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4428 A Phase I Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Preliminary Antitumor Activity of Dual CK1ε/PI3Kδ Inhibitor HZ-H08905 in Adult Patients with Relapsed and/or Refractory Hematologic Malignancies

Program: Oral and Poster Abstracts
Session: 624. Hodgkin Lymphomas and T/NK cell Lymphomas: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Research, clinical trials, Clinical Research
Monday, December 11, 2023, 6:00 PM-8:00 PM

Juying Wei1*, Wenjuan Yu, MD2*, Zhengming Jin, B.S.3*, Keshu Zhou, MD4*, Haiyan Yang5*, Fei Li6*, Lanfang Li7*, Miao Hu8, Xinglu Zhou8* and Jie Jin9

1Department of Hematology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China;, Hangzhou, China
2First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
3Department of Hematology, Collaborative Innovation Center of Hematology, Institute of Blood and Marrow Transplantation, the First Affiliated Hospital of Soochow University, Suzhou, China
4Department of Hematology, Henan Cancer Hospital, Zhengzhou, China
5Department of Hematology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
6Department of Hematology, The First Affiliated Hospital of Nanchang University, Nanchang, China
7Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
8HealZen Therapeutics Co., Ltd, Hangzhou, China
9Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

Background: HZ-H08905 is a first-class and potent CK1ε/PI3Kδ dual inhibitor, which was previously reported (Abstract 5502, ASH 2022). Phase I study is ongoing in China, and here we present preliminary results of HZ-H08905 monotherapy in hematologic malignancies.

Methods: HZ-H08905-101 is an ongoing Phase 1, first-in-human, open-label, multicenter, multiple-dose escalation and expansion study in China (CTR20213233). Primary objectives: safety/tolerability, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) of HZ-H08905 monotherapy; secondary objectives: pharmacokinetic properties and preliminary anti-tumor activity of HZ-H08905 in patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL), including B-cell lymphoma (BCM) and T-cell lymphoma (TCL). HZ-H08905 was administered orally once daily in 28-day cycles until disease progression or unacceptable toxicity. The dose escalation part was initiated with a dose titration in the initial cohort (50mg once daily), followed by a 3 + 3 design (100mg, 300 or 450 mg once daily). Dose-limiting toxicity (DLT) for each cohort was evaluated in the first 28-day cycle. Dose expansion was conducted in selected doses and cohorts. Safety was assessed per CTCAE 5.0 and efficacy was measured according to IWWM-7 for WM, or IWCLL 2018 for CLL/SLL, or Lugano 2014 criteria for other NHL.

Results: At the data cutoff date of 25 May 2023, 38 pts were analyzed, including 26 R/R TCL [12 AITL, 10 PTCL-NOS, 2 ALK negative ALCL, 1 NKTCL 1 EATCL] and 12 R/R BCM [5 DLBCL, 3 FL, 2 WM, 1 CLL, 1 MCL]. 1 pt received 50mg/d, 9 pts received 100mg/d, 14 pts received 200mg/d, 13 pts received 300mg/d and 1pts received 450mg/d. No DLT occurred and MTD was not reached. Pts were with a median age of 61 years (range: 38-78), median ECOG 1 (range: 0-2) and a median of 2 prior systemic therapies (range: 1-5). 35 of 38 pts (92%) experienced a treatment related adverse event (TRAE). TRAEs of ≥Grade 3 (≥5%) were neutropenia (26.3%), pneumonia (7.9%), leukopenia (5.3%), elevated aspartate aminotransferase (5.3%), elevated alanine aminotransferase (5.3%) and herpes zoster (5.3%). 10 pts (26.3%) had dose interruption, 3pts (7.9%) had dose reduction, and 1 pt (2.6%) discontinued from the study due to TRAEs. Of 35 pts available for tumor assessment (26 TCL; 12 BCM), the overall response rate (ORR) was 60% (95%CI: 42.11, 76.13), including 17% (6 pts) complete response (CR), 40% (14 pts) partial response (PR), 3% (1 pt) minor response (MR) and 20% (7 pts) stable disease (SD), contributing to an 80% (95%CI: 63.06, 91.56) disease control rate (DCR). The median time to response (mTTR) was 1.9 months (95%CI: 1.87, 2.10). The median duration of response (mDOR) and median progression free survival (mPFS) had not been reached, with 21 pts (55%) are still on HZ-H08905 treatment. HZ-H08905 exhibited excellent antitumor efficacy in several NHL subtypes, including CLL, DLBCL, FL, MCL, PTCL and WM, with ORR ranged from 50%~100% and DCR ranged from 76%~100%.

Conclusions: These results demonstrated that HZ-H08905 monotherapy was well tolerated and showed promising efficacy in patients with R/R NHL. A Phase 2 R/R PTCL registration study in China is currently planned.

Disclosures: No relevant conflicts of interest to declare.

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