PO.CT01.03 · 临床试验
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
作者与单位
摘要 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 ).