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.
abstract: 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.
authors.affiliation: Department of Medical Oncology, University Medical Center Utrecht, Heidelberglaan 100, 3584, CX Utrecht, The Netherlands.
authors.forename: Geert A
authors.initials: GA
authors.lastname: Cirkel
authors.affiliation: Department of Clinical Pharmacology, Netherlands Cancer Institute, Plesmanlaan 121, 1066, CX Amsterdam, The Netherlands.
authors.forename: Bojana Milojkovic
authors.initials: BM
authors.lastname: Kerklaan
authors.affiliation: Galapagos NV, Gen. De Wittelaan L11A3, 2800, Mechelen, Belgium.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Vanhoutte
authors.affiliation: Galapagos NV, Gen. De Wittelaan L11A3, 2800, Mechelen, Belgium.
authors.forename: Annegret
authors.initials: A
authors.lastname: Van der Aa
authors.affiliation: Galapagos SASU, 102 Avenue Gaston Roussel, 93230, Romainville, France.
authors.forename: Giocondo
authors.initials: G
authors.lastname: Lorenzon
authors.affiliation: Galapagos SASU, 102 Avenue Gaston Roussel, 93230, Romainville, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Namour
authors.affiliation: Galapagos SASU, 102 Avenue Gaston Roussel, 93230, Romainville, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Pujuguet
authors.affiliation: Galapagos SASU, 102 Avenue Gaston Roussel, 93230, Romainville, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Darquenne
authors.affiliation: Department of Medical Oncology, University Medical Center Utrecht, Heidelberglaan 100, 3584, CX Utrecht, The Netherlands.
authors.forename: Filip Y F
authors.initials: FY
authors.lastname: de Vos
authors.affiliation: Brain Center Rudolf Magnus, Department of Neurology and Neurosurgery, University Medical Center Utrecht, Heidelberglaan 100, 3584, CX Utrecht, The Netherlands.
authors.forename: Tom J
authors.initials: TJ
authors.lastname: Snijders
authors.affiliation: Department of Medical Oncology, University Medical Center Utrecht, Heidelberglaan 100, 3584, CX Utrecht, The Netherlands.|Netherlands Cancer Institute, Plesmanlaan 121, PO box: 90203, 1006, BE Amsterdam, The Netherlands.
authors.forename: Emile E
authors.initials: EE
authors.lastname: Voest
authors.affiliation: Department of Clinical Pharmacology, Netherlands Cancer Institute, Plesmanlaan 121, 1066, CX Amsterdam, The Netherlands.
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.affiliation: Department of Medical Oncology, University Medical Center Utrecht, Heidelberglaan 100, 3584, CX Utrecht, The Netherlands. m.lolkema@erasmusmc.nl.|Erasmus MC Kanker Instituut, Groene Hillededijk 301, Room G4-51, 3075, EA Rotterdam, The Netherlands. m.lolkema@erasmusmc.nl.
authors.forename: Martijn P
authors.initials: MP
authors.lastname: Lolkema
mesh_terms: D000328:Adult; D000368:Aged; D001862:Bone Resorption / Q000473:pathology; D001932:Brain Neoplasms / Q000097:blood / Q000188:drug therapy*; D015331:Cohort Studies; D024042:Collagen Type I / Q000378:metabolism; D003710:Demography; D004305:Dose-Response Relationship, Drug; D005260:Female; D005910:Glioma / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D016023:Integrins / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009287:Naphthyridines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D060787:Neoplasm Grading; D010455:Peptides / Q000378:metabolism; D011725:Pyridines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013449:Sulfonamides / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D024042:Collagen Type I; C000612647:GLPG0187; D016023:Integrins; D009287:Naphthyridines; D010455:Peptides; D011725:Pyridines; D011956:Receptors, Cell Surface; D013449:Sulfonamides; C052929:collagen type I trimeric cross-linked peptide
keywords: Antagonist; GLPG0187; Glioma; Integrin; Phase 1