PO.CT01.03 · 临床试验

ruxolitinib 与 CDK4/6 抑制剂 abemaciclib 联合在既往接受过治疗的骨髓纤维化患者中显示出安全性和疗效：一项 I 期研究的结果

The combination of ruxolitinib and the CDK4/6 inhibitor abemaciclib demonstrates safety and efficacy in previously treated myelofibrosis patients: Results of a Phase I study

编号 CT191 展板 13 时间 4/21 09:00–12:00 区域 Section 50 主讲 Brian Chernak, MD

分会场 Phase I Clinical Trials

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作者与单位 Authors & Affiliations

Jan Bewersdorf¹, Andriy Derkach², Amer Zeidan¹, Emily Burton², Katherine Kan², Marissa Guiliani², Jeetayu Biswas², Michael Mauro², Brian Chernak², Tamanna Haque², Nikolai Podoltsev¹, Prithviraj Bose³, Omar Abdel-Wahab², Ross Levine², Raajit Rampal²

¹Yale University, New Haven, CT,²Memorial Sloan Kettering Cancer Center, New York, NY,³MD Anderson Cancer Center, Houston, TX

摘要 Abstract

中文摘要

Janus 激酶（JAK）抑制剂如 ruxolitinib（RUX）可改善骨髓纤维化（MF）患者的疾病相关症状和脾肿大，但不改变潜在的疾病生物学。JAK-STAT 激活突变是 MF 的标志，并通过增加 CDC25A、Cyclin D 和 CDK6 的表达促进 G1/S 期细胞周期转换。检验 JAK 抑制剂与 CDK4/6 抑制剂联合的临床前研究已证明其具有超越单独 JAK 抑制所见的疾病定向生物学效应。我们开展了一项 I 期剂量递增试验（NCT05714072），以评估 RUX 与 abemaciclib（ABE）联合治疗的安全性。接受 RUX 治疗 ≥12 周且对 RUX 反应不佳的 MF 患者，定义为持续放射学脾肿大（≥450 cm3）或 MPN-SAF 总症状评分（TSS ≥5）、血小板 ≥75 × 109/L 且循环或骨髓原始细胞 < 10% 者有资格入组。使用“3+3”设计将 ABE 的三个递增剂量水平（DL）（50 mg、100 mg 和 150 mg 均为每日两次）与固定剂量的 10mg 每日两次或 15mg 每日两次的 RUX 联合。主要终点是安全性和确定联合治疗的推荐 II 期剂量。使用 CTCAE v5.0 对不良事件（AE）进行分级。剂量限制性毒性（DLT）定义为联合治疗前 28 天内与任一研究药物相关的 ≥3 级 AE。次要终点包括：脾体积缩小 25%（SVR25）和 35%（SVR35）以及绝对 MPN-SAF TSS 变化。截至 2025/11/30，入组已完成（入组 11 例患者：DL0 和 DL1 各 3 例，DL2 5 例）。入组时中位年龄为 66 岁[范围：54-76]，8 例患者有 JAK2 V617F，3 例患者有 CALR 突变。所有患者均为 DIPSS 中危/高危疾病。基线疾病特征包括（中位数及范围）：脾体积 1991cm3（531-3587cm3）、MPN-SAF TSS 33（14-47）、WBC 26.4/μL（5-70/μL）、外周血原始细胞 2%（0-7%）、LDH 943 U/L（202-2915 U/L）。中位研究时间为 5 个周期（范围：1-20），数据截止时 7 例患者仍在治疗中。未观察到 DLT 或 AE 相关的治疗中止。除了 3 级贫血（n=2）和中性粒细胞减少（n=1）外，所有 AE 均为 1/2 级，其中腹泻（62.5%）、贫血（25%）和中性粒细胞减少（25%）是最常见的治疗中出现的 AE。数据截止时，11 例接受治疗的患者中有 9 例可评估脾体积和症状反应。9 例可评估患者中有 7 例（78%）达到 SVR25，9 例患者中有 4 例（44%）达到 SVR35，中位 SVR 为 -31%（-55.3% - +19.6%）。9 例患者中有 6 例出现 TSS 降低，绝对 TSS 中位变化为 -4（-13 - +12）。9 例可评估患者中有 7 例的白细胞增多在第 4 周期时消退（中位基线和 C4 WBC 分别为 26.5/μL（13.5-73.3/μL）和 6.8/μL（3.9-22.5/μL））。关于骨髓纤维化、细胞因子和分子反应的数据将在会议上呈现。RUX 与 CDK 4/6 抑制剂 ABE 联合治疗晚期、既往接受过治疗的 MF 患者是安全的，具有令人鼓舞的疗效，并将在既往接受过治疗的 MF 患者中推进至 II 期研究。

查看英文原文 English abstract

Janus kinase (JAK) inhibitors such as ruxolitinib (RUX) improve disease-related symptoms and splenomegaly in patients with myelofibrosis (MF) but do not change the underlying disease biology. JAK-STAT activating mutations are a hallmark of MF and promote G1/S-phase cell cycle transition via increased expression of CDC25A, Cyclin D and CDK6. Preclinical studies testing the combination of JAK inhibitors and CDK4/6 inhibitors have demonstrated disease-directed biologic effects beyond those seen with JAK inhibition alone. We conducted a phase I dose-escalation trial (NCT05714072) to evaluate the safety of combination therapy with RUX and abemaciclib (ABE). Patients with MF treated with RUX for ≥12 weeks and an inadequate response to RUX, defined as either persistent radiographic splenomegaly (≥450 cm 3 ) or MPN-SAF Total Symptom Score (TSS ≥5), platelets ≥75 × 10 9 /L and < 10% circulating or bone marrow blasts were eligible to enroll. Three escalating dose levels (DL) of ABE (50 mg, 100 mg, and 150 mg all BID) were combined with fixed doses of 10mg BID or 15mg BID of RUX using a “3+3” design. The primary endpoint was safety and identification of the recommended phase II dose of the combination. CTCAE v5.0 was used to grade adverse events (AEs). Dose-limiting toxicities (DLTs) were defined as grade ≥3 AEs during the first 28 days of combination therapy if related to either study drug. Secondary endpoints included: spleen volume reduction by 25% (SVR25) and 35% (SVR35) and absolute MPN-SAF TSS change. As of 11/30/2025, enrollment is complete (11 pts enrolled: 3 pts each at DL0 and DL1, 5 at DL2). Median age at enrollment was 66 years [range: 54-76], 8 pts had a JAK2 V617F and 3 pts a CALR mutation. All pts had DIPSS intermediate/high risk disease. Baseline disease characteristics included (medians, with range): spleen volume 1991cm 3 (531-3587cm 3 ), MPN-SAF TSS 33 (14-47), WBC 26.4/µL (5-70/µL), peripheral blood blasts 2% (0-7%), LDH 943 U/L (202-2915 U/L). Median time on study was 5 cycles (range: 1 -20) with 7 patients still on treatment at data cut-off. No DLTs or AE-related treatment discontinuations were observed. Except for grade 3 anemia (n=2) and neutropenia (n=1), all AEs were grade 1/2 with diarrhea (62.5%), anemia (25%), and neutropenia (25%) being the most common treatment-emergent AEs. At data cut-off, 9 of 11 treated pts were evaluable for spleen volume and symptom response. 7 of 9 evaluable patients (78%) achieved SVR25 and 4 of 9 patients (44%) achieved SVR35, with median SVR of -31% (-55.3% - +19.6%). 6 out 9 pts had TSS reduction with median change in absolute TSS of -4 (-13 - +12). Leukocytosis resolved in 7/9 evaluable patients by cycle 4 (median baseline and C4 WBC 26.5/µL (13.5-73.3/µL) and 6.8/µL (3.9-22.5/µL), respectively). Data on bone marrow fibrosis, cytokines and molecular responses will be presented at the meeting. The combination of RUX and the CDK 4/6 inhibitor ABE among pts with advanced, previously treated MF is safe, has encouraging efficacy and will proceed to a phase II study in previously treated MF patients.

利益披露 Disclosure

J. Bewersdorf, None.. A. Derkach, None. A. Zeidan, Abbvie Independent Contractor, ). Akesobio ). Agios ). Amgen ). Astellas ). BioCryst ). Boehringer-Ingelheim ). Celgene/BMS ). Chiesi/Cornerstone biopharma ). Daiichi Sankyo ). Dr. Reddy ). Epizyme ). Faron ). Fibrogen ). GSK ). Glycomimetics ). Genentech ). Gilead ). Geron ). Several others as below Other, AMZ participated in advisory boards, consulted, participated in clinical trial committees, and/or received honoraria from Janssen, Jasper, Karyopharm, Kyowa Kirin, Keros, Kura, Novartis, Notable, Orum, Otsuka, Pfizer, Regeneron, Rigel, Seattle Genetics, Shattuck labs, Schrodinger, Syros, Syndax, Servier, Takeda, Treadwell, Taiho, Vincerx, and Zentalis. E. Burton, None.. K. Kan, None.. M. Guiliani, None.. J. Biswas, None. M. Mauro, Enliven ). Terns Pharmaceuticals ). Pfizer ). Novartis ). Bristol-Myers-Squibb ). Takeda ). B. Chernak, None. T. Haque, Morphosys ). BMS ). Servier ). N. Podoltsev, Incyte ). PharamEssentia ). Sobi ). Constellation Pharmaceuticals ). Aptose ). Abbvie ). Karyopharm ). Syndax ). Novartis ). Amgen ). Takeda ). Cycle Pharmaceuticals ). Cogent Bioscience ). Boehringer Ingelheim ). Daiichi Sankyo ). Astellas ). Sunesis ). Jazz ). Pfizer ). Several ), Other, research funding (to conduct clinical trials, all to the institution) from Astex Pharmaceuticals, CTI biopharma, Celgene, Genentech, AI Therapeutics, Samus Therapeutics, Arog Pharmaceuticals, Kartos Therapeutics, MorphoSys, Aptose Biosciences, Karyopharm Therapeutics, Novartis, and Geron. P. Bose, Ionis ). Blueprint ). Kartos ). Takeda ). Morphic ). PharmaEssentia ). Karyopharm ). Sumitomo ). Novartis ). BMS ). Merck ). Ajax ). Cogent ). Raythera ). CTI Biopharma ). Janssen ). Disc ). Geron ). Jubillant ). Incyte ). O. Abdel-Wahab, Alchemy Other, Equity; Professional Services and Activities (Uncompensated). Array Biopharma ). Astra Zeneca ). Codify Therapeutics, Inc. Equity; Intellectual Property Rights; Professional Services and Activities. Envisagenics Other, Equity; Professional Services and Activities (Uncompensated). Epizyme Other Intellectual Property. Harmonic Discovery Inc. Equity. Janssen Global Services, LLC ). Loxo Oncoloy ). R. Levine, Ajax Therapeutics Equity; Intellectual Property Rights; Professional Services and Activities. Auron Therapeutics Equity. Cure Breast Cancer Foundation Other Intellectual Property. The Mark Foundation for Cancer Research g., Board of Directors, non-salaried role). Qiagen Equity; Professional Services and Activities. R. Rampal, BMS/Celgene ). MorphoSys ). Incyte ). Blueprint ). Zentalis ). Constellation Pharmaceuticals ). Stemline Therapeutics ). Ryvu Therapeutics ). Galecto ). Karyopharm ). Protagonist ). Promedior ). Merck ). CTI Biopharma ). Abbvie ). Servier ). Sierra Oncology ). Sumitomo ). Disc Medicine ). GSK ).

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