Literature DB >> 25652454

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 Shapiro1, Katherine M Bell-McGuinn2, Julian R Molina3, Johanna Bendell4, James Spicer5, Eunice L Kwak6, Susan S Pandya7, Robert Millham8, Gary Borzillo8, Kristen J Pierce8, Lixin Han9, Brett E Houk10, Jorge D Gallo11, Maria Alsina12, Irene Braña12, Josep Tabernero13.   

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 American Association for Cancer Research.

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Year:  2015        PMID： 25652454      PMCID： PMC4508327          DOI： 10.1158/1078-0432.CCR-14-1306

Source DB:  PubMed          Journal:  Clin Cancer Res        ISSN： 1078-0432            Impact factor:   12.531


  20 in total

1.  A phase II study of PD-0325901, an oral MEK inhibitor, in previously treated patients with advanced non-small cell lung cancer.

Authors:  Eric B Haura; Alejandro D Ricart; Timothy G Larson; Philip J Stella; Lyudmila Bazhenova; Vincent A Miller; Roger B Cohen; Peter D Eisenberg; Paulina Selaru; Keith D Wilner; Shirish M Gadgeel
Journal:  Clin Cancer Res       Date:  2010-03-23       Impact factor: 12.531

2.  Some practical improvements in the continual reassessment method for phase I studies.

Authors:  S N Goodman; M L Zahurak; S Piantadosi
Journal:  Stat Med       Date:  1995-06-15       Impact factor: 2.373

3.  Antitumor efficacy of PKI-587, a highly potent dual PI3K/mTOR kinase inhibitor.

Authors:  Robert Mallon; Larry R Feldberg; Judy Lucas; Inder Chaudhary; Christoph Dehnhardt; Efren Delos Santos; Zecheng Chen; Osvaldo dos Santos; Semiramis Ayral-Kaloustian; Aranapakam Venkatesan; Irwin Hollander
Journal:  Clin Cancer Res       Date:  2011-02-15       Impact factor: 12.531

4.  Randomized phase II study of dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor inhibitor, versus erlotinib in patients with advanced non-small-cell lung cancer.

Authors:  Suresh S Ramalingam; Fiona Blackhall; Maciej Krzakowski; Carlos H Barrios; Keunchil Park; Isabel Bover; Dae Seog Heo; Rafael Rosell; Denis C Talbot; Richard Frank; Stephen P Letrent; Ana Ruiz-Garcia; Ian Taylor; Jane Q Liang; Alicyn K Campbell; Joseph O'Connell; Michael Boyer
Journal:  J Clin Oncol       Date:  2012-07-02       Impact factor: 44.544

Review 5.  The PI3K pathway as drug target in human cancer.

Authors:  Kevin D Courtney; Ryan B Corcoran; Jeffrey A Engelman
Journal:  J Clin Oncol       Date:  2010-01-19       Impact factor: 44.544

6.  Dose- and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid tumors.

Authors:  Josep Tabernero; Federico Rojo; Emiliano Calvo; Howard Burris; Ian Judson; Katharine Hazell; Erika Martinelli; Santiago Ramon y Cajal; Suzanne Jones; Laura Vidal; Nicholas Shand; Teresa Macarulla; Francisco Javier Ramos; Sasa Dimitrijevic; Ulrike Zoellner; Pui Tang; Michael Stumm; Heidi A Lane; David Lebwohl; José Baselga
Journal:  J Clin Oncol       Date:  2008-03-10       Impact factor: 44.544

Review 7.  Development of PI3K inhibitors: lessons learned from early clinical trials.

Authors:  Jordi Rodon; Rodrigo Dienstmann; Violeta Serra; Josep Tabernero
Journal:  Nat Rev Clin Oncol       Date:  2013-02-12       Impact factor: 66.675

8.  Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma.

Authors:  Gary Hudes; Michael Carducci; Piotr Tomczak; Janice Dutcher; Robert Figlin; Anil Kapoor; Elzbieta Staroslawska; Jeffrey Sosman; David McDermott; István Bodrogi; Zoran Kovacevic; Vladimir Lesovoy; Ingo G H Schmidt-Wolf; Olga Barbarash; Erhan Gokmen; Timothy O'Toole; Stephanie Lustgarten; Laurence Moore; Robert J Motzer
Journal:  N Engl J Med       Date:  2007-05-31       Impact factor: 91.245

9.  Mutations in the phosphatidylinositol-3-kinase pathway predict for antitumor activity of the inhibitor PX-866 whereas oncogenic Ras is a dominant predictor for resistance.

Authors:  Nathan T Ihle; Robert Lemos; Peter Wipf; Adly Yacoub; Clint Mitchell; Doris Siwak; Gordon B Mills; Paul Dent; D Lynn Kirkpatrick; Garth Powis
Journal:  Cancer Res       Date:  2009-01-01       Impact factor: 12.701

Review 10.  Clinical development of phosphatidylinositol 3-kinase inhibitors for cancer treatment.

Authors:  Irene Brana; Lillian L Siu
Journal:  BMC Med       Date:  2012-12-11       Impact factor: 8.775
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  46 in total

1.  Dual PI3K/mTOR Inhibition in Colorectal Cancers with APC and PIK3CA Mutations.

Authors:  Tyler M Foley; Susan N Payne; Cheri A Pasch; Alex E Yueh; Dana R Van De Hey; Demetra P Korkos; Linda Clipson; Molly E Maher; Kristina A Matkowskyj; Michael A Newton; Dustin A Deming
Journal:  Mol Cancer Res       Date:  2017-02-09       Impact factor: 5.852

Review 2.  Hyperglycemia Associated With Targeted Oncologic Treatment: Mechanisms and Management.

Authors:  Jonathan W Goldman; Melody A Mendenhall; Sarah R Rettinger
Journal:  Oncologist       Date:  2016-07-29

3.  A First-in-Human, Phase I, Dose-Escalation Study of TAK-117, a Selective PI3Kα Isoform Inhibitor, in Patients with Advanced Solid Malignancies.

Authors:  Dejan Juric; Johann S de Bono; Patricia M LoRusso; John Nemunaitis; Elisabeth I Heath; Eunice L Kwak; Teresa Macarulla Mercadé; Elena Geuna; Maria Jose de Miguel-Luken; Chirag Patel; Keisuke Kuida; Serap Sankoh; Eric H Westin; Fabian Zohren; Yaping Shou; Josep Tabernero
Journal:  Clin Cancer Res       Date:  2017-05-10       Impact factor: 12.531

Review 4.  Targeting the PI3K pathway in cancer: are we making headway?

Authors:  Filip Janku; Timothy A Yap; Funda Meric-Bernstam
Journal:  Nat Rev Clin Oncol       Date:  2018-03-06       Impact factor: 66.675

Review 5.  Alterations and molecular targeting of the GSK-3 regulator, PI3K, in head and neck cancer.

Authors:  Michelle J Lee; Nan Jin; Jennifer R Grandis; Daniel E Johnson
Journal:  Biochim Biophys Acta Mol Cell Res       Date:  2020-02-19       Impact factor: 4.739

Review 6.  PI3K Inhibitors in Cancer: Clinical Implications and Adverse Effects.

Authors:  Rosalin Mishra; Hima Patel; Samar Alanazi; Mary Kate Kilroy; Joan T Garrett
Journal:  Int J Mol Sci       Date:  2021-03-27       Impact factor: 5.923

7.  Cancer Stem Cell-Based Models of Colorectal Cancer Reveal Molecular Determinants of Therapy Resistance.

Authors:  Maria Laura De Angelis; Ann Zeuner; Eleonora Policicchio; Giorgio Russo; Alessandro Bruselles; Michele Signore; Sara Vitale; Gabriele De Luca; Emanuela Pilozzi; Alessandra Boe; Giorgio Stassi; Lucia Ricci-Vitiani; Carla Azzurra Amoreo; Alfredo Pagliuca; Federica Francescangeli; Marco Tartaglia; Ruggero De Maria; Marta Baiocchi
Journal:  Stem Cells Transl Med       Date:  2016-03-08       Impact factor: 6.940

Review 8.  Autophagy: controlling cell fate in rheumatic diseases.

Authors:  Jason S Rockel; Mohit Kapoor
Journal:  Nat Rev Rheumatol       Date:  2016-06-23       Impact factor: 20.543

9.  PKI-587 enhances chemosensitivity of oxaliplatin in hepatocellular carcinoma through suppressing DNA damage repair pathway (NHEJ and HR) and PI3K/AKT/mTOR pathway.

Authors:  Yinci Zhang; Chunmei Xie; Amin Li; Xueke Liu; Yingru Xing; Jing Shen; Zhen Huo; Shuping Zhou; Xinkuang Liu; Yinghai Xie; Weiya Cao; Yongfang Ma; Ruyue Xu; Shiyu Cai; Xiaolong Tang; Dong Ma
Journal:  Am J Transl Res       Date:  2019-08-15       Impact factor: 4.060

10.  Inhibition of mTOR's Catalytic Site by PKI-587 Is a Promising Therapeutic Option for Gastroenteropancreatic Neuroendocrine Tumor Disease.

Authors:  Helma Freitag; Friederike Christen; Florentine Lewens; Irina Grass; Franziska Briest; Sara Iwaszkiewicz; Britta Siegmund; Patricia Grabowski
Journal:  Neuroendocrinology       Date:  2016-08-12       Impact factor: 4.914
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