Randomized, Phase II Study of the Thrombospondin-1-Mimetic Angiogenesis Inhibitor ABT-510 in Patients With Advanced Soft Tissue Sarcoma
Randomized, Phase II Study of the Thrombospondin-1-Mimetic Angiogenesis Inhibitor ABT-510 in Patients With Advanced Soft Tissue Sarcoma
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DOI：
10.1200/jco.2008.17.4706
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发表时间：
2008-12-01
影响因子：
45.3
通讯作者：
Demetri, George D.
中科院分区：
文献类型：
--
作者：
Baker, Laurence H.;Rowinsky, Eric K.;Demetri, George D.
肉瘤是临床前模型中最常见的促血管生成的恶性肿瘤之一。ABT-510通过一种新的血小板反应蛋白模拟机制抑制血管生成，其I期研究结果表明其在软组织肉瘤（STS）患者中具有活性。这项II期研究进一步评估了ABT-510在晚期STS patients.Patients和MethodsPatients中的安全性和有效性转移性或不可切除的STS患者被随机分配到两个ABT-510剂量方案之一治疗（20 mg每日一次[20 mg]，n = 42;或100 mg每日两次[200 mg]，n = 46），在28天治疗期内自我皮下给药。终点包括无进展生存期（PFS），客观反应率（ORR），总生存期（OS），和safety.ResultsMedian PFS为20毫克组为94天，4个月和6个月的PFS率估计分别为42%和24%。200 mg组的中位PFS为64天，4和6个月PFS率估计值分别为41%和32%。虽然仅观察到一个客观缓解，但在52%（20 mg）和48%（200 mg）的患者中观察到疾病稳定。中位OS为431天（20 mg）和295天（200 mg）。ABT-510耐受性良好。罕见的治疗相关3级或4级不良事件为低血压、深静脉血栓形成和低磷血症各1例。结论ABT-510具有良好的安全性，疾病控制率和OS时间是令人鼓舞的。然而，由于ORR较低且缺乏剂量反应，该研究未能获得STS中强单药活性的令人信服的证据。
PurposeSarcomas are among the most proangiogenic malignancies in preclinical models. Phase I study results for ABT-510, which inhibits angiogenesis via a novel thrombospondin-mimetic mechanism, suggested activity in soft tissue sarcoma (STS) patients. This phase II study further evaluated the safety and efficacy of ABT-510 in advanced STS patients.Patients and MethodsPatients with metastatic or unresectable STS were randomly assigned to treatment with one of two ABT-510 dose schedules (20 mg once a day [20 mg], n = 42; or 100 mg twice a day [200 mg], n = 46), which were self-administered subcutaneously in 28-day treatment periods. End points included progression-free survival (PFS), objective response rate (ORR), overall survival (OS), and safety.ResultsMedian PFS for the 20-mg arm was 94 days, with 4- and 6-month PFS rate estimates of 42% and 24%, respectively. Median PFS for the 200-mg arm was 64 days, with 4- and 6-month PFS rate estimates of 41% and 32%, respectively. Although only one objective response was noted, stable disease was observed in 52% (20 mg) and 48% (200 mg) of patients. Median OS was 431 days (20 mg) and 295 days (200 mg). ABT-510 was well tolerated. Rare treatment-related grade 3 or 4 adverse events were one event each of hypotension, deep vein thrombosis, and hypophosphatemia. ABT-510 pharmacokinetics were dose proportional, time independent, and consistent with those in previous studies.ConclusionABT-510 had a favorable safety profile, and the rate of disease control and OS times were encouraging. However, with low ORR and lack of dose response, the study failed to yield compelling evidence of strong single-agent activity in STS.