Phase 1 study of ixazomib, an investigational proteasome inhibitor, in advanced non-hematologic malignancies

Investigational New Drugs
David C SmithJohn A Thompson

Abstract

Ixazomib is an investigational proteasome inhibitor with demonstrated antitumor activity in xenograft models of multiple myeloma (MM), lymphoma, and solid tumors. This open-label, phase 1 study investigated intravenous (IV) ixazomib, in adult patients with advanced non-hematologic malignancies. Patients received IV ixazomib twice-weekly for up to twelve 21-day cycles. The 0.125 mg/m(2) starting dose was doubled (one patient/dose) until 1.0 mg/m(2) based on dose-limiting toxicities (DLTs) in cycle 1. This was followed by 3 + 3 dose-escalation and expansion at the maximum tolerated dose (MTD). Primary objectives included safety and MTD assessment. Secondary objectives included assessment of pharmacokinetics, pharmacodynamics, and disease response. Ixazomib was escalated from 0.125 to 2.34 mg/m(2) to determine the MTD (n = 23); patients were then enrolled to MTD expansion (n = 73) and pharmacodynamic (n = 20) cohorts. Five patients experienced DLTs (1.0 and 1.76 mg/m(2): grade 3 pruritic rash; 2.34 mg/m(2): grade 3 and 4 thrombocytopenia, and grade 3 acute renal failure); thus, the MTD was 1.76 mg/m(2). Drug-related grade ≥3 adverse events (AEs) included thrombocytopenia (23 %), skin and subcutaneous (SC) tissue disorders (16 %), ...Continue Reading

References

Apr 18, 1998·Proceedings of the National Academy of Sciences of the United States of America·A Ciechanover, A L Schwartz
Jan 1, 2004·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Nancy B DavisWalter M Stadler
Jan 20, 2004·Molecular and Cellular Biology·Hao-Yuan JiangRonald C Wek
Jun 1, 2004·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Christos N PapandreouChristopher J Logothetis
Sep 15, 2004·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·G Varuni KondaguntaRobert J Motzer
Sep 28, 2004·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Manisha H ShahMichael Grever
Dec 1, 2004·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Susan M BlaneyPeter C Adamson
Sep 2, 2005·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·A L HamiltonF M Muggia
Oct 28, 2005·Clinical Lung Cancer·David P Schenkein
Jul 20, 2006·The Journal of Clinical Endocrinology and Metabolism·Constantine S MitsiadesNicholas Mitsiades
Nov 8, 2006·Annals of Internal Medicine·Eyal Reinstein, Aaron Ciechanover
Mar 4, 2008·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Howard I ScherUNKNOWN Prostate Cancer Clinical Trials Working Group
Mar 19, 2008·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Robert Z Orlowski, Deborah J Kuhn
Feb 2, 2010·Drug Discovery Today·Lawrence R Dick, Paul E Fleming
Jan 18, 2011·Current Clinical Pharmacology·Ron J KeizerAlwin D R Huitema
Jul 5, 2011·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Dharminder ChauhanKenneth C Anderson
Sep 10, 2011·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Edmund C LeeSiegfried Janz
May 31, 2012·Blood·Philippe MoreauJean-Luc Harousseau
Mar 13, 2013·Expert Review of Anticancer Therapy·Ali McBride, Patricia Y Ryan
Aug 27, 2013·Cancer Chemotherapy and Pharmacology·Kyriakos P PapadopoulosJeffery R Infante

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Citations

Jul 4, 2015·Expert Opinion on Investigational Drugs·Massimo GentileSilvia Gentili
Mar 1, 2016·Investigational New Drugs·Jeffrey R InfanteKyriakos P Papadopoulos
Jun 16, 2016·Hospital Pharmacy·Fern E LawsonDominic A Solimando
Nov 14, 2018·Expert Opinion on Pharmacotherapy·Paul G RichardsonSagar Lonial
Mar 26, 2019·Expert Opinion on Investigational Drugs·Piotr Smolewski, Dominika Rydygier
Apr 13, 2018·Journal of Virology·Sekar NatesampillaiAndrew D Badley
Nov 30, 2019·Case Reports in Hematology·Heather KatzYehuda Lebowicz
Jan 18, 2020·International Journal of Molecular Sciences·Amy NorthropSenthil K Radhakrishnan
Nov 23, 2019·Proceedings of the National Academy of Sciences of the United States of America·Sourav BanerjeeXiaoguang Lei
Aug 18, 2018·Clinical Pharmacokinetics·Neeraj GuptaKarthik Venkatakrishnan
Mar 2, 2021·Biochemical and Biophysical Research Communications·Qingqing WangXuyan Chen

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Methods Mentioned

BETA
xenograft
biopsies
biopsy

Clinical Trials Mentioned

NCT01564537
NCT01850524
NCT01659658
NCT00830869

Software Mentioned

WinNonlin

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