Abstract
The PI3K/AKT/mTOR signaling pathways are frequently dysregulated in multiple human cancers, including multiple myeloma (MM), non-Hodgkin lymphoma (NHL), and Waldenström's macroglobulinemia (WM). This was the first clinical study to evaluate the safety, tolerability, maximal-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics, and preliminary clinical activity of TAK-228, an oral TORC1/2 inhibitor, in patients with MM, NHL, or WM. Thirty-nine patients received TAK-228 once daily (QD) at 2, 4, 6, or 7 mg, or QD for 3 days on and 4 days off each week (QDx3d QW) at 9 or 12 mg, in 28-day cycles. The overall median age was 61.0 years (range 46-85); 31 patients had MM, four NHL, and four WM. Cycle 1 DLTs occurred in five QD patients (stomatitis, urticaria, blood creatinine elevation, fatigue, and nausea and vomiting) and four QDx3d QW patients (erythematous rash, fatigue, asthenia, mucosal inflammation, and thrombocytopenia). The MTDs were determined to be 4 mg QD and 9 mg QDx3d QW. Thirty-six patients (92%) reported at least one drug-related toxicity; the most common grade ≥3 drug-related toxicities were thrombocytopenia (15%), fatigue (10%), and neutropenia (5%). TAK-228 exhibited a dose-dependent increase in plasma...Continue Reading
References
Sep 30, 1998·British Journal of Haematology·J BladéD Vesole
Jul 10, 2003·Cell Cycle·Jiyong Liang, Joyce M Slingerland
Oct 18, 2005·Molecular Cancer Therapeutics·Yijiang ShiAlan Lichtenstein
Feb 3, 2006·Cancer Research·Kathryn E O'ReillyNeal Rosen
Apr 28, 2006·Clinical Lymphoma & Myeloma·Eva KimbyJoan Bladé
Jul 21, 2006·Leukemia·B G M DurieUNKNOWN International Myeloma Working Group
Aug 18, 2006·Nature Reviews. Cancer·David M Sabatini
Nov 24, 2006·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Lanie K FrancisIrene M Ghobrial
Jan 24, 2007·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Bruce D ChesonUNKNOWN International Harmonization Project on Lymphoma
Mar 12, 2008·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Josep TaberneroJosé Baselga
Dec 3, 2008·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Meletios Athanasios DimopoulosSteven P Treon
Dec 23, 2008·Cell Cycle·Arkaitz CarracedoPier Paolo Pandolfi
Jan 20, 2009·The Journal of Biological Chemistry·Carson C ThoreenNathanael S Gray
Feb 13, 2009·PLoS Biology·Morris E FeldmanKevan M Shokat
May 19, 2009·Cell·Timothy R PetersonDavid M Sabatini
Dec 17, 2009·Biochimica Et Biophysica Acta·Ryan J O DowlingNahum Sonenberg
Feb 10, 2010·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Irene M GhobrialThomas E Witzig
Aug 6, 2010·Blood·Bao HoangAlan Lichtenstein
Sep 10, 2010·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Collin Vu, David A Fruman
Dec 8, 2010·Leukemia·T E WitzigT M Habermann
Dec 16, 2010·Nature Reviews. Molecular Cell Biology·Roberto ZoncuDavid M Sabatini
Jan 11, 2011·Molecular Cancer Therapeutics·Eduardo VilarJosep Tabernero
Feb 25, 2011·The Lancet Oncology·Irene M GhobrialPaul G Richardson
Jun 3, 2011·The Oncologist·Anas Younes, Nousheen Samad
Oct 4, 2011·Current Opinion in Cell Biology·Eva Dazert, Michael N Hall
Nov 1, 2011·Nature Reviews. Drug Discovery·Don BenjaminMichael N Hall
Nov 3, 2011·Blood·Patricia MaisoIrene M Ghobrial
Mar 1, 2012·Nature·Andrew C HsiehDavide Ruggero
Jul 11, 2012·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Naifa L BusaidyLillian L Siu
Oct 23, 2012·Breast Cancer Research and Treatment·Yesim Gökmen-PolarGeorge W Sledge
Oct 24, 2012·Leukemia·M R JanesD A Fruman
Feb 13, 2013·Nature Reviews. Clinical Oncology·Jordi RodonJosep Tabernero
May 21, 2013·Cancer Treatment Reviews·Shanthi SivendranMatthew D Galsky
Oct 30, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Geoffrey I ShapiroGerald Edelman
Dec 10, 2013·Experimental Hematology & Oncology·James SignorovitchPeter Metrakos
Mar 22, 2014·Clinical Lymphoma, Myeloma & Leukemia·Jason R Westin
Apr 10, 2014·American Journal of Hematology·Irene M GhobrialSteven P Treon
Apr 26, 2014·British Journal of Haematology·Andrew J YeeNoopur S Raje
Jul 26, 2014·American Journal of Hematology·Ilyas SahinIrene M Ghobrial
Aug 31, 2014·Molecular Cancer Therapeutics·Diana CirsteaNoopur Raje
Oct 3, 2014·Clinical & Translational Oncology : Official Publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico·J BellmuntI Duran
Oct 17, 2014·Journal of breast cancer·Rishi AgarwalVivek Subbiah
Dec 21, 2014·Neuro-oncology·Daniel J MaJann N Sarkaria
Feb 16, 2015·Haematologica·Andreas GüntherMartin Gramatzki
Citations
Mar 7, 2014·Journal of Hematology & Oncology·Raoul Tibes, Ruben A Mesa
Feb 2, 2017·British Journal of Haematology·Teresa Calimeri, Andrés J M Ferreri
May 26, 2017·Expert Opinion on Therapeutic Targets·Yoko TabeMarina Konopleva
Feb 9, 2017·PeerJ·Tian XiangYan Xiao
Mar 7, 2018·Nature Reviews. Clinical Oncology·Filip JankuFunda Meric-Bernstam
Jan 13, 2018·Leukemia & Lymphoma·Vijay Ramakrishnan, Shaji Kumar
Feb 6, 2018·Current Hematologic Malignancy Reports·Helen MaJennifer E Amengual
Feb 12, 2019·Cell Death & Disease·Pan WangXin Chen
Mar 7, 2018·Investigational New Drugs·Laura GrahamDana E Rathkopf
Mar 11, 2018·Clinical Science·Alberto M MartelliJames A McCubrey
Jun 7, 2019·Cancers·Chiara TarantelliFrancesco Bertoni
Jun 25, 2019·Current Hematologic Malignancy Reports·Ipsita PalChangchun Deng
Feb 22, 2018·ESMO Open·Kathleen N MooreManish R Patel
Jul 23, 2019·Expert Opinion on Emerging Drugs·Judith LindKlaus Podar
Dec 17, 2016·Hematological Oncology·Kevin J FreiseAhmed Hamed Salem
Dec 11, 2019·Cells·Cedric MagawayEstela Jacinto
Feb 22, 2018·Oncotarget·Moran GotesmanDavid A Fruman
May 15, 2018·Oncotarget·Aurelia LamanuzziRoberto Ria
Nov 2, 2017·Oncotarget·Toshiya TsujiShuichan Xu
Aug 27, 2016·Oncotarget·Jianchang QianKer Yu
Jun 4, 2020·Clinical Pharmacology in Drug Development·Chirag PatelA Craig Lockhart
Sep 7, 2019·Oncotarget·Nicci Owusu-BrackettFunda Meric-Bernstam
Jun 12, 2020·Aging·Haiyan LiuHongming Huang
Jul 7, 2019·Cancers·Xianqiong LiuXin Chen
Sep 12, 2020·British Journal of Cancer·Martin H VossHoward A Burris
Jan 16, 2020·Nature Reviews. Molecular Cell Biology·Grace Y Liu, David M Sabatini
Nov 23, 2019·International Journal of Molecular Sciences·Petra Hillmann, Doriano Fabbro
Sep 15, 2020·Exploration of Targeted Anti-tumor Therapy·Joe TaylorGraham Packham
Oct 28, 2016·Blood·Changchun DengOwen A O'Connor
Jun 6, 2017·Neuro-oncology·Jeffrey A RubensEric H Raabe
Jun 12, 2017·Cancer Chemotherapy and Pharmacology·Howard A BurrisJ R Infante
Feb 21, 2019·MBio·Carolina Caro-VegasDirk P Dittmer
Dec 17, 2019·Neuro-oncology·Antje ArnoldEric H Raabe
Aug 17, 2018·International Journal of Molecular Sciences·Simone MirabiliiAgostino Tafuri
Nov 16, 2018·Annals of Hematology·Seiichi OkabeKazuma Ohyashiki
Nov 8, 2019·Blood Advances·Yu-Hsiu T LinArun P Wiita
May 19, 2018·Oncotarget·Maria BhattiMatthew J Barth
Apr 25, 2018·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Sónia R VeigaSara C Kozma
Jul 12, 2017·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Qi Wen FanWilliam A Weiss
May 18, 2020·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·S Lindsey DavisJennifer R Diamond
Feb 24, 2019·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Qianwen ZhangKer Yu
Sep 19, 2020·Molecular Cancer Therapeutics·Bih-Rong WeiR Mark Simpson
Aug 8, 2018·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Xinhua SongXin Chen
Jul 17, 2019·Molecular Cancer Therapeutics·Thomas MühlenbergSebastian Bauer
Jul 20, 2019·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Dean C BottinoArijit Chakravarty
Dec 12, 2020·JAAD Case Reports·Carlo De la SanchaMehdi Nassiri
Nov 7, 2019·Cell Reports·Helena AspernigAntje Thien
Jan 7, 2021·Cancers·Luca MologniAlfonso Zambon
Feb 12, 2021·Cancer Letters·Rachael E MaynardEric H Raabe
Nov 1, 2020·Translational Oncology·Anusara DaenthanasanmakThomas A Waldmann