Reference Detail

Ref Type

Journal Article

PMID

(26792581)

Authors

Cirkel GA, Kerklaan BM, Vanhoutte F, Van der Aa A, Lorenzon G, Namour F, Pujuguet P, Darquenne S, de Vos FY, Snijders TJ, Voest EE, Schellens JH, Lolkema MP

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Investigational new drugs	34	2	2016 Apr	184-92	Invest New Drugs

URL

Abstract Text

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 at the lowest dose level tested. Single agent treatment did not result in tumor responses.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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
GLPG0187	GLPG0187	0	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
GLPG0187				GLPG0187 is an integrin receptor antagonist, which may decrease angiogenesis and reduce tumor growth and metastasis (PMID: 25156971, PMID: 26792581).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References