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First-in-Human Phase I Study of Pictilisib (GDC-0941), a Potent Pan–Class I Phosphatidylinositol-3-Kinase (PI3K) Inhibitor, in Patients with Advanced Solid Tumors

Sarker, Debashis, Ang, Joo Ern, Baird, Richard, Kristeleit, Rebecca, Shah, Krunal, Moreno, Victor, Clarke, Paul A., Raynaud, Florence I., Levy, Gallia, Ware, Joseph A., Mazina, Kathryn, Lin, Ray, Wu, Jenny, Fredrickson, Jill, Spoerke, Jill M., Lackner, Mark R., Yan, Yibing, Friedman, Lori S., Kaye, Stan B., Derynck, Mika K., Workman, Paul, de Bono, Johann S.·2015·Clinical Cancer Research
DOI 10.1158/1078-0432.ccr-14-0947PMC PMC4287394

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Abstract

Purpose: This first-in-human dose-escalation trial evaluated the safety, tolerability, maximal-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, pharmacodynamics, and preliminary clinical activity of pictilisib (GDC-0941), an oral, potent, and selective inhibitor of the class I phosphatidylinositol-3-kinases (PI3K). Patients and Methods: Sixty patients with solid tumors received pictilisib at 14 dose levels from 15 to 450 mg once-daily, initially on days 1 to 21 every 28 days and later, using continuous dosing for selected dose levels. Pharmacodynamic studies incorporated 18F-FDG-PET, and assessment of phosphorylated AKT and S6 ribosomal protein in platelet-rich plasma (PRP) and tumor tissue. Results: Pictilisib was well tolerated. The most common toxicities were grade 1–2 nausea, rash, and fatigue, whereas the DLT was grade 3 maculopapular rash (450 mg, 2 of 3 patients; 330 mg, 1 of 7 patients). The pharmacokinetic profile was dose-proportional and supported once-daily dosing. Levels of phosphorylated serine-473 AKT were suppressed >90% in PRP at 3 hours after dose at the MTD and in tumor at pictilisib doses associated with AUC >20 h·μmol/L. Significant increase in plasma insulin and glucose levels, and >25% decrease in 18F-FDG uptake by PET in 7 of 32 evaluable patients confirmed target modulation. A patient with V600E BRAF–mutant melanoma and another with platinum-refractory epithelial ovarian cancer exhibiting PTEN loss and PIK3CA amplification demonstrated partial response by RECIST and GCIG-CA125 criteria, respectively. Conclusion: Pictilisib was safely administered with a dose-proportional pharmacokinetic profile, on-target pharmacodynamic activity at dose levels ≥100 mg and signs of antitumor activity. The recommended phase II dose was continuous dosing at 330 mg once-daily. Clin Cancer Res; 21(1); 77–86. ©2014 AACR.

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Research works printed but not linked: 30

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Cited by

Metadata

Authors
Sarker, D., Ang, J. E., Baird, R., Kristeleit, R., Shah, K., Moreno, V., Clarke, P. A., Raynaud, F. I., Levy, G., Ware, J. A., Mazina, K., Lin, R., Wu, J., Fredrickson, J., Spoerke, J. M., Lackner, M. R., Yan, Y., Friedman, L. S., Kaye, S. B., Derynck, M. K., Workman, P., & de Bono, J. S.
Venue
Clinical Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2015-01-01
Volume
21
Issue
1
Pages
77-86
ISSN
  • 1078-0432
  • 1557-3265
DOI
10.1158/1078-0432.ccr-14-0947
PMC
PMC4287394
Cited by
313
References
6
Language
en

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