A randomized, phase 2 trial of docetaxel with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic head and neck squamous cell cancer.
A randomized, phase 2 trial of docetaxel with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic head and neck squamous cell cancer.
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DOI：
10.1016/j.oraloncology.2014.12.013
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发表时间：
2015-04
期刊：
影响因子：
4.8
通讯作者：
Shirai K
中科院分区：
文献类型：
--
作者：
Jimeno A;Bauman JE;Weissman C;Adkins D;Schnadig I;Beauregard P;Bowles DW;Spira A;Levy B;Seetharamu N;Hausman D;Walker L;Rudin CM;Shirai K
磷脂酰肌醇-3激酶（PI 3 K）/丝氨酸-苏氨酸激酶（AKT）/哺乳动物雷帕霉素靶蛋白（mTOR）信号通路在头颈部鳞状细胞癌（HNSCC）中经常发生改变。PX-866是一种口服、不可逆的PI 3 K泛亚型抑制剂。临床前模型显示了与多西他赛的协同作用，1期试验证明了该组合的耐受性。这项随机化II期研究评价了PX-866联合多西他赛治疗晚期难治性HNSCC患者的疗效。接受过至少一种且不超过两种既往全身治疗方案的局部晚期、复发性或转移性HNSCC患者随机（1：1）接受多西他赛（75 mg/m2 IV，每21天一次）联合或不联合PX-866（8 mg PO，每日一次;分别为A组和B组）。主要终点是无进展生存期（PFS）。次要终点包括客观缓解率（RR）、总生存期（OS）、毒性以及生物标志物分析与疗效结局的相关性。85例患者入组。联合治疗组的缓解率无显著改善（14% vs. 5%; P = 0.13）。A组的中位PFS为92天，B组为82天（P = 0.42）。两组的OS无差异（263 vs. 195天; P = 0.62）。3级或3级以上不良事件不常见，但在联合治疗组中腹泻（17% vs. 2%）、恶心（7% vs. 0%）和发热性中性粒细胞减少症（21% vs. 5%）更常见; 3级或3级以上贫血在B组中更常见（7% vs. 27%）。很少观察到PIK 3CA突变或PTEN丢失。在未进行分子预选的晚期难治性HNSCC患者中，将PX-866加至多西他赛并未改善PFS、RR或OS。
The phosphotidylinositol-3 kinase (PI3K)/serine–threonine kinase (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is frequently altered in head and neck squamous cell cancer (HNSCC). PX-866 is an oral, irreversible, pan-isoform inhibitor of PI3K. Preclinical models revealed synergy with docetaxel and a phase 1 trial demonstrated tolerability of this combination. This randomized phase 2 study evaluated PX-866 combined with docetaxel in patients with advanced, refractory HNSCC. Patients with locally advanced, recurrent or metastatic HNSCC who had received at least one and no more than two prior systemic treatment regimens were randomized (1:1) to a combination of docetaxel (75 mg/m2 IV every 21 days) with or without PX-866 (8 mg PO daily; Arms A and B, respectively). The primary endpoint was progression free survival (PFS). Secondary endpoints included objective response rate (RR), overall survival (OS), toxicity, and correlation of biomarker analyses with efficacy outcomes. 85 patients were enrolled. There was a non-significant improvement in response rate in the combination arm (14% vs. 5%; P = 0.13). Median PFS was 92 days in Arm A and 82 days in Arm B (P = 0.42). There was no difference in OS between the two arms (263 vs. 195 days; P = 0.62). Grade 3 or higher adverse events were infrequent, but more common in the combination arm with respect to diarrhea (17% vs. 2%), nausea (7% vs. 0%), and febrile neutropenia (21% vs. 5%); grade 3 or higher anemia was more frequent in arm B (7% vs. 27%). PIK3CA mutations or PTEN loss were infrequently observed. The addition of PX-866 to docetaxel did not improve PFS, RR, or OS in patients with advanced, refractory HNSCC without molecular pre-selection.