Phase I Study of Apitolisib (GDC-0980), Dual Phosphatidylinositol-3-Kinase and Mammalian Target of Rapamycin Kinase Inhibitor, in Patients with Advanced Solid Tumors

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Saoirse DollyJohann S de Bono

Abstract

This first-in-human phase I trial assessed the safety, tolerability, and preliminary antitumor activity of apitolisib (GDC-0980), a dual inhibitor of class I PI3K, and mTOR kinases. Once-daily oral apitolisib was administered to patients with solid tumors for days 1 to 21 or 1 to 28 of 28-day cycles. Pharmacokinetic and pharmacodynamic parameters were assessed. Overall, 120 patients were treated at doses between 2 and 70 mg. The commonest ≥G3 toxicities related to apitolisib at the recommended phase 2 dose (RP2D) at 40 mg once daily included hyperglycemia (18%), rash (14%), liver dysfunction (12%), diarrhea (10%), pneumonitis (8%), mucosal inflammation (6%), and fatigue (4%). Dose-limiting toxicities (1 patient each) were G4 fasting hyperglycemia at 40 mg (21/28 schedule) and G3 maculopapular rash and G3 fasting hyperglycemia at 70 mg (21/28 schedule). The pharmacokinetic profile was dose-proportional. Phosphorylated serine-473 AKT levels were suppressed by ≥90% in platelet-rich plasma within 4 hours at the MTD (50 mg). Pharmacodynamic decreases in fluorodeoxyglucose positron emission tomography uptake of >25% occurred in 66% (21/32) of patients dosed at 40 mg once daily. Evidence of single-agent activity included 10 RECIST par...Continue Reading

References

Oct 1, 1992·Proceedings of the National Academy of Sciences of the United States of America·J Q ChengJ R Testa
Jul 1, 1987·Proceedings of the National Academy of Sciences of the United States of America·S P Staal
Aug 6, 1997·Journal of the National Cancer Institute·R SimonM C Christian
Feb 5, 2004·Annals of Oncology : Official Journal of the European Society for Medical Oncology·M J Byrne, A K Nowak
Mar 16, 2004·Science·Yardena SamuelsVictor E Velculescu
Jul 16, 2004·Cancer Biology & Therapy·Kurtis E BachmanBen Ho Park
Jan 14, 2005·Proceedings of the National Academy of Sciences of the United States of America·Sohye KangPeter K Vogt
Aug 12, 2005·Nature·D Williams ParsonsVictor E Velculescu
May 26, 2006·Nature·Reuben J Shaw, Lewis C Cantley
Jul 19, 2006·Nature Reviews. Genetics·Jeffrey A EngelmanLewis C Cantley
Feb 6, 2008·European Journal of Cardio-thoracic Surgery : Official Journal of the European Association for Cardio-thoracic Surgery·Isabelle OpitzWalter Weder
Jan 21, 2010·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Kevin D CourtneyJeffrey A Engelman
Mar 18, 2010·Nature Reviews. Clinical Oncology·Janet Dancey
Dec 14, 2011·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Johanna C BendellJosé Baselga
Feb 24, 2012·Annals of Oncology : Official Journal of the European Society for Medical Oncology·B MarkmanJ Baselga
Mar 31, 2012·Lung Cancer : Journal of the International Association for the Study of Lung Cancer·S CedrésE Felip
Mar 31, 2012·Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc·Alison H M ReidColin S Cooper
Jun 14, 2012·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·David S HongAntonio Jimeno
Aug 28, 2012·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·D MahadevanR K Ramanathan
Dec 18, 2012·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Vijay AgarwalMichael J Lind
Feb 13, 2013·Nature Reviews. Clinical Oncology·Jordi RodonJosep Tabernero
Apr 27, 2013·Cancer Discovery·Vivian W Y LuiJennifer R Grandis
Oct 30, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Geoffrey I ShapiroGerald Edelman
Feb 1, 2014·Nature Reviews. Drug Discovery·David A Fruman, Christian Rommel
Mar 4, 2014·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Kyriakos P PapadopoulosPatricia M Lorusso
Mar 7, 2014·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Andrew SewellWendell G Yarbrough
Apr 3, 2014·Lung Cancer : Journal of the International Association for the Study of Lung Cancer·Marjorie G ZaudererLee M Krug
Nov 6, 2014·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Debashis SarkerJohann S de Bono
Oct 11, 2015·International Journal of Cancer. Journal International Du Cancer·Annelieke E C A B WillemsenJolien Tol
Sep 1, 2012·Annals of Oncology : Official Journal of the European Society for Medical Oncology·B MarkmanJ Baselga

❮ Previous
Next ❯

Citations

Dec 17, 2016·Drug Safety : an International Journal of Medical Toxicology and Drug Experience·Rashmi R Shah
Feb 9, 2017·Future Medicinal Chemistry·Lixia GaoYong Teng
Apr 9, 2017·Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer·Rossella ParrottaEmanuela Felley-Bosco
Jul 26, 2017·Nature Reviews. Cancer·Timothy A YapDean A Fennell
Mar 7, 2018·Nature Reviews. Clinical Oncology·Filip JankuFunda Meric-Bernstam
Jun 23, 2018·International Journal of Molecular Sciences·Juncal AldaregiaIdoia Garcia
Jul 12, 2018·PLoS Neglected Tropical Diseases·Frederick A PartridgeDavid B Sattelle
Jan 17, 2019·Drug Safety : an International Journal of Medical Toxicology and Drug Experience·Giuseppe Curigliano, Rashmi R Shah
Feb 16, 2019·The European Respiratory Journal·Pauline T LukeyToby M Maher
Jun 24, 2016·Nature Reviews. Rheumatology·Jason S Rockel, Mohit Kapoor
May 6, 2019·Annals of Oncology : Official Journal of the European Society for Medical Oncology·J Pascual, N C Turner
Jul 31, 2019·Medicina·Stefania CrisciRaffaele Di Francia
Nov 23, 2019·International Journal of Molecular Sciences·Antonino BelfioreFederica Perrone
Dec 11, 2019·Cells·Cedric MagawayEstela Jacinto
Feb 9, 2020·International Journal of Molecular Sciences·Chiara TarantelliFrancesco Bertoni
Jul 21, 2020·Expert Opinion on Pharmacotherapy·Piotr Smolewski, Dominika Rydygier
May 10, 2017·Targeted Oncology·César SerranoJoan Carles
Aug 6, 2020·Frontiers in Molecular Biosciences·Ritika TiwariBushra Ateeq
Apr 1, 2020·Frontiers in Oncology·Luca CantiniJoachim G J V Aerts
May 28, 2020·Cancers·Stefanie SchmidtArmin Wiegering
Feb 21, 2019·Molecular Cancer·Jing YangXiawei Wei
Apr 11, 2018·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Johanna C BendellKathleen N Moore
May 7, 2020·Molecular Cancer Therapeutics·Alfonso García-ValverdeCésar Serrano
Oct 27, 2017·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Chiara TarantelliFrancesco Bertoni
Jan 16, 2020·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Aaron T ScottJames R Howe
Mar 31, 2018·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Chang XuEduardo Méndez
Jan 24, 2021·Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc·Xiaoqin ZhuJacob R Bledsoe
Jan 22, 2021·The Cancer Journal·Joanna A Young, Antoinette R Tan
Apr 4, 2021·International Journal of Molecular Sciences·Rosalin MishraJoan T Garrett
Jan 29, 2020·Annals of Oncology : Official Journal of the European Society for Medical Oncology·J Pascual, N C Turner

❮ Previous
Next ❯

Related Concepts

Related Feeds

AKT Pathway

This feed focuses on the AKT serine/threonine kinase, which is an important signaling pathway involved in processes such as glucose metabolism and cell survival.

Cancer Genomics (Keystone)

Cancer genomics approaches employ high-throughput technologies to identify the complete catalog of somatic alterations that characterize the genome, transcriptome and epigenome of cohorts of tumor samples. Discover the latest research using such technologies in this feed.