HZ-A-018 / Hangzhou HeZheng Pharma - LARVOL DELTA

Design, preclinical evaluation, and multicenter phase 1 clinical study of HZ-A-018 for relapsed or refractory central nervous system lymphoma. (PubMed, Acta Pharm Sin B) - P1/2 | "The Center for Drug Evaluation in China has authorized the initiation of this single-arm Phase II study as a pivotal registrational clinical trial for accelerated approval of HZ-A-018 for monotherapy in patients with r/r PCNSL. This trial has been registered under the identifiers ChiCTR2400091821 at www.chictr.org.cn and CTR20210181 at www.chinadrugtrials.org.cn."

Journal • P1 data • Preclinical • Brain Cancer • CNS Lymphoma • Hematological Malignancies • Lymphoma • Oncology • Primary Central Nervous System Lymphoma

Covalent Bruton's tyrosine kinase inhibitor HZ-A-018 in patients with relapsed or refractory B cell malignancies: A multicenter phase I study. (PubMed, iScience) - "Pharmacokinetics revealed dose-proportional exposure, and median BTK occupancy in peripheral blood mononuclear cells surpassed 95% across all dose levels at steady state. HZ-A-018 demonstrated acceptable safety and antitumor activity, supporting further clinical development."

Journal • P1 data • B Cell Lymphoma • Cardiovascular • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Hypertension • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma • Waldenstrom Macroglobulinemia • BTK

A Phase I/II Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Preliminary Antitumor Activity of BTK Inhibitor HZ-a-018 in Adult Patients with Relapsed and/or Refractory Central Nervous System Lymphoma (ASH 2023) - "All patients had received HD-MTX based chemotherapy, 19 pts (90.5%) had received rituximab and 1 pt had received whole brain radiation therapy (WBRT)... These results demonstrated that HZ-A-018 was efficacious and well-tolerated in CNS lymphoma patients with high CNS penetrating profile. The monotherapy RP2D for R/R PCNSL was determined as 600 mg QD and a phase 2 R/R PCNSL registration study in China is currently planned."

Clinical • P1/2 data • PK/PD data • CNS Lymphoma • Hematological Disorders • Hematological Malignancies • Leukopenia • Lymphoma • Neutropenia • Oncology • Primary Central Nervous System Lymphoma • Primary Vitreoretinal Lymphoma • Secondary Central Nervous System Lymphoma • Thrombocytopenia

Preliminary Efficacy and Safety of Bruton Tyrosine Kinase (BTK) Inhibitor HZ-a-018 in Adult Patients with Relapsed and/or Refractory(R/R)Central Nervous System Lymphoma, Results from the Phase Ia Monotherapy of HZ-a-018-102 Study (ASH 2024) - "The median number of prior antitumor regimens was 1 (range, 1-4), including methotrexate (MTX)-based chemotherapy (100%) and rituximab (92.3%). At the clinical recommended dose of 600mg, patients had achieved great responses, and an improvement of the clinical outcomes, which has the potential to convert to a long survival benefit. A pivotal phase 2 R/R PCNSL registration study in China is currently planned."

Clinical • Monotherapy • P1 data • Cardiovascular • CNS Lymphoma • Hematological Disorders • Hematological Malignancies • Leukopenia • Lymphoma • Neutropenia • Oncology • Primary Central Nervous System Lymphoma • Primary Vitreoretinal Lymphoma • Secondary Central Nervous System Lymphoma

Preliminary Efficacy and Safety of Bruton Tyrosine Kinase (BTK) Inhibitor HZ-a-018 in Adult Patients with Relapsed and/or Refractory (R/R) Central Nervous System Lymphoma or Treatment-Naïve (TN) Central Nervous System Lymphoma, Results from the Phase Ib Combination Part of HZ-a-018-102 Study (ASH 2024) - "The median number of prior antitumor regimens was one (range : 1-3), which included methotrexate (MTX)-based chemotherapy (100%) and rituximab (77.8%)...Two patients completed the four cycles of the induction phase, both achieving PR, resulting in an ORR of 100%.Conclusion : Preliminary data from this ongoing study of HZ-A-018 in combination with HD-MTX showed a tolerable safety profile and encouraging antitumor activity, not only in pretreated patients with R/R PCNSL but also in untreated TN PCNSL patients. The efficacy and safety of HZ-A-018 combination with HD-MTX in TN PCNSL patients will be investigated further in phase III study."

Clinical • P1 data • CNS Lymphoma • Hematological Malignancies • Lymphoma • Oncology • Primary Central Nervous System Lymphoma • Secondary Central Nervous System Lymphoma

A Phase I/II study to evaluate the safety and efficacy of HZ-A-018 in relapsed/refractory primary or secondary central nervous system lymphoma(HZ-A-018-102) (ChiCTR) - P1/2 | N=101 | Recruiting | Sponsor: Beijing TianTan Hospital,Captial Medical University; Hangzhou Healzen Therapeutics Co., Ltd.

New P1/2 trial • CNS Lymphoma • Hematological Malignancies • Lymphoma • Oncology • Primary Central Nervous System Lymphoma • Primary Vitreoretinal Lymphoma • Secondary Central Nervous System Lymphoma • IL10 • IL6

HZ-A-018, a novel inhibitor of Bruton tyrosine kinase, exerts anti-cancer activity and sensitizes 5-FU in gastric cancer cells. (PubMed, Front Pharmacol) - "Mechanismly, the combination of HZ-A-018 and 5-FU remarkably reduced the expression of RRM2, which played an essential role in proliferation and drug sensitivity in gastric cancer cells. In summary, our work demonstrated the stronger anti-cancer activity of HZ-A-018 than ACP-196 in gastric cancer cells, and revealed synergistic effects of HZ-A-018 and 5-FU combination probably through the inhibition of RRM2 via AKT/S6 pathway, thereby providing a promising therapeutic strategy in gastric cancer."

Journal • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BTK • RRM2

HZ-a-018 Is a Highly Selective and Potent BTK Inhibitor with CNS-Penetrating Profile for Central Nervous System Lymphoma (ASH 2022) - "Oral administration of HZ-A-018 can significantly improve survival relative to treatment with vehicle and ibrutinib...The results provide preliminarily evidence that HZ-A-018 offers a new treatment strategy for R/R CNS lymphoma. The efficacy, safety, and tolerability of HZ-A-018 at the RP2D established in the phase I dose escalation and expansion part will be investigated in phase 2."

Brain Cancer • Chronic Lymphocytic Leukemia • CNS Lymphoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma • Waldenstrom Macroglobulinemia