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

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

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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.

Original languageEnglish (US)
Pages (from-to)1888-1895
Number of pages8
JournalClinical Cancer Research
Volume21
Issue number8
DOIs
StatePublished - Apr 15 2015

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Phosphatidylinositol 3-Kinases
Maximum Tolerated Dose
Neoplasms
Pharmacokinetics
Therapeutics
Safety
1-(4-((4-(dimethylamino)piperidin-1-yl)carbonyl)phenyl)-3-(4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl)urea
Stomatitis
Appetite
Hyperglycemia
Nausea
Vomiting
Fatigue
Half-Life
Protein Isoforms
Research Design
Inflammation
Biopsy
Population

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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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.; Bell-McGuinn, Katherine M.; Molina, Julian R; Bendell, Johanna; Spicer, James; Kwak, Eunice L.; Pandya, Susan S.; Millham, Robert; Borzillo, Gary; Pierce, Kristen J.; Han, Lixin; Houk, Brett E.; Gallo, Jorge D.; Alsina, Maria; Braña, Irene; Tabernero, Josep.

In: Clinical Cancer Research, Vol. 21, No. 8, 15.04.2015, p. 1888-1895.

Research output: Contribution to journalArticle

Shapiro, GI, Bell-McGuinn, KM, Molina, JR, Bendell, J, Spicer, J, Kwak, EL, Pandya, SS, Millham, R, Borzillo, G, Pierce, KJ, Han, L, Houk, BE, Gallo, JD, Alsina, M, Braña, I & Tabernero, J 2015, 'First-in-human study of PF-05212384 (PKI-587), a small-molecule, intravenous, dual inhibitor of PI3K and mTOR in patients with advanced cancer', Clinical Cancer Research, vol. 21, no. 8, pp. 1888-1895. https://doi.org/10.1158/1078-0432.CCR-14-1306
Shapiro, Geoffrey I. ; Bell-McGuinn, Katherine M. ; Molina, Julian R ; Bendell, Johanna ; Spicer, James ; Kwak, Eunice L. ; Pandya, Susan S. ; Millham, Robert ; Borzillo, Gary ; Pierce, Kristen J. ; Han, Lixin ; Houk, Brett E. ; Gallo, Jorge D. ; Alsina, Maria ; Braña, Irene ; Tabernero, Josep. / First-in-human study of PF-05212384 (PKI-587), a small-molecule, intravenous, dual inhibitor of PI3K and mTOR in patients with advanced cancer. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 8. pp. 1888-1895.
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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.",
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AU - Shapiro, Geoffrey I.

AU - Bell-McGuinn, Katherine M.

AU - Molina, Julian R

AU - Bendell, Johanna

AU - Spicer, James

AU - Kwak, Eunice L.

AU - Pandya, Susan S.

AU - Millham, Robert

AU - Borzillo, Gary

AU - Pierce, Kristen J.

AU - Han, Lixin

AU - Houk, Brett E.

AU - Gallo, Jorge D.

AU - Alsina, Maria

AU - Braña, Irene

AU - Tabernero, Josep

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