Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Investigational New Drugs
Published in: Investigational New Drugs 2/2016

Open Access 01-04-2016 | PHASE I STUDIES

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

Authors: Geert A. Cirkel, Bojana Milojkovic Kerklaan, Frédéric Vanhoutte, Annegret Van der Aa, Giocondo Lorenzon, Florence Namour, Philippe Pujuguet, Sophie Darquenne, Filip Y. F. de Vos, Tom J. Snijders, Emile E. Voest, Jan H. M. Schellens, Martijn P. Lolkema

Published in: Investigational New Drugs | Issue 2/2016

Login to get access

Summary

Background 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. Methods 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. Results 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 at the lowest dose level tested. Single agent treatment did not result in tumor responses. Conclusions GLPG0187 was well tolerated with a dose-proportional PK profile upon continuous infusion. No formal maximal tolerated dose could be established. GLPG0187 showed signs of target engagement with a favourable toxicity profile. However, continuous infusion of GLPG0187 failed to show signs of monotherapy efficacy.
Appendix
Available only for authorised users
Literature
1.
Hoshino A, Costa-Silva B, Shen TL, Rodrigues G, Hashimoto A, Tesic Mark M, Molina H, Kohsaka S, Di Giannatale A, Ceder S, et al. (2015) Tumour exosome integrins determine organotropic metastasis. Nature 527:329–335CrossRefPubMed
2.
3.
Zaman MH, Trapani LM, Sieminski AL, Mackellar D, Gong H, Kamm RD, Wells A, Lauffenburger DA, Matsudaira P (2006) Migration of tumor cells in 3D matrices is governed by matrix stiffness along with cell-matrix adhesion and proteolysis. Proc Natl Acad Sci U S A 103:10889–10894CrossRefPubMedPubMedCentral
4.
5.
Roth P, Silginer M, Goodman SL, Hasenbach K, Thies S, Maurer G, Schraml P, Tabatabai G, Moch H, Tritschler I, et al. (2013) Integrin control of the transforming growth factor-beta pathway in glioblastoma. Brain 136:564–576CrossRefPubMed
6.
7.
Nabors LB, Mikkelsen T, Hegi ME, Ye X, Batchelor T, Lesser G, Peereboom D, Rosenfeld MR, Olsen J, Brem S, et al. (2012) A safety run-in and randomized phase 2 study of cilengitide combined with chemoradiation for newly diagnosed glioblastoma (NABTT 0306). Cancer 118:5601–5607CrossRefPubMedPubMedCentral
8.
Reardon DA, Fink KL, Mikkelsen T, Cloughesy TF, O'Neill A, Plotkin S, Glantz M, Ravin P, Raizer JJ, Rich KM, et al. (2008) Randomized phase II study of cilengitide, an integrin-targeting arginine-glycine-aspartic acid peptide, in recurrent glioblastoma multiforme. J Clin Oncol 26:5610–5617CrossRefPubMed
9.
Stupp R, Hegi ME, Neyns B, Goldbrunner R, Schlegel U, Clement PMJ, Grabenbauer GG, Ochsenbein AF, Simon M, Dietrich PY, et al. (2010) Phase I/IIa study of cilengitide and temozolomide with concomitant radiotherapy followed by cilengitide and temozolomide maintenance therapy in patients with newly diagnosed glioblastoma. J Clin Oncol 28:2712–2718CrossRefPubMed
10.
Stupp R, Hegi ME, Gorlia T, Erridge SC, Perry J, Hong YK, Aldape KD, Lhermitte B, Pietsch T, Grujicic D, et al. (2014) Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 15:1100–1108CrossRefPubMed
11.
Mason WP (2015) End of the road: confounding results of the CORE trial terminate the arduous journey of cilengitide for glioblastoma. Neuro Oncol 17:634–635CrossRefPubMed
12.
Nabors LB, Fink KL, Mikkelsen T, Grujicic D, Tarnawski R, Nam dH, Mazurkiewicz M, Salacz M, Ashby L, Zagonel V, et al. (2015) Two cilengitide regimens in combination with standard treatment for patients with newly diagnosed glioblastoma and unmethylated MGMT gene promoter: results of the open-label, controlled, randomized phase II CORE study. Neuro Oncol 17:708–717
13.
Pujuguet P, Berrocal E, Heckmann B, Wigerinck P, Lorenzon G, Clement-Lacroix P, Bormans G, Deroose C (2011) PP 87 molecular imaging demonstrates GLPG0187, a small-molecule integrin antagonist, binds to RGD-integrin receptors in vivo and is efficacious in tumor and metastasis models. Eur J Cancer 47:S28CrossRef
14.
15.
van der Horst G, van den Hoogen C, Buijs JT, Cheung H, Bloys H, Pelger RC, Lorenzon G, Heckmann B, Feyen J, Pujuguet P, et al. (2011) Targeting of alpha(v)-integrins in stem/progenitor cells and supportive microenvironment impairs bone metastasis in human prostate cancer. Neoplasia 13:516–525CrossRefPubMedPubMedCentral
16.
Clement-Lacroix P, Berrocal E, Heckmann B, Wigerinck P, Lorenzon G, P P (2011) GLPG0187 inhibits progression of established bone metastasis and achieves maximum efficacy when combined with standard-of-care metastatic breast cancer treatments. Bone 48:S45CrossRef
17.
Zhao Y, Bachelier R, Treilleux I, Pujuguet P, Peyruchaud O, Baron R, Clement-Lacroix P, Clezardin P (2007) Tumor alphavbeta3 integrin is a therapeutic target for breast cancer bone metastases. Cancer Res 67:5821–5830CrossRefPubMed
18.
Lorenzon G, Gheyle L, Vets E, Namour F, Pujuguet P, Clement-Lacroix P, Wigerinck P, Vanhoutte F (2010) Abstract 1568: GLPG0187, a small molecule integrin antagonist, shows good safety and decrease in CTX levels in single ascending dose study. Cancer Res 70:1568
19.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, et al. (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247CrossRefPubMed
20.
Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, DeGroot J, Wick W, Gilbert MR, Lassman AB, et al. (2010) Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 28:1963–1972CrossRefPubMed
21.
Engleman VW, Nickols GA, Ross FP, Horton MA, Griggs DW, Settle SL, Ruminski PG, Teitelbaum SL (1997) A peptidomimetic antagonist of the alpha(v)beta3 integrin inhibits bone resorption in vitro and prevents osteoporosis in vivo. J Clin Invest 99:2284–2292CrossRefPubMedPubMedCentral
22.
Davies J, Warwick J, Totty N, Philp R, Helfrich M, Horton M (1989) The osteoclast functional antigen, implicated in the regulation of bone resorption, is biochemically related to the vitronectin receptor. J Cell Biol 109:1817–1826CrossRefPubMed
23.
Rosen HN, Moses AC, Garber J, Iloputaife ID, Ross DS, Lee SL, Greenspan SL (2000) Serum CTX: a new marker of bone resorption that shows treatment effect more often than other markers because of low coefficient of variability and large changes with bisphosphonate therapy. Calcif Tissue Int 66:100–103CrossRefPubMed
24.
Uhm JH, Dooley NP, Kyritsis AP, Rao JS, Gladson CL (1999) Vitronectin, a glioma-derived extracellular matrix protein, protects tumor cells from apoptotic death. Clin Cancer Res 5:1587–1594PubMed
25.
Bello L, Francolini M, Marthyn P, Zhang J, Carroll RS, Nikas DC, Strasser JF, Villani R, Cheresh DA, Black PM (2001) Alpha(v)beta3 and alpha(v)beta5 integrin expression in glioma periphery. Neurosurgery 49:380–389PubMed
26.
Bouza E, Burillo A, Muños P (2002) Catheter-related infections: diagnosis and intravascular treatment. Clin Microbiol Infect 8:265–274CrossRefPubMed
27.
Aoshima H, Kushida K, Takahashi M, Ohishi T, Hoshino H, Suzuki M, Inoue T (1998) Circadian variation of urinary type I collagen crosslinked C-telopeptide and free and peptide-bound forms of pyridinium crosslinks. Bone 22:73–78CrossRefPubMed
28.
Wichers M, Schmidt E, Bidlingmaier F, D K (1999) Diurnal rhythm of CrossLaps in human serum. Clin Chem 45:1858–1860PubMed
29.
Tucci M, Stucci S, Silvestris F (2014) Does cilengitide deserve another chance? Lancet Oncol 15:e584–e585CrossRefPubMed
Metadata
Title
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
Authors
Geert A. Cirkel
Bojana Milojkovic Kerklaan
Frédéric Vanhoutte
Annegret Van der Aa
Giocondo Lorenzon
Florence Namour
Philippe Pujuguet
Sophie Darquenne
Filip Y. F. de Vos
Tom J. Snijders
Emile E. Voest
Jan H. M. Schellens
Martijn P. Lolkema
Publication date
01-04-2016
Publisher
Springer US
Published in
Investigational New Drugs / Issue 2/2016
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI
https://doi.org/10.1007/s10637-015-0320-9

Other articles of this Issue 2/2016

Investigational New Drugs 2/2016 Go to the issue

PHASE I STUDIES

A phase I study of selumetinib (AZD6244/ARRY-142866), a MEK1/2 inhibitor, in combination with cetuximab in refractory solid tumors and KRAS mutant colorectal cancer

PRECLINICAL STUDIES

Preclinical toxicity evaluation of a novel immunotoxin, D2C7-(scdsFv)-PE38KDEL, administered via intracerebral convection-enhanced delivery in rats

PHASE II STUDIES

A phase II study of cediranib, an oral VEGF inhibitor, in previously untreated patients with metastatic or recurrent malignant melanoma

PHASE I STUDIES

A multicenter phase 1/2a dose-escalation study of the antioxidant moiety of vitamin E 2,2,5,7,8-pentamethyl-6-chromanol (APC-100) in men with advanced prostate cancer

PHASE II STUDIES

An open-label, single-arm, phase 2 study of the Aurora kinase A inhibitor alisertib in patients with advanced urothelial cancer

PRECLINICAL STUDIES

The novel pyrrolo-1,5-benzoxazepine, PBOX-15, synergistically enhances the apoptotic efficacy of imatinib in gastrointestinal stromal tumours; suggested mechanism of action of PBOX-15
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits