A randomized phase II study of cediranib alone versus cediranib in combination with dasatinib in docetaxel resistant, castration resistant prostate cancer patients.
A randomized phase II study of cediranib alone versus cediranib in combination with dasatinib in docetaxel resistant, castration resistant prostate cancer patients.
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DOI：
10.1007/s10637-014-0106-5
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发表时间：
2014-10
影响因子：
3.4
通讯作者：
Hotte, Sebastien J.
中科院分区：
文献类型：
--
作者：
Spreafico, Anna;Chi, Kim N.;Sridhar, Srikala S.;Smith, David C.;Carducci, Michael A.;Kavsak, Peter;Wong, Tracy S.;Wang, Lisa;Ivy, S. Percy;Mukherjee, Som Dave;Kollmannsberger, Christian K.;Sukhai, Mahadeo A.;Takebe, Naoko;Kamel-Reid, Suzanne;Siu, Lillian L.;Hotte, Sebastien J.
在临床前模型中，血管内皮生长因子受体(VEGFR)和致癌的Src通路的激活与去势耐受前列腺癌(CRPC)的发生有关。头孢拉尼和达沙替尼分别是针对VEGFR和Src的多激酶抑制剂。CRPC中头孢拉尼和达沙替尼的第二阶段研究显示了单药活性。接受多西紫杉醇预处理的CRPC患者被随机分为A组：单用头孢拉尼(20 mg/d)或B组：头孢拉尼(20 mg/d)加达沙替尼(100 mg/d)口服，疗程4周。根据前列腺癌临床试验工作组(PCWG2)，主要终点是12周无进展生存期(PFS)。患者报告的结果使用癌症治疗-前列腺功能评估(FACT-P)和当前疼痛强度(PPI)量表进行评估。对骨转换标志物(BTM)进行相关研究，包括骨碱性磷酸酶(BAP)和血清β-C端肽(B-CTX)。共有22名患者入选，每支手臂11名。两组患者的基线人口学数据相似。A臂(范围1-12)周期数中位数为4，B臂(1-9)周期数中位数为2。12周后，A组PFS为73%，B组为18%(p=0.03)。几个月的中位数PFS(A组对B组)为：5.2对2.6(95%CI：1.9-6.5对1.4-未达到)。A组最常见的3级毒副反应是高血压、贫血和血小板减少，B组出现高血压、腹泻和乏力，A组出现1例与治疗相关的死亡(腹膜后出血)，两组FACT-P和PPI评分均无明显变化。在两个手臂中，BTM和PFS之间没有相关性。尽管数量有限，但这项随机研究表明，联合使用VEGFR和Src靶向治疗并不能改善疗效，而且可能与CRPC患者中单独使用VEGFR靶向治疗的结果更差有关。
Activation of the vascular endothelial growth factor receptor (VEGFR) and the oncogenic Src pathway has been implicated in the development of castration-resistant prostate cancer (CRPC) in preclinical models. Cediranib and dasatinib are multi-kinase inhibitors targeting VEGFR and Src respectively. Phase II studies of cediranib and dasatinib in CRPC have shown single agent activity. Docetaxel-pretreated CRPC patients were randomized to arm A: cediranib alone (20 mg/day) versus arm B: cediranib (20 mg/day) plus dasatinib (100 mg/day) given orally on 4-week cycles. Primary endpoint was 12-week progression-free survival (PFS) as per the Prostate Cancer Clinical Trials Working Group (PCWG2). Patient reported outcomes were evaluated using Functional Assessment of Cancer Therapy- Prostate (FACT-P) and Present Pain Intensity (PPI) scales. Correlative studies of bone turnover markers (BTM), including bone alkaline phosphate (BAP) and serum beta-C telopeptide (B-CTx) were serially assayed. A total of 22 patients, 11 per arm, were enrolled. Baseline demographics were similar in both arms. Median number of cycles =4 in arm A (range 1–12) and 2 in arm B (range 1–9). Twelve-week PFS was 73 % in arm A versus 18 % in arm B (p=0.03). Median PFS in months (arm A versus B) was: 5.2 versus 2.6 (95 % CI: 1.9–6.5 versus 1.4-not reached). Most common grade 3 toxicities were hypertension, anemia and thrombocytopenia in arm A and hypertension, diarrhea and fatigue in arm B. One treatment-related death (retroperitoneal hemorrhage) was seen in arm A. FACT-P and PPI scores did not significantly change in either arm. No correlation between BTM and PFS was seen in either arm. Although limited by small numbers, this randomized study showed that the combination of VEGFR and Src targeted therapy did not result in improved efficacy and may be associated with a worse outcome than VEGFR targeted therapy alone in patients with CRPC.
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SRC抑制剂dasatinib加速了人骨骨髓衍生的间充质基质细胞分化成成骨细胞。
影响因子：
3.8
作者：
Id Boufker H;Lagneaux L;Najar M;Piccart M;Ghanem G;Body JJ;Journé F
通讯作者：
Journé F
影响因子：
6.2
作者：
Araujo JC;Mathew P;Armstrong AJ;Braud EL;Posadas E;Lonberg M;Gallick GE;Trudel GC;Paliwal P;Agrawal S;Logothetis CJ
通讯作者：
Logothetis CJ
影响因子：
3.7
作者：
Garcia-Gomez A;Ocio EM;Crusoe E;Santamaria C;Hernández-Campo P;Blanco JF;Sanchez-Guijo FM;Hernández-Iglesias T;Briñón JG;Fisac-Herrero RM;Lee FY;Pandiella A;San Miguel JF;Garayoa M
通讯作者：
Garayoa M
影响因子：
158.5
作者：
Kantoff, Philip W.;Higano, Celestia S.;Young, J.
通讯作者：
Young, J.
影响因子：
4
作者：
Garcia-Martin, Adela;Acitores, Alicia;Esbrit, Pedro
通讯作者：
Esbrit, Pedro