A Phase Ib/II, Dose Escalation and Dose Expansion Study of Valemetostat Tosylate (DS-3201b) With Atezolizumab and Bevacizumab in Advanced Hepatocellular Carcinoma (HCC)

This is a phase Ib/II, dose escalation and dose expansion study of valemetostat (DS-3201) with atezolizumab and bevacizumab in patients advanced Hepatocellular carcinoma (HCC) who did not receive prior systemic therapy for advanced HCC.

开始日期2024-10-31

申办/合作机构

The University of Alabama at Birmingham

NCT05879484 / Not yet recruiting临床1/2期IIT

A Phase Ib/II Multicenter Study of Front Line Pembrolizumab and Valemetostat in PD-L1 Positive, HPV-Negative Recurrent/Metastatic Squamous Cell Carcinoma (SCC) of the Head and Neck: The PANTHERAS

Background:
Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer worldwide. These cancers have different causes, with smoking/tobacco exposure and human papilloma virus infection being the most common. . When HNSCC occurs in people who are not infected with HPV, the cancers are more likely to return after treatment; when this happens, overall survival is only about 10 months, thus better treatments are needed.
Objective:
To test a combination treatment using 2 drugs (valemetostat and pembrolizumab) in people with HNSCC. Phase 1b of the study will determine a recommended dose of the 2 drugs and evaluate how safe the combination is.; this will include patients with HPV-positive and HPV-negative HNSCC, as well as squamous cell NSCLC that have progressed on anti-PD-1/anti-PD-L1 therapies.Phase II will determine how effective the combination is and will focus on patients with HPV-negative HNSCC.
Eligibility:
People aged 18 years and older with HPV-negative HNSCC, sinonasal carcinoma of the head and neck, or squamous non-small cell lung cancer (NSCLC).
Design:
Participants will be screened. They will have a physical exam. They will have blood and urine tests and tests of their heart function. They will have imaging scans. They may have a biopsy: A small sample of tissue will be removed from the tumor.
Treatment will be given in 21-day cycles.
Pembrolizumab is administered through a tube attached to a needle inserted into a vein in the arm. Participants will receive pembrolizumab on the first day of each cycle.
Valemetostat is a tablet taken by mouth. Participants will take the tablet once a day at home. They will record the date and time of each dose in a diary. They will also write down any adverse effects they experience.
Participants may remain in the study up to 2 years.

开始日期2024-09-10

申办/合作机构

National Cancer Institute

NCT06244485 / Recruiting临床1期

A Phase 1b, Multicenter, Open-Label Study of Valemetostat Tosylate in Combination With DXd ADCs in Subjects With Solid Tumors

This study will evaluate the safety, tolerability, and efficacy of valemetostat tosylate in combination with DXd ADC in patients with advanced solid tumors.

开始日期2024-02-16

申办/合作机构

Daiichi Sankyo Co., Ltd.

100 项与 Valemetostat Tosilate 相关的临床结果

登录后查看更多信息

100 项与 Valemetostat Tosilate 相关的转化医学

登录后查看更多信息

100 项与 Valemetostat Tosilate 相关的专利（医药）

登录后查看更多信息

项与 Valemetostat Tosilate 相关的文献（医药）

2024-01-01·Clinical pharmacology in drug development

Safety, Tolerability, and Pharmacokinetics of Valemetostat Tablets and the Effect of Food on Valemetostat Pharmacokinetics in Healthy Subjects: Two Phase 1 Studies

Article

作者: Shimizu, Takako ; Ishizuka, Hitoshi ; Tsutsumi, Junko ; Tachibana, Masaya ; Toyama, Kaoru ; Maekawa, Yutaro ; Fukae, Masato ; Shinohara, Sayaka ; Matsuki, Shunji

Abstract:

Valemetostat is an oral, selective inhibitor of enhancer of zeste homolog‐2 (EZH2) and EZH1. In a first‐in‐human phase‐1 trial, valemetostat capsules were well tolerated and clinically active in patients with relapsed/refractory non‐Hodgkin lymphoma. Subsequently, a film‐coated tablet formulation was developed for future clinical trials and commercialization. We report outcomes from 2 phase 1 trials in healthy Japanese participants, assessing the safety, tolerability, and pharmacokinetics (PK) of valemetostat tablets at single ascending doses (50, 100, and 200‐mg), the relative bioavailability between capsules and tablets, and the effect of food (high‐fat or low‐fat meals) on the PK of valemetostat tablets. In the ascending‐dose study, valemetostat maximum plasma concentration (Cmax) and area under the concentration–time curve (AUC) increased dose‐proportionally. Valemetostat plasma PK parameters were similar between the capsule and tablet formulations following a single 200‐mg dose. Administration of valemetostat, 200 mg after a meal, was associated with 50%‐60% lower Cmax, 30%‐50% lower AUC, and a median Tmax delay of 2.5‐3 hours relative to fasted administration. Valemetostat was well tolerated in healthy subjects; treatment‐emergent adverse events were mild (grade 1) in severity. Based on these trials, the tablet formulation of valemetostat is suitable for use in subsequent clinical trials and should be administered under fasted conditions to avoid a negative food effect.

2023-12-07·Japanese journal of clinical oncology

An update on the developments in the treatment of adult T-cell leukemia–lymphoma: current knowledge and future perspective

Review

作者: Makiyama, Junya ; Maruyama, Dai ; Ishitsuka, Kenji ; Nagai, Hirokazu ; Munakata, Wataru

Abstract:

Adult T-cell leukemia–lymphoma is defined as peripheral T-cell lymphoma caused by the human T-cell leukemia virus type I. Adult T-cell leukemia–lymphoma is classified into indolent (favorable chronic or smoldering) or aggressive (acute, lymphoma or unfavorable chronic) types. This review discusses the therapeutic developments for patients with adult T-cell leukemia–lymphoma and unmet issues in treating adult T-cell leukemia–lymphoma. For indolent adult T-cell leukemia–lymphoma, a watchful waiting strategy is recommended until the disease progresses to aggressive adult T-cell leukemia–lymphoma. For aggressive adult T-cell leukemia–lymphoma, multi-agent chemotherapy with or without allogeneic hematopoietic stem cell transplantation has been recommended. However, many patients with adult T-cell leukemia–lymphoma relapse, and their prognosis is poor. Recently, novel agents, including mogamulizumab, lenalidomide, brentuximab vedotin, tucidinostat and valemetostat, have been approved for patients with relapsed or refractory aggressive adult T-cell leukemia–lymphoma, and the combination of mogamulizumab with multi-agent chemotherapy or brentuximab vedotin with cyclophosphamide, doxorubicin and prednisone has been approved for patients with untreated aggressive adult T-cell leukemia–lymphoma in Japan. Importantly, the aging of patients with adult T-cell leukemia–lymphoma has recently been reported, and no standard of care for elderly patients with adult T-cell leukemia–lymphoma has been established. New evidence must be obtained from prospective clinical trials to improve the prognosis of patients with adult T-cell leukemia–lymphoma.

2023-11-01·Clinical and translational science

Effect of itraconazole and fluconazole on the pharmacokinetics of valemetostat: An open‐label, phase I study in healthy subjects

Article

作者: Tsutsumi, Junko ; Ishizuka, Hitoshi ; Shimizu, Takako ; Tachibana, Masaya ; Maekawa, Yutaro ; Matsuki, Shunji ; Kuroda, Kana

Abstract:

Valemetostat tosylate (valemetostat) is an oral, potent, dual inhibitor of enhancer of zeste homolog (EZH) 2 and EZH1 under investigation for the treatment of cancer, including non‐Hodgkin's lymphomas and solid tumors. Itraconazole and fluconazole are antifungal medications often used as typical inhibitors of cytochrome P450 3A (CYP3A [itraconazole and fluconazole]) and P‐glycoprotein (P‐gp [itraconazole]) in drug–drug interaction studies. Valemetostat is a substrate of CYP3A and P‐gp in vitro. This phase I, open‐label, single‐sequence crossover study (JapicCTI‐183902) assessed the pharmacokinetics (PK) of valemetostat when co‐administered with itraconazole (a strong CYP3A inhibitor and P‐gp inhibitor) or fluconazole (a moderate CYP3A inhibitor) in healthy Japanese male participants 20–45 years of age. Participants were equally allocated to receive two doses of valemetostat 25 mg, once alone and once with either itraconazole or fluconazole (400‐mg induction and 200‐mg once daily maintenance). Valemetostat PK parameters with versus without itraconazole or fluconazole were compared using analysis of variance models. Overall, 32 participants were enrolled. Co‐administration with itraconazole increased valemetostat peak concentration (Cmax) by 2.9‐fold and area under the plasma concentration–time curve extrapolated to infinity (AUCinf) by 4.2‐fold compared with valemetostat alone. When co‐administered with fluconazole, the Cmax and AUCinf of valemetostat were each increased by 1.6‐fold. No treatment‐related or grade ≥3 adverse events were reported. Appropriate valemetostat dose reductions are warranted when used concomitantly with strong CYP3A and P‐gp dual inhibitors.

项与 Valemetostat Tosilate 相关的新闻（医药）

2024-09-04

·Business Wire

Daiichi Sankyo Unveils New Research Across Industry-Leading ADC Portfolio in Multiple Cancers at WCLC and ESMO

BASKING RIDGE, N.J.--( BUSINESS WIRE )--Daiichi Sankyo (TSE: 4568) will present new clinical research across its antibody drug conjugate (ADC) portfolio with more than 25 abstracts across multiple types of cancer at the IASLC 2024 World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer (#WCLC24) and the 2024 European Society for Medical Oncology (#ESMO24). Data at WCLC and ESMO showcasing Daiichi Sankyo’s progress towards its goal of creating new standards of care for patients with cancer will include six late-breaking presentations, including two back-to-back presentations during Presidential Symposium 1 featuring datopotamab deruxtecan (Dato-DXd) data at WCLC, and the first presentation of clinical data of DS-9606, a CLDN6 directed modified pyrrolobenzodiazepine (PBD) ADC from Daiichi Sankyo’s second ADC platform, at ESMO. “ New data in lung, breast, gastric, ovarian, endometrial and other cancers from several of our DXd antibody drug conjugates demonstrates how we are making substantial progress toward creating new standards of care for patients with cancer,” said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. “ We look forward to presenting initial clinical data from our second antibody drug conjugate platform at ESMO, which underscores how Daiichi Sankyo is applying our expertise in this technology to craft new innovation for patients.” Progress in Lung Cancer at WCLC and ESMO Late-breaking data at WCLC to be reported during back-to-back presentations at Presidential Symposium 1 will highlight the first interim results from the NeoCOAST-2 phase 2 platform trial evaluating novel perioperative treatment combinations including one arm studying datopotamab deruxtecan with durvalumab and chemotherapy as neoadjuvant treatment followed by adjuvant treatment with durvalumab in patients with resectable early-stage (IIA to IIIB) non-small cell lung cancer (NSCLC). The second Presidential Symposium 1 presentation will feature results from the application of quantitative continuous scoring (QCS), AstraZeneca’s proprietary computational pathology platform, to measure TROP2 in tissue samples collected in the TROPION-Lung01 phase 3 trial that evaluated datopotamab deruxtecan versus docetaxel in patients with locally advanced or metastatic NSCLC treated with at least one prior line of therapy. Overall survival results from TROPION-Lung01 also will be presented as a late-breaking oral presentation. Other data at WCLC include two oral presentations featuring the interim results from the dose optimization part of the IDeate-Lung01 phase 2 trial of ifinatamab deruxtecan (I-DXd) in patients with pretreated extensive-stage small cell lung cancer and results from the ENHERTU ® (trastuzumab deruxtecan) monotherapy arm of the DESTINY-Lung03 phase 1b trial in patients with previously treated HER2 overexpressing unresectable, locally advanced or metastatic NSCLC. A trial-in-progress poster from the NSCLC cohort of a phase 1b trial evaluating the combination of datopotamab deruxtecan and valemetostat, a dual inhibitor of EZH1 and EZH2, in previously treated locally advanced, unresectable or metastatic nonsquamous NSCLC with or without actionable genomic alterations also will be highlighted. At ESMO, additional data in lung cancer being reported include poster presentations featuring a post-hoc analysis of patients with nonsquamous NSCLC by baseline brain metastases status in the TROPION-Lung01 phase 3 trial of datopotamab deruxtecan and intracranial responses seen in the IDeate-Lung01 phase 2 trial of ifinatamab deruxtecan, as well as a trial-in-progress poster featuring the design of the IDeate-Lung03 phase 1b/2 trial of ifinatamab deruxtecan in combination with atezolizumab with or without carboplatin as first-line induction or maintenance therapy in patients with extensive-stage small cell lung cancer. Continued Innovation in Breast Cancer at ESMO Late-breaking presentations in breast cancer at ESMO will include a proffered paper session featuring the primary results of the DESTINY-Breast12 phase 3b/4 trial evaluating ENHERTU in patients with HER2 positive advanced or metastatic breast cancer with or without brain metastases, and two mini oral sessions highlighting patient reported outcomes and determination of the HER2 low and HER2 ultralow status of tumors from the DESTINY-Breast06 phase 3 trial in patients with HR positive, HER2 low and HER2 ultralow metastatic breast cancer. Two proffered paper sessions will highlight results from the ICARUS-BREAST01 phase 2 study of patritumab deruxtecan (HER3-DXd) in patients with HR positive, HER2 negative advanced breast cancer with disease progression following two or more treatments and the investigator-initiated ERICA phase 2 trial evaluating olanzapine-based triplet antiemetic therapy for prevention of nausea and vomiting in combination with ENHERTU in patients with metastatic breast cancer. A mini oral session will feature a supplementary biomarker analysis from the DAISY phase 2 trial evaluating ENHERTU in three cohorts of patients with HER2 expressing metastatic breast cancer and a poster presentation will report on an exploratory biomarker analysis of ENHERTU in patients with HR positive, HER2 low metastatic breast cancer from the DESTINY-Breast04 phase 3 trial. A poster reporting on exposure-adjusted incidence rates of adverse events from the TROPION-Breast01 phase 3 trial of datopotamab deruxtecan versus chemotherapy in patients with previously treated HR positive, HER2 negative metastatic breast cancer also will be featured. Data from Daiichi Sankyo’s Second ADC Platform and DXd ADC Data in Multiple Additional Cancers at ESMO At ESMO, a proffered paper session will highlight preliminary results from a phase 1 trial of DS-9606, a CLDN6 directed modified PBD ADC from Daiichi Sankyo’s second ADC platform, in patients with solid tumors known to express CLDN6. Results from the DESTINY-Gastric03 phase 1b/2 trial evaluating ENHERTU monotherapy or ENHERTU combinations with chemotherapy and/or immunotherapy in patients with HER2 expressing advanced/metastatic gastric or gastroesophageal junction carcinoma also will be presented at a proffered paper session. A mini oral session will feature results from the TROPION-PanTumor03 phase 2 trial of datopotamab deruxtecan in patients with previously treated recurrent endometrial or ovarian cancer. Trial-in-progress poster presentations will highlight the HERTHENA-PanTumor01 phase 2 trial evaluating patritumab deruxtecan in patients with a broad range of solid tumors including bladder, cervical, endometrial, esophageal, gastric, head and neck, melanoma, ovarian, pancreatic and prostate and a phase 1 trial of DS-1471, a CD147 monoclonal antibody, in patients with locally advanced or metastatic solid cancers. Investor Conference Call Following ESMO Daiichi Sankyo will hold a virtual conference call for investors on Tuesday, September 17, 2024 from 8:00 to 9:30 am EDT / 9:00 to 10:30 pm JST. Executives from Daiichi Sankyo will provide an overview of the WCLC and ESMO research data and address questions. WCLC and ESMO Data Highlights Highlights of data from Daiichi Sankyo’s ADC portfolio at WCLC 2024 include: Presentation Title Author Abstract Presentation (PDT) NSCLC NeoCOAST-2: efficacy and safety of neoadjuvant durvalumab (D) + novel anticancer agents + CT and adjuvant D ± novel agents in resectable NSCLC T. Cascone PL02.07 Presidential Symposium 1 Sunday, September 8 8:30 - 10:00 am Normalized membrane ratio of TROP2 by quantitative continuous scoring is predictive of clinical outcomes in TROPION-Lung01 M.C. Garassino PL02.11 Presidential Symposium 1 Sunday, September 8 8:30 - 10:00 am Datopotamab deruxtecan vs docetaxel in patients with non-small cell lung cancer: final overall survival from TROPION-Lung01 J. Sands OA08.03 Oral Presentation Monday, September 9 10:45 - 12:00 pm Trastuzumab deruxtecan monotherapy in pretreated HER2 overexpressing nonsquamous non-small cell lung cancer: DESTINY-Lung03 part 1 D. Planchard OA16.05 Oral Presentation Tuesday, September 10 1:30 - 2:45 pm Valemetostat and datopotamab deruxtecan in previously treated, advanced, unresectable, or metastatic non-squamous NSCLC A. Spira P2.10A.04 Poster Session Sunday, September 8 6:15 - 7:45 pm SCLC Ifinatamab deruxtecan (I-DXd) in extensive-stage small cell lung cancer (ES-SCLC): interim analysis of IDeate-Lung01 C. Rudin OA04.03 Oral Presentation Sunday, September 8 2:00 - 3:15 pm Exposure-response analyses to support phase 3 dose selection for I-DXd (ifinatamab deruxtecan) in extensive stage SCLC patients N. Midde P1.13A.12 Poster Session Sunday, September 8 12:00 - 2:00 pm Highlights of data from Daiichi Sankyo’s ADC portfolio at ESMO 2024 include: Presentation Title Author Abstract Presentation (CEST) NSCLC Datopotamab deruxtecan (Dato-DXd) vs docetaxel in patients with advanced nonsquamous non-small cell lung cancer with brain metastases: results from TROPION-Lung01 E. Pons-Tostivint 1312P Poster Session Saturday, September 14 SCLC Intracranial response in patients with baseline brain metastases and extensive-stage small cell lung cancer treated with ifinatamab deruxtecan (I-DXd) in the IDeate-Lung01 study M. Johnson 1787P Poster Session Saturday, September 14 IDeate-Lung03: a phase 1b/2 study of ifinatamab deruxtecan (I-DXd) plus atezolizumab with or without carboplatin as first line induction or maintenance in patients with extensive stage small cell lung cancer C. Rudin 1812TiP Poster Session Saturday, September 14 BREAST Trastuzumab deruxtecan (T-DXd) in patients with HER2+ advanced/metastatic breast cancer with or without brain metastases: primary results from DESTINY-Breast12 N. Lin LBA18 Proffered Paper Session Friday, September 13 4:00 - 5:30 pm HER2 low and HER2 ultralow status determination in tumors of patients with HR+ mBC in DESTINY-Breast06 G. Viale LBA 21 Mini Oral Session Sunday, September 15 8:30 - 10:00 am Effects of trastuzumab deruxtecan (T-DXd) vs treatment of physician’s choice on patient-reported outcomes in hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2) low/ultralow metastatic breast cancer: results from DESTINY-Breast06 X. Hu LBA22 Mini Oral Session Sunday, September 15 8:30 - 10:00 am Efficacy, safety and biomarker analysis of ICARUS-BREAST01: a phase 2 study of patritumab deruxtecan (HER3-DXd) in patients with HR+/HER2- advanced breast cancer B. Pistilli 340O Proffered Paper Session Friday, September 13 4:00 - 5:30 pm A multicenter, randomized, double-blind, placebo-controlled study of olanzapine-based triplet antiemetic therapy for prevention of delayed and persistent nausea and vomiting induced by trastuzumab deruxtecan in patients with metastatic breast cancer: ERICA study H. Sakai 1816O Proffered Paper Session Saturday, September 14 2:45 - 4:25 pm Unraveling the mechanisms of action and resistance to trastuzumab deruxtecan (T-DXd): supplementary biomarker analyses from DAISY trial F. Mosele 343MO Mini Oral Session Sunday, September 15 8:30 - 10:00 am Exploratory biomarker analysis of trastuzumab deruxtecan versus treatment of physician’s choice in HER2-low, hormone receptor-positive metastatic breast cancer in DESTINY-Breast04 N. Ueno 432P Poster Session Monday, September 16 Exposure-adjusted incidence rates of adverse events from the TROPION-Breast01 study of datopotamab deruxtecan (Dato-DXd) vs investigator’s choice of chemotherapy in patients with pretreated, inoperable/ metastatic HR+/HER2- breast cancer H. Rugo 431P Poster Session Monday, September 16 Treatment patterns and outcomes in HER2 low, HR+ metastatic breast cancer patients previously treated with endocrine therapy in the United States S. Modi 399P Poster Session Monday, September 16 OTHER SOLID TUMORS Preliminary results from a phase 1, first-in-human study of DS-9606a, a Claudin 6 (CLDN6) directed antibody drug conjugate, in patients with tumor types known to express CLDN6 M. Patel 610O Proffered Paper Session Sunday, September 15 2:45 - 4:15 pm Trastuzumab deruxtecan (T-DXd) monotherapy and combinations in patients with advanced/metastatic HER2 positive esophageal, gastric or gastroesophageal junction adenocarcinoma: DESTINY-Gastric03 Y. Janjigian 1401O Proffered Paper Session Saturday, September 14 8:30 - 10:00 am Datopotamab deruxtecan (Dato-DXd) monotherapy in patients with endometrial or ovarian cancer: results from the phase 2 TROPION-PanTumor03 study A. Oaknin 714MO Mini Oral Session Sunday, September 15 2:45 - 4:15 pm HERTHENA-PanTumor01: A global phase 2 trial of HER3-DXd in metastatic solid tumors T. Powles 690TiP Poster Session Saturday, September 14 A phase 1, first-in-human study of DS-1471 in patients with advanced/metastatic solid tumors S. Koganemaru 682TiP Poster Session Saturday, September 14 Claudin-6 expression in primary and recurrent epithelial ovarian cancer: a potential therapeutic target for high-grade serous ovarian cancer D. Shintani 771P Poster Session Saturday, September 14 About the ADC Portfolio of Daiichi Sankyo The Daiichi Sankyo ADC portfolio consists of seven ADCs in clinical development crafted from two distinct ADC technology platforms discovered in-house by Daiichi Sankyo. The ADC platform furthest in clinical development is Daiichi Sankyo’s DXd ADC Technology where each ADC consists of a monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. The DXd ADC portfolio currently consists of ENHERTU, a HER2 directed ADC, and datopotamab deruxtecan (Dato-DXd), a TROP2 directed ADC, which are being jointly developed and commercialized globally with AstraZeneca. Patritumab deruxtecan (HER3-DXd), a HER3 directed ADC, ifinatamab deruxtecan (I-DXd), a B7-H3 directed ADC, and raludotatug deruxtecan (R-DXd), a CDH6 directed ADC, are being jointly developed and commercialized globally with Merck. DS-3939, a TA-MUC1 directed ADC, is being developed by Daiichi Sankyo. The second Daiichi Sankyo ADC platform consists of a monoclonal antibody attached to a modified PBD payload. DS-9606, a CLDN6 directed PBD ADC, is the first of several planned ADCs in clinical development utilizing this platform. Datopotamab deruxtecan, ifinatamab deruxtecan, patritumab deruxtecan, raludotatug deruxtecan, DS-3939 and DS-9606 are investigational medicines that have not been approved for any indication in any country. Safety and efficacy have not been established. About Daiichi Sankyo Daiichi Sankyo is an innovative global healthcare company contributing to the sustainable development of society that discovers, develops and delivers new standards of care to enrich the quality of life around the world. With more than 120 years of experience, Daiichi Sankyo leverages its world-class science and technology to create new modalities and innovative medicines for people with cancer, cardiovascular and other diseases with high unmet medical needs. For more information, please visit www.daiichisankyo.com .

抗体药物偶联物临床结果临床1期临床2期临床3期

2024-07-08

·CPHI制药在线

EZH2抑制剂浅谈：和黄医药他泽司他国内报产，恒瑞医药SHR2554进入3期临床

关注并星标CPHI制药在线 7月4日，Epizyme/和黄医药递交的「氢溴酸他泽司他片」的5.1类进口申请获CDE受理。他泽司他（tazemetostat，Tazverik/达唯珂）是Epizyme开发的一款强效、口服EZH2抑制剂，目前已在美国获批多项适应症：16岁及以上不能完全切除的转移性或局部晚期上皮样肉瘤；至少接受两次全身治疗、EZH2突变阳性的成人复发或难治性(R/R)滤泡性淋巴瘤(FL)；没有令人满意的替代治疗方案的成人R/R FL。 2021年8月，和黄医药与Epizyme公司达成合作，获得他泽司他在大中华区（包括中国大陆、中国香港、中国澳门和中国台湾地区）的开发和商业化授权。2022年5月，他泽司他的临床急需进口药品申请获海南省卫生健康委员会和海南省药品监督管理局批准，用于治疗某些上皮样肉瘤和滤泡性淋巴瘤患者。2024年6月，他泽司他被CDE纳入优先审评，用于EZH2 突变阳性且既往接受过至少两种系统性治疗的复发或难治性滤泡性淋巴瘤成人患者。关于EZH2及其抑制剂进展表观遗传调控因子PcG蛋白（PcG）以多梳抑制复合物(PRC) 的形式参与染色质基因表观遗传负性调控，发挥转录抑制作用。EZH2，即果蝇Zeste增强子同源物2，是多梳蛋白抑制复合体2（PRC2）的核心亚基，具有组蛋白甲基转移酶活性，主要参与组蛋白H3第27位赖氨酸残基（H3K27）的三甲基化修饰，从而发挥转录抑制作用。正常的EZH2表达在细胞密度维持、干细胞自我更新、细胞周期调节以及肿瘤的发生发展中起着重要的作用。研究发现，EZH2 在胃癌、乳腺癌、头颈癌、血液系统恶性肿瘤等多种肿瘤中过表达，且其表达与肿瘤预后存在相关性。 EZH2的过表达被证实可通过多种作用机制来促进癌症的发生和进展，如沉默肿瘤抑制基因的表达、促进参与细胞增殖和存活的基因表达等等。此外，EZH2还被证明可通过调节参与上皮-间质转化的基因表达来促进癌症转移，上皮-间质转化是癌细胞获得迁移和侵袭特性的过程。 EZH2被认为是表观遗传学领域肿瘤药研发的潜力靶点。据不完全统计，全球已批准两款治疗肿瘤的EZH2抑制剂，即第一三共的Ezharmia（valemetostat）、和黄医药/Epizyme的Tazverik （他泽司他）。其中Ezharmia是全球首个获批的EZH1/2双重抑制剂,已在日本获批两项适应症：复发或难治性成人T细胞白血病/淋巴瘤 (ATL)和复发或难治性成人外周T细胞淋巴瘤(PTCL)。此外，目前全球还有多款在研EZH2抑制剂，其中恒瑞医药的SHR2554进展最快，其Vs西达本胺治疗T细胞淋巴瘤的临床试验已进入3期阶段。SHR2554是恒瑞开发的一款新型、高效、选择性口服EZH2抑制剂，可选择性抑制野生型和突变型EZH2酶活性，其复发或难治的外周T细胞淋巴瘤（PTCL）适应症被CDE纳入突破性治疗程序。现有研究结果显示：每天2次350mg给药SHR2554安全性良好，对包括复发难治PTCL和滤泡性淋巴瘤（FL）在内的多种淋巴瘤中显示出良好的抗肿瘤活性；2期推荐剂量下，60.7%的复发难治PTCL获得缓解，预估中位PFS为11.1个月。值得一提的是，2023年2月，恒瑞医药将SHR2554在大中华区（包括中国内地、中国香港、中国澳门及中国台湾）以外的全球开发、生产及商业化权利独家授权给美国Treeline 公司，交易总额超7亿美元，首付款1100万美元。信诺维自主研发的XNW5004处于2期临床，它是一种特异的、靶向EZH2的底物竞争性的小分子药物。临床前试验结果显示：XNW5004单用或与包括PD-1抗体在内的其他药物联用在多种血液瘤和实体瘤肿瘤模型中显示出卓越的抗肿瘤疗效和安全性。在1期临床试验中，XNW5004显示出优于同类EZH2选择性抑制剂的疗效和安全性。2023年4月，信诺维与默沙东就XNW5004联用KEYTRUDA®（帕博利珠单抗）治疗晚期实体瘤达成临床试验合作协议。海和药物与上海药物所合作开发的HH2853也处于2期临床，它是一款强效、高选择性EZH1/2双重小分子抑制剂。临床前研究显示：HH2853能强效抑制细胞内的整体H3K27me3水平，在PTCL、含有EZH2突变的弥漫性大B细胞淋巴瘤（DLBCL）以及含有SWI/SNF复合物亚基突变的多种实体瘤模型中，HH2853均显示强效的体内外抗肿瘤活性，且在同等剂量下，HH2853抗肿瘤活性与tazemetostat相比更优。1期临床数据显示：HH2853具有良好的安全性和药代动力学特征，并在多瘤种中展示出初步疗效。辉瑞开发的PF-06821497处于1期临床，是一款口服、选择性EZH2抑制剂，被开发用于治疗晚期恶性肿瘤，如小细胞肺癌、去势抵抗性前列腺癌、FL。2024年6月，PF-06821497在国内递交的临床试验申请获CDE受理。除了小分子EZH2抑制剂，目前已有企业在开发EZH2降解剂。2024年5月，南京正济医药公布了一类新型EZH2 PROTAC降解剂，用于治疗淋巴瘤和恶性横纹肌瘤。总结相较其他表观遗传学靶点，EZH2已取得小小成功，已上市的2款药物已在淋巴瘤和上皮样肉瘤中得到验证。我国药企也积极开发EZH2抑制剂，其中恒瑞医药SHR2554进展相对较快，并获得国外药企的认可。若顺利，SHR2554或成为下一款获批的EZH2抑制剂。此外，EZH2抑制剂还有望治疗前列腺癌等实体瘤。【智药研习社抗体系列直播预告】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~

优先审批临床3期申请上市临床2期临床结果

2024-06-25

·PipelineReview

EZHARMIA® Approved in Japan as First Dual EZH1 and EZH2 Inhibitor Therapy for Patients with Peripheral T-Cell Lymphoma

TOKYO, Japan I June 24, 2024 I Daiichi Sankyo’s (TSE: 4568) EZHARMIA® (valemetostat tosilate) has been approved in Japan for the treatment of adult patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). EZHARMIA is now the first dual inhibitor of EZH1 and EZH2 to be approved for PTCL after receiving SAKIGAKE designation for this indication. PTCL is a group of rare and often aggressive blood cancers, which represent about 10 to 15% of all non-Hodgkin lymphomas (NHL).1 PTCL is more common in Asia, including in Japan, compared to other parts of the world.2 A majority of patients with PTCL experience disease progression following initial treatment with a multi-drug chemotherapy-based regimen and median overall survival following relapse is approximately 5.8 months.1 The approval of EZHARMIA by the Japan Ministry of Health, Labour and Welfare (MHLW) is based on results of the VALENTINE-PTCL01 phase 2 trial, which were presented at the 2023 American Society of Hematology (ASH) Annual Meeting. In VALENTINE-PTCL01, an objective response rate (ORR) of 43.7% (n=52, 95% CI: 34.6-53.1) was observed for EZHARMIA in 119 efficacy evaluable patients with relapsed or refractory PTCL as assessed by CT-based blinded independent central review (BICR). Seventeen complete responses (CRs) and 35 partial responses (PRs) were observed. Responses were seen across a variety of PTCL subtypes including angioimmunoblastic T-cell lymphoma (AITL), PTCL not otherwise specified (PTCL-NOS) and other PTCL subtypes. “This second indication for EZHARMIA in Japan is an important advance for the treatment of relapsed or refractory peripheral T-cell lymphoma, as new and effective treatment options are needed to improve patient outcomes,” said Toshinori Agatsuma, PhD, Executive Officer, Head of R&D Division in Japan, Daiichi Sankyo. “EZHARMIA exemplifies the innovative research being conducted by Daiichi Sankyo aimed at creating new medicines with potential to change the standard of care for patients with cancer.” The safety profile of EZHARMIA in VALENTINE-PTCL01 was consistent with previous clinical trials. Treatment-related adverse events occurred in 106 of 133 patients (79.7%) with the most common including platelet count decrease (44.4%), anemia (27.1%), dysgeusia (24.8%) and neutrophil count decrease (21.1%). About VALENTINE-PTCL01 Trial VALENTINE-PTCL01 is a global, open-label, single-arm, two-cohort phase 2 study evaluating the efficacy and safety of EZHARMIA in patients with relapsed or refractory PTCL and adult T-cell leukemia/lymphoma (ATLL) who received at least one systemic therapy and were ineligible for hematopoietic stem cell transplant at the time of screening. One cohort enrolled patients with PTCL and a second cohort enrolled patients with ATLL. The primary endpoint of VALENTINE-PTCL01 is ORR assessed by CT-based BICR. Secondary endpoints include duration of response, CR, PR, duration of CR and progression-free survival – all assessed by both BICR and investigator assessment – as well as ORR assessed by investigator, overall survival, safety and pharmacokinetics. Exploratory endpoints include PET-CT-based BICR and biomarker mutational status. Responses were evaluated based on Lugano 2014 response criteria. VALENTINE-PTCL01 enrolled 133 patients at multiple sites in Asia, Europe, North America and Oceania. For more information about this study, visit ClinicalTrials.gov. About Peripheral T-Cell Lymphoma PTCL is a group of rare and often aggressive blood cancers, which represent 10 to 15% of all NHLs.1 Approximately 553,000 new cases of NHL were diagnosed worldwide in 2022.3 There are at least 29 recognized subtypes of PTCL, which occur with significant geographic variation.4 PTCL is more common in Asia, including in Japan, compared to other parts of the world.2 Prognosis of PTCL is generally poor, with a five-year overall survival rate of 32% in AITL and PTCL-NOS, and 7% or lower in certain subtypes.5 A majority of patients with PTCL experience disease progression following initial treatment with a multi-drug chemotherapy-based regimen and median overall survival following relapse is approximately 5.8 months.1 Development of more effective medicines for PTCL continues to be an unmet clinical need, particularly in the relapsed or refractory setting.1 About EZH1 and EZH2 The EZH1 (enhancer of zeste homolog 1) and EZH2 (enhancer of zeste homolog 2) enzymes help regulate the expression of genes involved in maintaining healthy hematopoietic stem cells (immature blood cells).6 Both enzymes are recurrently mutated or overexpressed in hematologic malignancies, including T-cell lymphomas, and research shows they contribute to the silencing of tumor suppressor genes and drive oncogenic growth. 7,8 About EZHARMIA EZHARMIA (valemetostat tosilate) is first-in-class dual inhibitor of EZH1 and EZH2 that was discovered by Daiichi Sankyo. EZHARMIA is approved in Japan for the treatment of patients with relapsed or refractory PTCL and for the treatment of patients with relapsed or refractory ATLL. It is an investigational medicine in all countries outside of Japan. About EZHARMIA Clinical Development Program A global clinical development program is underway for EZHARMIA in hematologic and solid cancers. In addition to VALENTINE-PTCL01, EZHARMIA is being evaluated in the VALYM phase 2 trial in patients with relapsed or refractory B-cell lymphomas, which is being conducted under a strategic research collaboration with the LYSA-LYSARC-CALYM group in Europe, and a phase 1b study in combination with DXd antibody drug conjugates ENHERTU® (trastuzumab deruxtecan) and datopotamab deruxtecan (Dato-DXd) in patients with solid cancers. About Daiichi Sankyo Daiichi Sankyo is an innovative global healthcare company contributing to the sustainable development of society that discovers, develops and delivers new standards of care to enrich the quality of life around the world. With more than 120 years of experience, Daiichi Sankyo leverages its world-class science and technology to create new modalities and innovative medicines for people with cancer, cardiovascular and other diseases with high unmet medical need. For more information, please visit www.daiichisankyo.com . References 1 Bellei et al. haematologica. Vol. 103 No. 7 (2018): July 2018 2 Vose JM et al. J Clin Oncol. 2008;26:4124-4130 3 Global Cancer Observatory. Cancer Fact Sheet. February 2024 4 Liang X et al. Medicine 2021; 2021 Apr 2;100(13): e25194. 5 Vose JM et al. J Clin Oncol. 2008;26:4124-4130 6 Honma D et al. Cancer Sci. 2017 Oct; 108(10): 2069–2078 7 Nakagawa M and Kitabayashi I. Cancer Sci. 2018;109:2342–2348 8 Yamagishi et al. Cell Reports. 2019; 29, 2321–2337

临床2期临床结果上市批准ASH会议临床1期

100 项与 Valemetostat Tosilate 相关的药物交易

登录后查看更多信息

外链

KEGG	Wiki	ATC	Drug Bank
D11551 D16662	-	-	-

研发状态

批准上市

10 条最早获批的记录,

后查看更多信息

适应症	国家/地区	公司	日期
成人T细胞白血病/淋巴瘤	日本	Daiichi Sankyo Co., Ltd.	2022-09-26
外周T细胞淋巴瘤	日本	Daiichi Sankyo Co., Ltd.	2022-09-26

未上市

10 条进展最快的记录,

后查看更多信息

适应症	最高研发状态	国家/地区	公司	日期
滤泡性淋巴瘤	临床2期	美国	Daiichi Sankyo Co., Ltd.	2023-05-19
B细胞淋巴瘤	临床2期	欧盟	Daiichi Sankyo Co., Ltd.	2022-01-30
难治性B细胞淋巴瘤	临床2期	比利时	Daiichi Sankyo Co., Ltd.	2021-06-11
难治性B细胞淋巴瘤	临床2期	法国	Daiichi Sankyo Co., Ltd.	2021-06-11
成人T细胞淋巴瘤/难治性白血病	临床2期	日本	Daiichi Sankyo Co., Ltd.	2019-11-21
晚期恶性实体瘤	临床1期	美国	Daiichi Sankyo Co., Ltd.	2024-02-16
晚期恶性实体瘤	临床1期	日本	Daiichi Sankyo Co., Ltd.	2024-02-16
肝病	临床1期	美国	Daiichi Sankyo, Inc.	2019-11-21
急性淋巴细胞白血病	临床1期	美国	Daiichi Sankyo, Inc.	2017-04-05
急性髓性白血病	临床1期	美国	Daiichi Sankyo, Inc.	2017-04-05

登录后查看更多信息

临床结果

适应症

分期

评价

查看全部结果

研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04703192 (VALENTINE-PTCL01, CTgov)	临床2期	成人T细胞白血病/淋巴瘤 \| 外周T细胞淋巴瘤	155	Valemetostat Tosylate	膚鏇築夢窪糧積鏇構淵(壓範憲蓋繭網蓋餘鏇願) = 夢餘顧繭構鏇餘繭鏇夢廠簾衊鏇淵蓋鹽顧餘鹹 (觸餘窪獵淵壓鬱構選遞, 窪鑰願築齋夢糧淵齋製 ~ 憲鹽獵夢鑰壓窪艱獵鹽) 更多	-	2024-07-22
NCT02732275 (DS3201-A-J101, EHA2024) 人工标引	临床1期	非霍奇金淋巴瘤 EZH2 mutation	90	valemetostat (PTCL)	淵鬱鑰製淵繭網衊製夢(鏇鹽獵範餘蓋網醖鑰願) = 獵餘襯窪觸淵範選構簾獵製廠網鏇衊選觸觸餘 (構遞鹽鹹糧構夢鬱廠遞 ) 更多	积极	2024-05-14
NCT02732275 (DS3201-A-J101, EHA2024) 人工标引	临床1期	非霍奇金淋巴瘤 EZH2 mutation	90	valemetostat (ATLL)	蓋衊衊艱簾鏇夢餘鹹鑰(夢醖製鑰齋醖願繭觸餘) = 觸廠範糧鹽憲網鹽願窪壓簾夢鑰鬱鬱鑰蓋鑰夢 (獵廠夢鏇鏇糧鬱遞壓蓋, 1.4 ~ 38.7) 更多	积极	2024-05-14
NCT03110354 (CTgov)	临床1期	急性髓性白血病 \| 急性淋巴细胞白血病	28	DS-3201b (DS-3201b 150 mg)	遞蓋顧繭構糧廠壓壓鏇(餘鑰壓築鏇簾範淵淵淵) = 範壓淵遞艱築餘築鏇膚積鏇鏇鏇願壓製願簾窪 (鹹醖願醖壓獵鹹獵顧齋, 膚襯遞憲積窪襯鹽餘積 ~ 網積衊鹹壓醖衊餘範淵) 更多	-	2024-01-30
NCT03110354 (CTgov)	临床1期	急性髓性白血病 \| 急性淋巴细胞白血病	28	DS-3201b (DS-3201b 250 mg)	遞蓋顧繭構糧廠壓壓鏇(餘鑰壓築鏇簾範淵淵淵) = 蓋衊遞願壓蓋獵網構積積鏇鏇鏇願壓製願簾窪 (鹹醖願醖壓獵鹹獵顧齋, 築窪選蓋網鹽簾蓋衊簾 ~ 廠觸顧簾顧壓鏇選積鑰) 更多	-	2024-01-30
ASH2023	临床1期	外周T细胞淋巴瘤	71	Valemetostat	積構鹹積築範築鑰齋膚(築築遞衊糧鬱簾積鏇製) = 窪膚窪膚範鑰鏇網鑰願艱築蓋廠積網襯選壓壓 (鑰餘糧蓋願夢顧蓋簾鑰 ) 更多	-	2023-12-09
VALENTINE-PTCL01 (ASH2023)	临床2期	外周T细胞淋巴瘤	133	Valemetostat 200 mg/day	壓網觸衊遞餘繭襯壓積(網製製蓋觸獵鏇鹹鹹憲) = 糧廠鬱遞壓膚餘鹽鹽齋衊夢衊齋醖顧壓網廠選 (壓遞膚願鑰顧製夢鏇願, 34.6 ~ 53.1) 更多	-	2023-12-09
ASH2023	临床1期	难治性B细胞淋巴瘤	19	Valemetostat	憲鹽襯築齋艱鑰膚網觸(遞觸顧願鹹選鹽範夢憲) = The most common TEAEs (any grade) were decreased platelet count (64%), dysgeusia (50%), anemia (43%), decreased neutrophil count (34%), and alopecia (33%) 願醖觸膚願鏇窪窪獵繭 (構獵淵鑰繭製顧齋憲遞 ) 更多	-	2023-12-09
NCT04102150 (VALENTINE-PTCL01, Pubmed) 人工标引	临床2期	成人T细胞白血病/淋巴瘤	25	Valemetostat Tosilate	鹽窪糧齋餘顧鏇廠糧繭(遞選範廠廠網選襯鏇齋) = 餘遞網鬱衊鏇齋鏇願鹽願艱憲積顧築製願繭鹹 (範遞製鑰膚衊鹹艱壓遞, 30.5 ~ 65.9) 更多	积极	2022-09-23
NCT04102150 (VALENTINE-PTCL01, ASH2021) 人工标引	临床2期	成人T细胞淋巴瘤/难治性白血病	25	Valemetostat Tosylate	鹽夢鏇簾憲繭餘鏇願衊(廠醖蓋淵獵糧鏇鑰積鏇) = 築醖積構蓋鑰壓糧願築艱觸鹹鹽網繭築鹹蓋鹹 (窪簾艱醖艱衊醖淵鑰壓, 27.8 ~ 68.7) 更多	积极	2021-11-05
NCT02732275 (phase 1 trial, ICML2021)	临床1期	非霍奇金淋巴瘤 EZH2 \| EZH1	78	Valemetostat tosylate (DS-3201b)	鏇築膚製範蓋網醖憲構(積鹹醖齋夢糧鬱鏇艱衊) = 淵構醖顧鑰鏇窪顧鏇衊鹽廠鏇繭簾壓糧鹽構獵 (糧鹹襯鹽鬱夢鏇鏇鏇餘 ) 更多	积极	2021-06-17