at 0.15 mg 14/21, seven at 0.2 mg 14/21, four at 0.25 mg 14/21. The DLTs were experienced with by two patients, one at 0.1 mg 28/28 (grade 3 herpes zoster persists for more than 7 days), one at 0.25 mg 14/21 (grade 3 platelet count decrease with bleeding). 35 patients received TQB3617 at least once. The most common treatment-emergent adverse events (TEAEs) were platelet count decrease (74.3%), anemia (40%), hypertriglyceridemia (28.6%), hyperglycemia (25.7%), most of TEAEs was grade 1~2. Grade ≥3 TEAEs were reported in 16 (45.7%) patients, the most common were platelet count decrease (31.4%) and anemia (11.4%). There was no death happened. After dosing, the peak concentration reached at 2~3 h and AUC increased proportionally from 0.05mg to 0.15mg. The elimination of TQB3617 was slow with t 1/2 of 30~58 h. After 14 or 28 days of consecutive administration, there was 3~5 fold accumulations of exposure. The overall response rate (ORR) was 31.25% in pts/w lymphoma. The spleen volume of two pts/w MF decreased 6.57%, 20.99% at four weeks, respectively. On the basis of tolerability, PK and efficacy, 0.1mg was identified as RP2D, and the schedule is being explored. Conclusions: TQB3617 was generally safe, well-tolerated and demonstrated encouraging efficacy in pts/w lymphoma or MF. Meanwhile, a phase Ib/II study is ongoing, aiming to assess the efficacy and safety of rovadicitinib combined with TQB3617 in pts/w MF (NCT06122831). More studies are planned. Clinical trial information: NCT05110807 .