A dose escalating phase I study of GLPG0187, a broad spectrum integrin receptor antagonist, in adult patients with progressive high-grade glioma and other advanced solid malignancies

Investigational New Drugs
Geert A CirkelMartijn P Lolkema

Abstract

Integrin signaling is an attractive target for anti-cancer treatment. GLPG0187 is a broad spectrum integrin receptor antagonist (IRA). GLPG0187 inhibited tumor growth and metastasis in mouse models. We aimed to determine the Recommended Phase II Dose (RP2D) and to assess safety and tolerability of continuous i.v. infusion in patients with advanced malignant solid tumors. Anticipated dose levels were 20, 40, 80, 160, 320, and 400 mg/day in a modified 3 + 3 design. Plasma concentrations of GLPG0187 were assessed to characterize the pharmacokinetics (PK). C-terminal telopeptide of type I collagen (CTX) was used as pharmacodynamics marker. Twenty patients received GLPG0187. No dose limiting toxicities (DLTs) were observed. The highest possible and tested dose was 400 mg/day. Fatigue was the most frequently reported side effect (25%). Recurrent Port-A-Cath-related infections and skin toxicity suggest cutaneous integrin inhibition. No dose-dependent toxicity could be established. PK analysis showed a short average distribution (0.16 h) and elimination (3.8 h) half-life. Continuous infusion resulted in dose proportional PK profiles. We observed decreases in serum CTX levels independent of the dose given, suggesting target engagement a...Continue Reading

References

Jun 6, 2002·Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases·E BouzaP Muñoz
Jul 13, 2006·Proceedings of the National Academy of Sciences of the United States of America·Muhammad H ZamanPaul Matsudaira
Jun 19, 2007·Cancer Research·Yingshe ZhaoPhilippe Clézardin
May 24, 2008·Nature Reviews. Cancer·Christie J AvraamidesJudith A Varner
Nov 5, 2008·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·David A ReardonL Burt Nabors
Dec 23, 2008·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·E A EisenhauerJ Verweij
Dec 24, 2009·Nature Reviews. Cancer·Jay S Desgrosellier, David A Cheresh
Mar 17, 2010·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Patrick Y WenSusan M Chang
May 5, 2010·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Roger StuppMichael Weller
Jun 17, 2011·Neoplasia : an International Journal for Oncology Research·Geertje van der HorstGabri van der Pluijm
Sep 3, 2011·Cold Spring Harbor Perspectives in Biology·Anna Huttenlocher, Alan Rick Horwitz
Apr 21, 2012·Cancer·L Burt NaborsUNKNOWN New Approaches to Brain Tumor Therapy (NABTT) Central Nervous System Consortium
Feb 5, 2013·Brain : a Journal of Neurology·Patrick RothMichael Weller
Jan 25, 2014·Cell Death & Disease·M SilginerP Roth
Dec 3, 2014·The Lancet Oncology·Marco TucciFranco Silvestris
Nov 3, 2015·Nature·Ayuko HoshinoDavid Lyden

❮ Previous
Next ❯

Citations

Dec 9, 2016·International Journal of Molecular Sciences·Daniela BianconiGerald W Prager
Sep 26, 2017·Angewandte Chemie·Richard J D HatleyPauline T Lukey
Jan 19, 2019·Molecular Cancer·Greta Sökeland, Udo Schumacher
Feb 6, 2020·International Journal of Molecular Sciences·Aleksandra Ellert-MiklaszewskaBozena Kaminska
Jun 8, 2017·Cancers·Hanadi Talal AhmedahHelen M Sheldrake
Aug 24, 2017·Cancers·Sabine Raab-WestphalSimon L Goodman
Apr 21, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Arwa MorshedHanmei Xu
Jun 25, 2019·Frontiers in Immunology·Heidi HarjunpääSusanna C Fagerholm
Mar 29, 2019·JBMR Plus·Miranda E Sowder, Rachelle W Johnson
Jul 13, 2017·Cancers·Kristin A Kwakwa, Julie A Sterling
Jan 12, 2021·Frontiers in Oncology·Hye Na KimYong-Mi Kim
Sep 19, 2021·Nature Reviews. Drug Discovery·R J SlackR J D Hatley
Oct 16, 2021·Scientific Reports·Peter SimonsTione Buranda
Oct 31, 2021·Journal of Hematology & Oncology·Jiangling XiongDingxiao Zhang
Dec 8, 2021·Journal of Chemotherapy·Xiao-Ying GuanZuo-Yi Jiao

❮ Previous
Next ❯

Methods Mentioned

BETA
pregnancy test

Clinical Trials Mentioned

NCT01313598

Related Concepts

Related Feeds

Adhesion Molecules in Health and Disease

Cell adhesion molecules are a subset of cell adhesion proteins located on the cell surface involved in binding with other cells or with the extracellular matrix in the process called cell adhesion. In essence, cell adhesion molecules help cells stick to each other and to their surroundings. Cell adhesion is a crucial component in maintaining tissue structure and function. Discover the latest research on adhesion molecule and their role in health and disease here.