Phase I trial of the combination of flavopiridol and imatinib mesylate in patients with Bcr-Abl+ hematological malignancies.
Phase I trial of the combination of flavopiridol and imatinib mesylate in patients with Bcr-Abl+ hematological malignancies.
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DOI：
10.1007/s00280-012-1839-5
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发表时间：
2012-06
影响因子：
3
通讯作者：
Grant, Steven
中科院分区：
文献类型：
--
作者：
Bose, Prithviraj;Perkins, Edward B.;Honeycut, Connie;Wellons, Martha D.;Stefan, Tammy;Jacobberger, James W.;Kontopodis, Emmanouil;Beumer, Jan H.;Egorin, Merrill J.;Imamura, Chiyo K.;Figg, W. Douglas, Sr.;Karp, Judith E.;Koc, Omer N.;Cooper, Brenda W.;Luger, Selina M.;Colevas, A. Dimitrios;Roberts, John D.;Grant, Steven
关键词：
伊马替尼是Bcr-Abl酪氨酸激酶的抑制剂;然而，耐药是常见的。Flavopiridol是一种细胞周期蛋白依赖性激酶（CDK）抑制剂，通过抑制转录下调短寿命抗凋亡蛋白。在临床前研究中，flavopiridol协同伊马替尼诱导细胞凋亡。我们在Bcr-Abl+恶性肿瘤患者中研究了这种新的联合方案。在一项I期剂量递增研究中，伊马替尼每日口服给药，flavopiridol每周1小时静脉输注给药，每四周给药3周。成人慢性粒细胞白血病（CML）或费城染色体阳性（Ph+）急性白血病符合条件。根据外周血和骨髓原始细胞计数将患者分为两个层。主要目的是确定联合用药的推荐II期剂量（RPTD）。还进行了相关的药代动力学和药效学研究。共有21例患者接受了研究治疗。在第二代Bcr-Abl酪氨酸激酶抑制剂（TKI）获批后，在研究结束前评价了4个剂量水平。5名患者有反应，包括4名持续反应。4例患者病情稳定。除一名应答者外，所有患者和所有病情稳定的患者既往均接受过伊马替尼治疗。1例患者完全缓解持续30个月。监测磷酸化-Bcr/Abl、-Stat 5和Mcl-1表达的变化。未观察到重大药代动力学相互作用。这是第一项评估CDK抑制剂和TKI联合治疗人体的研究。flavopiridol和伊马替尼的组合是可耐受的，并产生令人鼓舞的反应，包括在一些伊马替尼耐药疾病患者中。
Imatinib is an inhibitor of the Bcr-Abl tyrosine kinase; however, resistance is common. Flavopiridol, a cyclin-dependent kinase (CDK) inhibitor, down-regulates short-lived anti-apoptotic proteins via inhibition of transcription. In preclinical studies, flavopiridol synergizes with imatinib to induce apoptosis. We investigated this novel combination regimen in patients with Bcr-Abl+ malignancies. In a phase I dose-escalation study, imatinib was administered orally daily, and flavopiridol by 1-hour intravenous infusion weekly for three weeks every four weeks. Adults with chronic myelogenous leukemia (CML) or Philadelphia chromosome-positive (Ph+) acute leukemias were eligible. Patients were divided into two strata based on peripheral blood and bone marrow blast counts. The primary objective was to identify the recommended phase II doses (RPTD) for the combination. Correlative pharmacokinetic and pharmacodynamic studies were also performed. A total of 21 patients received study treatment. Four dose levels were evaluated before the study was closed following the approval of the second generation Bcr-Abl tyrosine kinase inhibitors (TKIs). Five patients responded, including four sustained responses. Four patients had stable disease. All but one responder, and all patients with stable disease had previously been treated with imatinib. One patient had a complete response sustained for 30 months. Changes in expression of phospho-Bcr/Abl, -Stat5, and Mcl-1 were monitored. No major pharmacokinetic interaction was observed. This is the first study to evaluate the combination of a CDK inhibitor and a TKI in humans. The combination of flavopiridol and imatinib is tolerable and produces encouraging responses, including in some patients with imatinib-resistant disease.
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影响因子：
2.7
作者：
Karp JE;Blackford A;Smith BD;Alino K;Seung AH;Bolaños-Meade J;Greer JM;Carraway HE;Gore SD;Jones RJ;Levis MJ;McDevitt MA;Doyle LA;Wright JJ
通讯作者：
Wright JJ
影响因子：
4
作者：
Dai, Y;Grant, S
通讯作者：
Grant, S
影响因子：
20.3
作者：
Byrd, John C.;Lin, Thomas S.;Grever, Michael R.
通讯作者：
Grever, Michael R.
影响因子：
4.8
作者：
Ilaria, RL;VanEtten, RA
通讯作者：
VanEtten, RA
影响因子：
20.3
作者：
Karp, Judith E.;Smith, B. Douglas;Rudek, Michelle A.
通讯作者：
Rudek, Michelle A.