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Author Notes:

Corresponding author: The West Clinic, Memphis, TN 38120, USA. Tel.: +1 011 683 0055; fax +1 011 901 685 2969. dmahadevan@westclinic.com (D. Mahadevan)

We wish to thank the patients who participated in this clinical study and their families and the clinical re- search support services (CRSS) at the Arizona Cancer Center, Indiana University Melvin and Bren Simon Cancer Center, Emory University and Virginia G. Piper Cancer Center/TGen.

We also thank Laurence Cooke for expert technical help in isolating CLL cells.

Disclosure: The study was sponsored, monitored and funded by Semafore Pharmaceuticals. JRG and CFS are employees of Semafore Pharmaceuticals.

Conflict of interest statement: The authors declare no conflict of interest.

Subjects:

Research Funding:

Dr. Durden thanks the NIH for grant support (CA94233).

The study was sponsored, monitored and funded by Semafore Pharmaceuticals.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Oncology
  • PI3K/mTORC pathway
  • SF1126
  • Pharmacokinetics
  • Pharmacodynamics
  • Refractory solid tumours
  • B-cell malignancies
  • CHRONIC LYMPHOCYTIC-LEUKEMIA
  • PHOSPHATIDYLINOSITOL 3-KINASE
  • PI3K PATHWAY
  • KINASE
  • CANCER
  • INHIBITOR
  • ANGIOGENESIS
  • ASSOCIATION
  • ACTIVATION
  • GUIDELINES

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

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Journal Title:

EJC Supplements

Volume:

Volume 48, Number 18

Publisher:

, Pages 3319-3327

Type of Work:

Article | Post-print: After Peer Review

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/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.

Copyright information:

© 2012 Elsevier Ltd. All rights reserved.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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