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.

• Authors: Geoffrey I Shapiro, Katherine M Bell-McGuinn, Julian R Molina, Johanna Bendell, James Spicer, Eunice L Kwak, Susan S Pandya, Robert Millham, Gary Borzillo, Kristen J Pierce, Lixin Han, Brett E Houk, Jorge D Gallo, Maria Alsina, Irene Braña, Josep Tabernero
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 21 Issue 8 Pg. 1888-95 (04 15 2015) ISSN: 1557-3265 [Electronic] United States
• PMID: 25652454 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Morpholines
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors
• Triazines
• gedatolisib
• TOR Serine-Threonine Kinases

Topics

• Adult
• Aged
• Combined Modality Therapy
• Drug Monitoring
• Female
• Humans
• Male
• Maximum Tolerated Dose
• Middle Aged
• Morpholines (pharmacology, therapeutic use)
• Neoplasm Staging
• Neoplasms (drug therapy, metabolism, pathology)
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Retreatment
• TOR Serine-Threonine Kinases (antagonists & inhibitors)
• Treatment Outcome
• Triazines (pharmacology, therapeutic use)
• Young Adult