Introduction CA-4948 is a novel oral small molecule inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4). IRAK4 is part of the Myddosome signaling pathway, and is essential for signaling downstream of toll-like receptors (TLR) and the interleukin-1 receptor (IL-1R) family in immune cells including B lymphocytes. . Dysregulated signaling in these pathways is frequently observed in Non-Hodgkin Lymphomas (NHL), particularly in ABC-subtype of Diffuse Large B-Cell Lymphoma (DLBCL) and Waldenström macroglobulinemia (WM)[1]. Furthermore, IRAK4 activation has recently been identified as a driver of an adaptive resistance mechanism of malignancies [2]. CA-4948 is the first clinical candidate targeting IRAK4 to be evaluated in cancer patients. Here we present Phase I results of CA-4948 in patients with relapsed/refractory hematologic malignancies. Method CA-4948-101 is a phase I trial dose escalation trial with a 3 + 3 design. Seven dosing cohorts were assessed including 50 and 100 mg daily (QD), and 50, 100, 200, 300, or 400 mg twice daily (BID) continuous oral monotherapy in 21-day cycles. Objectives included safety and tolerance (primary), pharmacokinetic (PK), pharmacodynamics (PD) and early efficacy (secondary), and biomarker correlations (exploratory). As of July 2020, 30 patients with relapsed or refractory, NHL have been enrolled, including DLBCL (n=14), FL (n=6), transformed HGBL (n=1), WM (n=3), LPL (n=2), MZL (n=2) and MCL (n=2). Median age is 68.5 (range 50 - 87; 5 female / 25 male). Median number of prior treatments is 4 (range 1 - 8, incl. 5 CAR-T-cell or ASCT treatments). Results CA-4948 has been generally well tolerated. Eight patients were exposed at the highest dose level of 400 mg BID: 2 of 5 DLT-evaluable patients had Grade 3 rhabdomyolysis (DLTs), without complications and reversible after treatment interruption and hydration / analgesic treatment - both subsequently continued treatment at lower doses of 200 or 300 mg BID, respectively. Six patients have tolerated 300 mg BID well without DLT. Most non-hematologic TEAEs were Grade 1 or 2 and manageable, including diarrhea, vomiting, fatigue, dyspnea, and myalgia. Hematologic TEAEs including neutropenia, anemia, thrombocytopenia was mild/moderate and without complications. There were only 4 Grade 3 combined episodes in 18 patients at dose levels ranging between 200 and 400 mg BID without complications (Table 1). Drug discontinuation occurred in only 3 cases for rash, fatigue, and asymptomatic amylase/lipase elevation at lower dose levels. No toxic deaths occurred. Favorable and predictable PK characteristics included rapid absorption with Tmax at 2-3 hours, T1/2 of 6 hours (supporting bid dosing), moderate accumulation, and dose-proportional increases in exposure. Dose proportional PD changes were shown for inflammatory cytokine reductions. Treatment duration ranged between 15 days and 19+ months with sustained disease control. Eight of 28 evaluable patients experienced overall tumor burden decreases of ≥20% from baseline - more at higher doses (Table 2). A WM patient with 6 prior lines of treatment, sustained PR underwent intra-patient dose escalation and had a dose/response relationship and very good treatment tolerance (Figure 1). The median duration at doses of 200 or 300 mg bid was >6 months (range 1-19+; including 3 cases of 11, 14, and 19+ mo.). Downstream pharmacodynamic markers of IRAK4 and molecular characteristics including cell-of-origin will be presented. Conclusion CA-4948 demonstrates good safety profile, desirable pharmacokinetic properties, and preliminary clinical activity. Enrollment is ongoing to support the anticipated RP2D of 300 mg bid. These encouraging results provide clinical validation of IRAK4 as a viable, novel therapeutic target in B-cell malignancies will lead to clinical combinations with synergistic drugs including BTK or BCL2 inhibitors [3] in patients with advanced hematological malignancies. Clinical trial: NCT03328078. References: 1. Treon, S. P. et al., 2012. N Engl J Med, 367: 826-33 2. Melgar, K. et al., 2019. Sci Transl Med, 11: eaaw8828 3. Booher R, Grayson D., 2019. Waldenstrom Roadmap Symposium, www.Curis.com Disclosures Nowakowski: Curis: Consultancy; MorphoSys: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Kite: Consultancy; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; Kymera: Consultancy; Seattle Genetics: Consultancy. Leslie:TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Speakers Bureau; Epizyme: Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Honoraria, Speakers Bureau; KitePharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; Celgene: Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Younes:Curis: Consultancy; Daiichi Sankyo: Consultancy; HCM: Consultancy; Epizyme: Consultancy; Takeda: Consultancy; Novartis: Consultancy; BioPath: Consultancy; BMS: Consultancy; Janssen: Consultancy; AstraZeneca: Current Employment. Lunning:Gilead: Consultancy, Honoraria; Curis: Research Funding; Beigene: Consultancy, Honoraria; Aeratech: Consultancy, Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria, Research Funding; Kite: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Legend: Consultancy; ADC Therapeutics: Consultancy; Acrotech: Consultancy; Verastem: Consultancy, Honoraria; TG Therapeutics: Research Funding. Patel:Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Kite: Consultancy; Genentech: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau. Landsburg:Takeda: Research Funding; Seattle Genetics: Speakers Bureau; Morphosys: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Curis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Triphase: Research Funding. Tun:Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Mundipharma: Research Funding; Curis: Research Funding; TG Therapeutics: Research Funding; Acrotech: Research Funding; DTRM Biopharma: Research Funding.

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CA-4948（一种 IRAK4 抑制剂）用于治疗复发性或难治性血液系统恶性肿瘤患者的安全性、药代动力学和活性：1 期研究结果

简介 CA-4948 是一种新型口服小分子白介素 1 受体相关激酶 4 (IRAK4) 抑制剂。IRAK4 是 Myddosome 信号通路的一部分，对于包括 B 淋巴细胞在内的免疫细胞中 toll 样受体 (TLR) 和白细胞介素-1 受体 (IL-1R) 家族的下游信号传导至关重要。. 在非霍奇金淋巴瘤 (NHL) 中经常观察到这些通路中的信号失调，特别是在弥漫性大 B 细胞淋巴瘤 (DLBCL) 的 ABC 亚型和瓦尔登斯特伦巨球蛋白血症 (WM) 中[1]。此外，IRAK4 激活最近已被确定为恶性肿瘤适应性抵抗机制的驱动因素 [2]。CA-4948 是第一个在癌症患者中评估的靶向 IRAK4 的临床候选药物。在这里，我们展示了 CA-4948 在复发/难治性血液系统恶性肿瘤患者中的 I 期结果。方法 CA-4948-101 是采用 3 + 3 设计的 I 期试验剂量递增试验。评估了 7 个剂量组，包括每天 50 和 100 毫克 (QD)，以及 50、100、200、300 或 400 毫克每天两次 (BID) 在 21 天的周期中的连续口服单一疗法。目标包括安全性和耐受性（主要）、药代动力学（PK）、药效学（PD）和早期疗效（次要）以及生物标志物相关性（探索性）。截至2020年7月，已纳入30例复发或难治性NHL患者，包括DLBCL（n=14）、FL（n=6）、转化HGBL（n=1）、WM（n=3）、LPL（n =2)、MZL (n=2) 和 MCL (n=2)。中位年龄为 68.5 岁（范围 50 - 87；5 名女性 / 25 名男性）。先前治疗的中位数为 4（范围 1 - 8，包括 5 CAR-T 细胞或 ASCT 治疗）。结果 CA-4948 的耐受性普遍良好。8 名患者接受了 400 mg BID 的最高剂量水平：5 名可进行 DLT 评估的患者中有 2 名患有 3 级横纹肌溶解症 (DLT)，没有并发症，并且在治疗中断和补水/镇痛治疗后可逆 - 随后均以较低剂量继续治疗分别为 200 或 300 毫克 BID。六名患者在没有 DLT 的情况下很好地耐受了 300 mg BID。大多数非血液学 TEAE 为 1 级或 2 级且可控，包括腹泻、呕吐、疲劳、呼吸困难和肌痛。包括中性粒细胞减少、贫血、血小板减少在内的血液学 TEAE 为轻度/中度且无并发症。在 200 至 400 mg BID 的剂量水平下，18 名患者中只有 4 次 3 级联合发作，没有并发症（表 1）。仅 3 例因皮疹、疲劳和低剂量水平的无症状淀粉酶/脂肪酶升高而停药。没有发生中毒死亡。有利且可预测的 PK 特征包括 Tmax 在 2-3 小时时的快速吸收，T1/2 为 6 小时（支持每天两次给药），中度蓄积，以及与剂量成比例的暴露增加。显示炎症细胞因子减少的剂量比例 PD 变化。治疗持续时间为 15 天至 19 个月以上，疾病持续得到控制。28 名可评估患者中的 8 名经历了与基线相比 ≥20% 的总体肿瘤负荷降低 - 更高剂量时更多（表 2）。一位曾接受过 6 条治疗的 WM 患者，持续 PR 经历了患者内剂量递增，并具有剂量/反应关系和非常好的治疗耐受性（图 1）。200 或 300 mg bid 剂量的中位持续时间大于 6 个月（范围 1-19+；包括 11、14 和 19+ 个月的 3 例）。将介绍 IRAK4 的下游药效学标志物和包括细胞来源在内的分子特征。结论 CA-4948 表现出良好的安全性、理想的药代动力学特性和初步的临床活性。正在进行注册以支持预期的 RP2D 300 mg bid。这些令人鼓舞的结果提供了 IRAK4 作为可行的临床验证，B 细胞恶性肿瘤的新治疗靶点将导致在晚期血液恶性肿瘤患者中与协同药物（包括 BTK 或 BCL2 抑制剂 [3]）进行临床组合。临床试验：NCT03328078。参考文献： 1. Treon, SP 等人，2012. N Engl J Med, 367: 826-33 2. Melgar, K. 等人, 2019. Sci Transl Med, 11: eaaw8828 3. Booher R, Grayson D. , 2019。Waldenstrom 路线图研讨会，www.Curis.com 披露 Nowakowski：Curis：咨询；MorphoSys：咨询、研究经费；Celgene/BMS：咨询、研究经费；风筝：咨询；Ryvu：咨询、实体董事会或咨询委员会的成员资格；NanoString：研究经费；Kymera：咨询；西雅图遗传学：咨询。Leslie：TG Therapeutics：咨询、成为实体董事会或咨询委员会的成员；艾伯维（AbbVie）：咨询、实体董事会或咨询委员会的成员资格；ADC 疗法：咨询、成为实体董事会或咨询委员会的成员；拜耳：咨询、实体董事会或咨询委员会的成员资格；Karyopharm：酬金，发言人局；Epizyme：Honoraria，发言人局；阿斯利康（AstraZeneca）：咨询、成为实体董事会或咨询委员会的成员、发言人局；Janssen：咨询，实体董事会或咨询委员会的成员资格，发言人局；Pharmacyclics：咨询、实体董事会或咨询委员会的成员资格、发言人局；百济神州：酬金，发言人局；KitePharma：咨询、成为实体董事会或咨询委员会的成员、发言人局；BMS：演讲者局；新基（Celgene）：发言人局；西雅图遗传学：咨询，实体董事会或咨询委员会的成员资格，发言人局。Younes：Curis：咨询；第一三共：咨询；HCM：咨询；Epizyme：咨询；武田：咨询；诺华：咨询；BioPath：咨询；BMS：咨询；杨森：咨询；阿斯利康：目前的就业。Lunning：Gilead：咨询，酬金；Curis：研究经费；贝金：咨询，酬金；Aeratech：咨询，酬金；Bristol Meyers Squibb：咨询、酬金、研究经费；风筝：咨询，酬金；Karyopharm：咨询，酬金；诺华：咨询，酬金；杨森：咨询，酬金；阿斯利康：咨询，酬金；图注：咨询；ADC Therapeutics：咨询；Acrotech：咨询；Verastem：咨询，酬金；TG Therapeutics：研究经费。Patel：Celgene/BMS：咨询、实体董事会或咨询委员会的成员资格；适应性生物技术：咨询；百济神州：咨询；Pharmacyclics：顾问，演讲者局；阿斯利康：顾问、研究经费、演讲者局；风筝：咨询；基因泰克：顾问、发言人局；Janssen：顾问，发言人局。Landsburg：武田：研究经费；西雅图遗传学：演讲者局；Morphosys：实体董事会或咨询委员会的成员；Karyopharm：实体董事会或咨询委员会的成员；Curis：咨询，实体成员资格 s 董事会或咨询委员会，研究经费；Celgene：实体董事会或咨询委员会的成员；三相：研究经费。敦：百时美施贵宝：研究经费；新基（Celgene）：研究经费；萌蒂制药：研究经费；Curis：研究经费；TG Therapeutics：研究经费；Acrotech：研究经费；DTRM 生物制药：研究经费。