Progression-Free Survival Among Patients With Well-Differentiated or Dedifferentiated Liposarcoma Treated With CDK4 Inhibitor Palbociclib: A Phase 2 Clinical Trial.
Progression-Free Survival Among Patients With Well-Differentiated or Dedifferentiated Liposarcoma Treated With CDK4 Inhibitor Palbociclib: A Phase 2 Clinical Trial.
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DOI：
10.1001/jamaoncol.2016.0264
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发表时间：
2016-07-01
期刊：
影响因子：
28.4
通讯作者：
Tap WD
中科院分区：
文献类型：
--
作者：
Dickson MA;Schwartz GK;Keohan ML;D'Angelo SP;Gounder MM;Chi P;Antonescu CR;Landa J;Qin LX;Crago AM;Singer S;Koff A;Tap WD
超过90%的高分化/去分化脂肪肉瘤（WD/DDLS）具有CDK 4扩增。选择性CDK 4/CDK 6抑制剂Palbociclib可抑制脂肪肉瘤细胞系和异种移植物的生长并诱导衰老。我们之前的II期研究表明，palbociclib治疗（每日200 mg × 14天，每21天一次）在WD/DDLS中产生了临床获益，但存在中度血液学毒性。重要的是要了解palbociclib在新的剂量和给药方案（125 mg/d × 21 d/28 d）下是否会产生临床获益和可管理的毒性。确定接受Palbociclib治疗的WD/DDLS患者12周时的无进展生存期（PFS）。II期、非随机、开放标签临床试验。患者于2011年12月至2014年1月入组，随访至2015年3月。Memorial Sloan Kettering癌症中心的60例晚期WD/DDLS患者，年龄≥ 18岁，根据RECIST 1.1干预措施可测量疾病：患者接受口服palbociclib，每日125 mg，共21天，28天为一个周期。主要终点为PFS。次要终点包括缓解率和毒性。30例患者入组初始队列，30例患者入组扩展队列。中位年龄为61.5岁（范围35-87岁）; 52%为男性;中位ECOG评分为0（范围0-1）。第12周的PFS为57.2%（双侧95% CI：42.4% - 68.8%）。中位PFS为17.9周（双侧95% CI：11.9 - 24.0周）。有1例完全缓解。毒性主要是血液学的，包括中性粒细胞减少（3级：33%，4级：3%），但没有贫血性发热。在晚期WD/DDLS患者中，palbociclib治疗与良好的PFS和偶尔的肿瘤缓解相关。该剂量和方案似乎是有效的，并且可能比200 mg × 14 d具有更小的毒性。
Over 90% of well-differentiated/de-differentiated liposarcomas (WD/DDLS) have CDK4 amplification. The selective CDK4/CDK6 inhibitor palbociclib inhibits growth and induces senescence in liposarcoma cell lines and xenografts. Our prior phase 2 study demonstrated that treatment with palbociclib (200mg daily × 14d every 21d) resulted in clinical benefit in WD/DDLS but moderate hematologic toxicity. It is important to understand whether palbociclib at a new dose and schedule, 125mg daily × 21d every 28d, results in clinical benefit and manageable toxicity. To determine the progression-free survival (PFS) at 12 weeks of patients with WD/DDLS treated with palbociclib. Phase 2, non-randomized, open label clinical trial. Patients enrolled from December 2011 to January 2014 and followed to March 2015. Memorial Sloan Kettering Cancer Center 60 patients with advanced WD/DDLS, age ≥ 18 years, and measurable disease by RECIST 1.1 Interventions: Patients received oral palbociclib at 125mg daily for 21 days in 28-day cycles. Primary endpoint was PFS. Secondary endpoints included response rate and toxicity. 30 patients were enrolled in the initial cohort and 30 more in an expansion cohort. Median age was 61.5 (range 35–87); 52% were male; median ECOG score was 0 (range 0–1). PFS at 12 weeks was 57.2% (2-sided 95% CI: 42.4% – 68.8%). The median PFS was 17.9 weeks (2-sided 95% CI: 11.9 – 24.0 weeks). There was 1 complete response. Toxicity was primarily hematologic and included neutropenia (grade 3: 33%, grade 4: 3%) but no neutropenic fever. In patients with advanced WD/DDLS, treatment with palbociclib was associated with a favorable PFS and occasional tumor response. This dose and schedule appears active and may have less toxicity than 200mg × 14d.