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

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74 Scopus citations

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 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/m2/day). Most toxicity was grade 1 and 2 with a single DLT at180 mg/m2 (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/m2. 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.

Original languageEnglish (US)
Pages (from-to)3319-3327
Number of pages9
JournalEuropean Journal of Cancer
Volume48
Issue number18
DOIs
StatePublished - Dec 2012

Keywords

  • B-cell malignancies
  • PI3K/mTORC pathway
  • Pharmacodynamics
  • Pharmacokinetics
  • Refractory solid tumours
  • SF1126

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Mahadevan, D., Chiorean, E. G., Harris, W. B., Von Hoff, D. D., Stejskal-Barnett, A., Qi, W., Anthony, S. P., Younger, A. E., Rensvold, D. M., Cordova, F., Shelton, C. F., Becker, M. D., Garlich, J. R., Durden, D. L., & Ramanathan, R. K. (2012). 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. European Journal of Cancer, 48(18), 3319-3327. https://doi.org/10.1016/j.ejca.2012.06.027