University of Arizona Cancer Center, Tucson, AZ, USA.
Eur J Cancer. 2012 Dec;48(18):3319-27. doi: 10.1016/j.ejca.2012.06.027. Epub 2012 Aug 23.
SF1126 is a peptidic pro-drug inhibitor of pan-PI3K/mTORC. A first-in-human study evaluated safety, dose limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of SF1126, in patients with advanced solid and B-cell malignancies.
SF1126 was administered IV days 1 and 4, weekly in 28day-cycles. Dose escalation utilised modified Fibonacci 3+3. Samples to monitor PK and PD were obtained.
Forty four patients were treated at 9 dose levels (90-1110 mg/m(2)/day). Most toxicity was grade 1 and 2 with a single DLT at180 mg/m(2) (diarrhoea). Exposure measured by peak concentration (C(max)) and area under the time-concentration curve (AUC(0-)(t)) was dose proportional. Stable disease (SD) was the best response in 19 of 33 (58%) evaluable patients. MTD was not reached but the maximum administered dose (MAD) was 1110 mg/m(2). The protocol was amended to enrol patients with CD20+ B-cell malignancies at 1110 mg/m(2). A CLL patient who progressed on rituximab [R] achieved SD after 2 months on SF1126 alone but in combination with R achieved a 55% decrease in absolute lymphocyte count and a lymph node response. PD studies of CLL cells demonstrated SF1126 reduced p-AKT and increased apoptosis indicating inhibition of activated PI3K signalling.
SF1126 is well tolerated with SD as the best response in patients with advanced malignancies.
SF1126 是一种肽类原药抑制剂，可抑制全 PI3K/mTORC。一项首次人体研究评估了 SF1126 在晚期实体瘤和 B 细胞恶性肿瘤患者中的安全性、剂量限制性毒性 (DLT)、最大耐受剂量 (MTD)、药代动力学 (PK)、药效学 (PD) 和疗效。
SF1126 于第 1 天和第 4 天静脉注射，每周一次，28 天为一个周期。剂量递增采用改良的 Fibonacci 3+3 法。采集样本以监测 PK 和 PD。
44 例患者在 9 个剂量水平（90-1110mg/m2/天）接受治疗。大多数毒性为 1 级和 2 级，180mg/m2 时发生 1 例 DLT（腹泻）。通过峰浓度 (C(max)) 和时间浓度曲线下面积 (AUC(0-)(t)) 来衡量的暴露量与剂量呈比例。33 例可评估患者中，19 例（58%）最佳疗效为疾病稳定（SD）。未达到 MTD，但最大给药剂量（MAD）为 1110mg/m2。方案修订后，1110mg/m2 招募 CD20+B 细胞恶性肿瘤患者。1 例接受利妥昔单抗 [R] 治疗后进展的 CLL 患者单独使用 SF1126 2 个月后达到 SD，但与 R 联合使用时，绝对淋巴细胞计数下降 55%，淋巴结反应。CLL 细胞的 PD 研究表明，SF1126 降低了 p-AKT 并增加了细胞凋亡，表明抑制了激活的 PI3K 信号通路。
SF1126 在晚期恶性肿瘤患者中具有良好的耐受性，最佳疗效为 SD。
