First-in-human study of PF-05212384 (PKI-587), a small-molecule, intravenous, dual inhibitor of PI3K and mTOR in patients with advanced cancer Journal Article


Authors: Shapiro, G. I.; Bell-Mcguinn, K. M.; Molina, J. R.; Bendell, J.; Spicer, J.; Kwak, E. L.; Pandya, S. S.; Millham, R.; Borzillo, G.; Pierce, K. J.; Han, L.; Houk, B. E.; Gallo, J. D.; Alsina, M.; Braña, I.; Tabernero, J.
Article Title: First-in-human study of PF-05212384 (PKI-587), a small-molecule, intravenous, dual inhibitor of PI3K and mTOR in patients with advanced cancer
Abstract: Purpose: To evaluate safety (primary endpoint), tolerability, pharmacokinetics, pharmacodynamic profile, and preliminary activity of the intravenous, pan-class I isoform PI3K/mTOR inhibitor PF-05212384 in patients with advanced solid tumors. Experimental Design: Part 1 of this open-label phase I study was designed to estimate the maximum-tolerated dose (MTD) in patients with nonselected solid tumors, using a modified continual reassessment method to guide dose escalation. Objectives of part 2 were MTD confirmation and assessment of preliminary activity in patients with selected tumor types and PI3K pathway dysregulation. Results: Seventy-seven of the 78 enrolled patients received treatment. The MTD for PF-05212384, administered intravenously once weekly, was estimated to be 154 mg. The most common treatment-related adverse events (AE) were mucosal inflammation/stomatitis (58.4%), nausea (42.9%), hyperglycemia (26%), decreased appetite (24.7%), fatigue (24.7%), and vomiting (24.7%). The majority of patients treated at the MTD experienced only grade 1 treatment-related AEs. Grade 3 treatment-related AEs occurred in 23.8% of patients at the MTD. No treatment-related grade 4-5 AEs were reported at any dose level. Antitumor activity was noted in this heavily pretreated patient population, with two partial responses (PR) and an unconfirmed PR. Eight patients had long-lasting stable disease (>6 months). Pharmacokinetic analyses showed a biphasic concentration-time profile for PF-05212384 (half-life, 30-37 hours after multiple dosing). PF-05212384 inhibited downstream effectors of the PI3K pathway in paired tumor biopsies. Conclusions: These findings demonstrate the manageable safety profile and antitumor activity of the PI3K/mTOR inhibitor PF-05212384, supporting further clinical development for patients with advanced solid malignancies. ©2015 AACR.
Journal Title: Clinical Cancer Research
Volume: 21
Issue: 8
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2015-04-15
Start Page: 1888
End Page: 1895
Language: English
DOI: 10.1158/1078-0432.ccr-14-1306
PROVIDER: scopus
PUBMED: 25652454
PMCID: PMC4508327
DOI/URL:
Notes: Export Date: 4 May 2015 -- Source: Scopus
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