Phase I dose-escalation study of AZD7762, a checkpoint kinase inhibitor, in combination with gemcitabine in US patients with advanced solid tumors.
Phase I dose-escalation study of AZD7762, a checkpoint kinase inhibitor, in combination with gemcitabine in US patients with advanced solid tumors.
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DOI：
10.1007/s00280-014-2380-5
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发表时间：
2014-03
影响因子：
3
通讯作者：
Senderowicz, Adrian
中科院分区：
文献类型：
--
作者：
Sausville, Edward;LoRusso, Patricia;Carducci, Michael;Carter, Judith;Quinn, Mary F.;Malburg, Lisa;Azad, Nilofer;Cosgrove, David;Knight, Richard;Barker, Peter;Zabludoff, Sonya;Agbo, Felix;Oakes, Patricia;Senderowicz, Adrian
AZD7762是一种Chk1激酶抑制剂，可以增加对DNA损伤剂的敏感性，包括吉西他滨。我们评估了AZD7762单药治疗和吉西他滨联合治疗晚期实体瘤患者的安全性。在这项第一阶段研究中，患者在14天磨合周期的第1天和第8天静脉注射AZD7762(周期0；AZD7762单一疗法)，然后在第1天和第8天(每21天)接受AZD7762递增剂量的AZD7762(周期1；联合疗法)加吉西他滨750-1000 mg/m2。AZD7762 6 mg(n=9)、9 mg(n=3)、14 mg(n=6)、21 mg(n=3)、30 mg(n=7)、32 mg(n=6)、40 mg(n=8)联合吉西他滨治疗42例。常见不良反应为乏力[41%(17/42)例]、中性粒细胞/白细胞减少[36%(15/42例)]、贫血/Hb降低[29%(12/42例)]、恶心、发热、丙氨酸氨基转移酶/天冬氨酸氨基转移酶升高[26%(11/42例)]。0周期和1周期分别有19%和52%的患者出现≥3级不良反应。两名患者(均为AZD7762单一治疗)出现心脏剂量限制毒性：3级肌钙蛋白I升高(32毫克)和3级心肌缺血伴胸痛、心电图改变、左室射血分数降低和肌钙蛋白I升高(40毫克)。AZD7762暴露呈线性增加。吉西他滨不影响AZD7762的药代动力学。2例非小细胞肺癌患者肿瘤部分缓解(AZD7762 6 mg/吉西他滨750 mg/m2和AZD7762 9 mg/m2队列)。AZD7762联合吉西他滨1000 mg/m2的最大耐受量为30 mg。尽管由于不可预测的心脏毒性，AZD7762的开发没有进展，但Chk1仍然是一个重要的治疗靶点。
AZD7762 is a Chk1 kinase inhibitor which increases sensitivity to DNA-damaging agents, including gemcitabine. We evaluated the safety of AZD7762 monotherapy and with gemcitabine in advanced solid tumor patients. In this Phase I study, patients received intravenous AZD7762 on days 1 and 8 of a 14-day run-in cycle (cycle 0; AZD7762 monotherapy), followed by AZD7762 plus gemcitabine 750–1,000 mg/m2 on days 1 and 8, every 21 days, in ascending AZD7762 doses (cycle 1; combination therapy). Forty-two patients received AZD7762 6 mg (n = 9), 9 mg (n = 3), 14 mg (n = 6), 21 mg (n= 3), 30 mg (n = 7), 32 mg (n = 6), and 40 mg (n = 8), in combination with gemcitabine. Common adverse events (AEs) were fatigue [41 % (17/42) patients], neutropenia/leukopenia [36 % (15/42) patients], anemia/Hb decrease [29 % (12/42) patients] and nausea, pyrexia and alanine aminotransferase/aspartate aminotransferase increase [26 % (11/42) patients each]. Grade ≥3 AEs occurred in 19 and 52 % of patients in cycles 0 and 1, respectively. Cardiac dose-limiting toxicities occurred in two patients (both AZD7762 monotherapy): grade 3 troponin I increase (32 mg) and grade 3 myocardial ischemia with chest pain, electrocardiogram changes, decreased left ventricular ejection fraction, and increased troponin I (40 mg). AZD7762 exposure increased linearly. Gemcitabine did not affect AZD7762 pharmacokinetics. Two non-small-cell lung cancer patients achieved partial tumor responses (AZD7762 6 mg/gemcitabine 750 mg/m2 and AZD7762 9 mg cohort). The maximum-tolerated dose of AZD7762 in combination with gemcitabine 1,000 mg/m2 was 30 mg. Although development of AZD7762 is not going forward owing to unpredictable cardiac toxicity, Chk1 remains an important therapeutic target.
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影响因子：
8
作者：
Sato, S;Fujita, N;Tsuruo, T
通讯作者：
Tsuruo, T
影响因子：
5.7
作者：
Zabludoff, Sonya D.;Deng, Chun;White, Anne M.
通讯作者：
White, Anne M.
影响因子：
4.8
作者：
Graves, PR;Yu, LJ;Piwnica-Worms, H
通讯作者：
Piwnica-Worms, H
影响因子：
4
作者：
Doganli, Canan;Kjaer-Sorensen, Kasper;Lykke-Hartmann, Karin
通讯作者：
Lykke-Hartmann, Karin
DOI：
10.1158/1078-0432.ccr-09-3277
发表时间：
2010-04-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Mitchell JB;Choudhuri R;Fabre K;Sowers AL;Citrin D;Zabludoff SD;Cook JA
通讯作者：
Cook JA