Phase I pharmacokinetic and pharmacodynamic study of the pan-PI3K/mTORC vascular targeted pro-drug SF1126 in patients with advanced solid tumours and B-cell malignancies

被引：108

作者：

Mahadevan, D. ^{[1
]}

Chiorean, E. G. ^{[2
]}

Harris, W. B. ^{[3
]}

Von Hoff, D. D. ^{[4
]}

Stejskal-Barnett, A. ^{[1
]}

Qi, W. ^{[1
]}

Anthony, S. P. ^{[5
]}

Younger, A. E. ^{[2
]}

Rensvold, D. M. ^{[1
]}

Cordova, F. ^{[1
]}

Shelton, C. F. ^{[5
]}

Becker, M. D. ^{[5
]}

Garlich, J. R. ^{[6
]}

Durden, D. L. ^{[7
]}

Ramanathan, R. K. ^{[4
]}

机构：

[1] Univ Arizona, Ctr Canc, Tucson, AZ USA

[2] Indiana Univ, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46204 USA

[3] Emory Univ, Atlanta, GA 30322 USA

[4] Virginia G Piper Canc Ctr TGen, Scottsdale, AZ USA

[5] Evergreen Hematol & Oncol, Spokane, WA USA

[6] SignalRx, Indianapolis, IN USA

[7] Univ Calif San Diego, San Diego, CA 92103 USA

来源：

EUROPEAN JOURNAL OF CANCER | 2012年 / 48卷 / 18期

关键词：

PI3K/mTORC pathway; SF1126; Pharmacokinetics; Pharmacodynamics; Refractory solid tumours; B-cell malignancies; CHRONIC LYMPHOCYTIC-LEUKEMIA; PHOSPHATIDYLINOSITOL; 3-KINASE; PI3K PATHWAY; INHIBITOR; KINASE; CANCER; ANGIOGENESIS; ASSOCIATION; ACTIVATION; GUIDELINES;

D O I：

10.1016/j.ejca.2012.06.027

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background: 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. Patients and methods: SF1126 was administered IV days 1 and 4, weekly in 28 day-cycles. Dose escalation utilised modified Fibonacci 3+3. Samples to monitor PK and PD were obtained. Results: 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. Conclusion: SF1126 is well tolerated with SD as the best response in patients with advanced malignancies. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：3319 / 3327

页数：9

共 29 条

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