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
D Mahadevan, E G Chiorean, W B Harris, D D Von Hoff, A Stejskal-Barnett, W Qi, S P Anthony, A E Younger, D M Rensvold, F Cordova, C F Shelton, M D Becker, J R Garlich, D L Durden, R K Ramanathan, D Mahadevan, E G Chiorean, W B Harris, D D Von Hoff, A Stejskal-Barnett, W Qi, S P Anthony, A E Younger, D M Rensvold, F Cordova, C F Shelton, M D Becker, J R Garlich, D L Durden, R K Ramanathan
Abstract
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 28day-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.
Conflict of interest statement
Conflict of interest statement: The authors declare no conflict of interest.
Copyright © 2012 Elsevier Ltd. All rights reserved.
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Source: PubMed