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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.

SUBMITTER: Shapiro GI

PROVIDER: S-EPMC4508327 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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First-in-Human Study of PF-05212384 (PKI-587), a Small-Molecule, Intravenous, Dual Inhibitor of PI3K and mTOR in Patients with Advanced Cancer.

Shapiro Geoffrey I GI Bell-McGuinn Katherine M KM Molina Julian R JR Bendell Johanna J Spicer James J Kwak Eunice L EL Pandya Susan S SS Millham Robert R Borzillo Gary G Pierce Kristen J KJ Han Lixin L Houk Brett E BE Gallo Jorge D JD Alsina Maria M Braña Irene I Tabernero Josep J

Clinical cancer research : an official journal of the American Association for Cancer Research 20150204 8

<h4>Purpose</h4>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.<h4>Experimental design</h4>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 ...[more]

PMID: 25652454

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Project description:BackgroundOverexpression of ABC transporters is a big challenge on cancer therapy which will lead cancer cells resistance to a series of anticancer drugs. Gedatolisib is a dual PI3K and mTOR inhibitor which is under clinical evaluation for multiple types of malignancies, including colorectal cancer. The growth inhibitory effects of gedatolisib on colorectal cancer cells have been specifically studied. However, the role of ABC transporters on gedatolisib resistance remained unclear. In present study, we illustrated the role of ABC transporters on gedatolisib resistance in colorectal cancer cells.MethodsCell viability investigations of gedatolisib on colorectal cancer cells were determined by MTT assays. The verapamil and Ko143 reversal studies were determined by MTT assays as well. ABCB1 and/or ABCG2 siRNA interference assays were conducted to verify the role of ABCB1- and ABCG2-overexpression on gedatolisib resistance. The accumulation assays of gedatolisib were conducted using tritium-labeled paclitaxel and mitoxantrone. The effects of gedatolisib on ATPase activity of ABCB1 or ABCG2 were conducted using PREDEASY ATPase Kits. The expression level of ABCB1 and ABCG2 after gedatolisib treatment were conducted by Western blotting and immunofluorescence assays. The well-docked position of gedatolisib with crystal structure of ABCB1 and ABCG2 were simulated by Autodock vina software. One-way ANOVA was used for the statistics analysis.ResultsGedatolisib competitively increased the accumulation of tritium-labeled substrate-drugs in both ABCB1- and ABCG2-overexpression colorectal cancer cells. Moreover, gedatolisib significantly increased the protein expression level of ABCB1 and ABCG2 in colorectal cancer cells. In addition, gedatolisib remarkably simulated the ATPase activity of both ABCB1 and ABCG2, suggesting that gedatolisib is a substrate drug of both ABCB1 and ABCG2 transporters. Furthermore, a gedatolisib-resistance colorectal cancer cell line, SW620/GEDA, was selected by increasingly treatment with gedatolisib to SW620 cells. The SW620/GEDA cell line was proved to resistant to gedatolisib and a series of chemotherapeutic drugs, except cisplatin. The ABCB1 and ABCG2 were observed overexpression in SW620/GEDA cell line.ConclusionsThese findings suggest that overexpression of ABCB1 and ABCG2 may restrict the efficacy of gedatolisib in colorectal cancer cells, while co-administration with ABC transporter inhibitors may improve the potency of gedatolisib.

Dataset Information

First-in-Human Study of PF-05212384 (PKI-587), a Small-Molecule, Intravenous, Dual Inhibitor of PI3K and mTOR in Patients with Advanced Cancer.

Publications

First-in-Human Study of PF-05212384 (PKI-587), a Small-Molecule, Intravenous, Dual Inhibitor of PI3K and mTOR in Patients with Advanced Cancer.

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