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.

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 (18)F-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 (18)F-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.

• Authors: Debashis Sarker, Joo Ern Ang, Richard Baird, Rebecca Kristeleit, Krunal Shah, Victor Moreno, Paul A Clarke, Florence I Raynaud, Gallia Levy, Joseph A Ware, Kathryn Mazina, Ray Lin, Jenny Wu, Jill Fredrickson, Jill M Spoerke, Mark R Lackner, Yibing Yan, Lori S Friedman, Stan B Kaye, Mika K Derynck, Paul Workman, Johann S de Bono
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 21 Issue 1 Pg. 77-86 (Jan 01 2015) ISSN: 1557-3265 [Electronic] United States
• PMID: 25370471 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• 2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine
• Indazoles
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors
• Sulfonamides
• BRAF protein, human
• Proto-Oncogene Proteins B-raf

Topics

• Administration, Oral
• Adult
• Aged
• Dose-Response Relationship, Drug
• Drug-Related Side Effects and Adverse Reactions (pathology)
• Female
• Humans
• Indazoles (administration & dosage, blood)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasms (blood, drug therapy, genetics, pathology)
• Phosphatidylinositol 3-Kinases (genetics)
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors (administration & dosage, blood, pharmacokinetics)
• Proto-Oncogene Proteins B-raf (genetics)
• Sulfonamides (administration & dosage, blood)