Phase I/II results of ceralasertib as monotherapy or in combination with acalabrutinib in high-risk relapsed/refractory chronic lymphocytic leukemia.
Phase I/II results of ceralasertib as monotherapy or in combination with acalabrutinib in high-risk relapsed/refractory chronic lymphocytic leukemia.
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DOI：
10.1177/20406207231173489
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发表时间：
2023
影响因子：
3.4
通讯作者：
Munir, Talha
中科院分区：
文献类型：
--
作者：
Jurczak, Wojciech;Elmusharaf, Nagah;Fox, Christopher P.;Townsend, William;Paulovich, Amanda G.;Whiteaker, Jeffrey R.;Krantz, Fanny;Wun, Chuan-Chuan;Parr, Graeme;Sharma, Shringi;Munugalavadla, Veerendra;Manwani, Richa;Dean, Emma;Munir, Talha
复发/难治性（R/R）慢性淋巴细胞白血病（CLL）患者的治疗选择有限。Ceralasertib是一种选择性共济失调性血管扩张和rad -3相关蛋白（ATR）抑制剂，在TP53和atm缺陷CLL细胞中显示出与布鲁顿酪氨酸激酶（BTK）抑制剂的协同临床前活性。阿卡拉布替尼是一种选择性BTK抑制剂，被批准用于治疗慢性淋巴细胞白血病。目的：评价ceralasertib±acalabrutinib在R/R CLL中的疗效。非随机、开放标签的I/II期研究。在A组中，患者接受ceralasertib单药治疗160 mg，每日两次（BID）连续（队列1）或2周开/2周停（队列2）。在B组中，患者连续接受阿卡拉布替尼100 mg BID（第1周期），随后联合ceralasertib 160 mg BID，从第2周期开始1周开/3周停。共同的主要目标是安全性和药代动力学。疗效是次要目标。11例患者接受治疗[A组，n = 8（队列1，n = 5；队列2，n = 3）；B组，n = 3 (acalabrutinib + ceralasertib, n = 2；仅acalabrutinib， n = 1)]。A组和B组ceralasertib的中位暴露持续时间分别为3.5和7.2个月，B组acalabrutinib的中位暴露持续时间为15.9个月。A组中最常见的小于或等于3级治疗出现的不良事件（teae）是贫血（75%）和血小板减少（63%），具有4级血小板减少的四种剂量限制性毒性（dlt）。在b组中没有发生小于3级的teae或dlt， Ceralasertib的血浆浓度在作为单一治疗或联合治疗时相似。在A组中位15.1个月的随访中，未观察到任何反应，中位无进展生存期（PFS）为3.8个月，中位总生存期（OS）为16.9个月。B组中位随访17.2个月，总有效率为100%，中位PFS和OS均未达到。Ceralasertib单独显示有限的临床益处。Acalabrutinib + ceralasertib在R/R CLL患者中具有可耐受的初步活性，但由于样本量小，研究结果尚无定论。NCT03328273
Patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) have limited treatment options. Ceralasertib, a selective ataxia telangiectasia and Rad-3-related protein (ATR) inhibitor, demonstrated synergistic preclinical activity with a Bruton tyrosine kinase (BTK) inhibitor in TP53- and ATM-defective CLL cells. Acalabrutinib is a selective BTK inhibitor approved for treatment of CLL. To evaluate ceralasertib ± acalabrutinib in R/R CLL. Nonrandomized, open-label phase I/II study. In arm A, patients received ceralasertib monotherapy 160 mg twice daily (BID) continuously (cohort 1) or 2 weeks on/2 weeks off (cohort 2). In arm B, patients received acalabrutinib 100 mg BID continuously (cycle 1), followed by combination treatment with ceralasertib 160 mg BID 1 week on/3 weeks off from cycle 2. Co-primary objectives were safety and pharmacokinetics. Efficacy was a secondary objective. Eleven patients were treated [arm A, n = 8 (cohort 1, n = 5; cohort 2, n = 3); arm B, n = 3 (acalabrutinib plus ceralasertib, n = 2; acalabrutinib only, n = 1)]. Median duration of exposure was 3.5 and 7.2 months for ceralasertib in arms A and B, respectively, and 15.9 months for acalabrutinib in arm B. Most common grade ⩾3 treatment-emergent adverse events (TEAEs) in arm A were anemia (75%) and thrombocytopenia (63%), with four dose-limiting toxicities (DLTs) of grade 4 thrombocytopenia. No grade ⩾3 TEAEs or DLTs occurred in arm B. Ceralasertib plasma concentrations were similar when administered as monotherapy or in combination. At median follow-up of 15.1 months in arm A, no responses were observed, median progression-free survival (PFS) was 3.8 months, and median overall survival (OS) was 16.9 months. At median follow-up of 17.2 months in arm B, overall response rate was 100%, and median PFS and OS were not reached. Ceralasertib alone showed limited clinical benefit. Acalabrutinib plus ceralasertib was tolerable with preliminary activity in patients with R/R CLL, though findings are inconclusive due to small sample size. NCT03328273
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DOI：
10.3390/molecules27082491
发表时间：
2022-04-12
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
通讯作者：
--
影响因子：
20.3
作者：
Hallek, Michael;Cheson, Bruce D.;Kipps, Thomas J.
通讯作者：
Kipps, Thomas J.
影响因子：
5.2
作者：
Whiteaker JR;Wang T;Zhao L;Schoenherr RM;Kennedy JJ;Voytovich U;Ivey RG;Huang D;Lin C;Colantonio S;Caceres TW;Roberts RR;Knotts JG;Kaczmarczyk JA;Blonder J;Reading JJ;Richardson CW;Hewitt SM;Garcia-Buntley SS;Bocik W;Hiltke T;Rodriguez H;Harrington EA;Barrett JC;Lombardi B;Marco-Casanova P;Pierce AJ;Paulovich AG
通讯作者：
Paulovich AG
影响因子：
8.8
作者：
Jones GN;Rooney C;Griffin N;Roudier M;Young LA;Garcia-Trinidad A;Hughes GD;Whiteaker JR;Wilson Z;Odedra R;Zhao L;Ivey RG;Howat WJ;Harrington EA;Barrett JC;Ramos-Montoya A;Lau A;Paulovich AG;Cadogan EB;Pierce AJ
通讯作者：
Pierce AJ
影响因子：
20.3
作者：
Kwok, Marwan;Davies, Nicholas;Stankovic, Tatjana
通讯作者：
Stankovic, Tatjana