Phase I First-in-Human Dose Escalation Study of the oral SF3B1 modulator H3B-8800 in myeloid neoplasms.
Phase I First-in-Human Dose Escalation Study of the oral SF3B1 modulator H3B-8800 in myeloid neoplasms.
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DOI：
10.1038/s41375-021-01328-9
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发表时间：
2021-12
期刊：
影响因子：
11.4
通讯作者：
Platzbecker U
中科院分区：
文献类型：
--
作者：
Steensma DP;Wermke M;Klimek VM;Greenberg PL;Font P;Komrokji RS;Yang J;Brunner AM;Carraway HE;Ades L;Al-Kali A;Alonso-Dominguez JM;Alfonso-Piérola A;Coombs CC;Deeg HJ;Flinn I;Foran JM;Garcia-Manero G;Maris MB;McMasters M;Micol JB;De Oteyza JP;Thol F;Wang ES;Watts JM;Taylor J;Stone R;Gourineni V;Marino AJ;Yao H;Destenaves B;Yuan X;Yu K;Dar S;Ohanjanian L;Kuida K;Xiao J;Scholz C;Gualberto A;Platzbecker U
我们在MDS、CMML或AML患者中进行了H3 B-8800（一种结合剪接因子3B 1（SF 3B 1）的口服小分子）的I期临床试验。在84例入组患者（42例MDS、4例CMML和38例AML）中，62例患者在入组研究时依赖红细胞（RBC）输注。剂量递增队列检查了两种每日一次给药方案：方案I（给药5天/停药9天，研究的剂量范围为1-40 mg，n = 65）和方案II（给药21天/停药7天，7-20 mg，n = 19）; 27例患者接受治疗≥180天。最常见的治疗相关、治疗后出现的不良事件包括腹泻、恶心、疲乏和呕吐。没有观察到符合IWG标准的完全或部分反应;然而，在9名在研究入组时依赖输血的患者中观察到RBC无输血间隔>56天（15%）。在15例SF 3B 1错义突变的MDS患者中，有5例发生了RBC输注不依赖性（TI）。在发生RBC TI的MDS患者中观察到跨膜蛋白14 C（TMEM 14 C）（一种编码线粒体卟啉转运蛋白的SF 3B 1剪接靶点）异常转录物的治疗前表达升高。总之，H3 B-8800治疗与生物标志物定义的MDS子集中的大多数低级别TAE和诱导RBC TI相关。
We conducted a phase I clinical trial of H3B-8800, an oral small molecule that binds Splicing Factor 3B1 (SF3B1), in patients with MDS, CMML, or AML. Among 84 enrolled patients (42 MDS, 4 CMML and 38 AML), 62 were red blood cell (RBC) transfusion dependent at study entry. Dose escalation cohorts examined two once-daily dosing regimens: schedule I (5 days on/9 days off, range of doses studied 1–40 mg, n = 65) and schedule II (21 days on/7 days off, 7–20 mg, n = 19); 27 patients received treatment for ≥180 days. The most common treatment-related, treatment-emergent adverse events included diarrhea, nausea, fatigue, and vomiting. No complete or partial responses meeting IWG criteria were observed; however, RBC transfusion free intervals >56 days were observed in nine patients who were transfusion dependent at study entry (15%). Of 15 MDS patients with missense SF3B1 mutations, five experienced RBC transfusion independence (TI). Elevated pre-treatment expression of aberrant transcripts of Transmembrane Protein 14C (TMEM14C), an SF3B1 splicing target encoding a mitochondrial porphyrin transporter, was observed in MDS patients experiencing RBC TI. In summary, H3B-8800 treatment was associated with mostly low-grade TAEs and induced RBC TI in a biomarker-defined subset of MDS.
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影响因子：
10.5
作者：
Finci LI;Zhang X;Huang X;Zhou Q;Tsai J;Teng T;Agrawal A;Chan B;Irwin S;Karr C;Cook A;Zhu P;Reynolds D;Smith PG;Fekkes P;Buonamici S;Larsen NA
通讯作者：
Larsen NA
影响因子：
82.9
作者：
Seiler M;Yoshimi A;Darman R;Chan B;Keaney G;Thomas M;Agrawal AA;Caleb B;Csibi A;Sean E;Fekkes P;Karr C;Klimek V;Lai G;Lee L;Kumar P;Lee SC;Liu X;Mackenzie C;Meeske C;Mizui Y;Padron E;Park E;Pazolli E;Peng S;Prajapati S;Taylor J;Teng T;Wang J;Warmuth M;Yao H;Yu L;Zhu P;Abdel-Wahab O;Smith PG;Buonamici S
通讯作者：
Buonamici S
影响因子：
1.9
作者：
STORER, BE
通讯作者：
STORER, BE
影响因子：
45.3
作者：
Ostgard, Lene Sofie Granfeldt;Medeiros, Bruno C.;Norgaard, Jan Maxwell
通讯作者：
Norgaard, Jan Maxwell
影响因子：
3.4
作者：
Hong, D. S.;Kurzrock, R.;LoRusso, P.
通讯作者：
LoRusso, P.