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

SummaryBackground 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s10637-015-0320-9) contains supplementary material, which is available to authorized users.

Integrin Signaling in Glioma Pathogenesis: From Biology to Therapy

“…GLPG0187 showed anti-tumor activity in preclinical models of breast and prostate cancer [119], as well as effectiveness against glioma cells [66]. Preliminary results of the phase Ib study confirmed a favorable toxicity profile of the drug and early signs of clinical response in patients with progressive high-grade glioma and other solid tumors [120].…”

Glut3 Addiction Is a Druggable Vulnerability for a Molecularly Defined Subpopulation of Glioblastoma

“…Aside from cilengitide, there are a number of αvβ3-targeted strategies in development for GBM, including GLPG0187, a small molecule antagonist of multiple integrins including αvβ3, αvβ5, αvβ6, and α5β1 (Cirkel et al, 2016), as well as approaches that use RGD peptides for αvβ3-targeted delivery of radionuclides (Jin et al, 2017), siRNA (He et al, 2017), and chemotherapy-loaded nanoparticles or nanogels (Chen et al, 2017; Fang et al, 2017). Considering that Glut3 addiction is also a feature of GBM cancer stem cells (Flavahan et al, 2013), targeting this phenotype with an αvβ3 antagonist has the potential to eradicate the most aggressive and drug resistant subpopulation within the tumor.…”

Bone as a Preferential Site for Metastasis

“…Similarly, substantial preclinical evidence suggests that pharmacological targeting of αvβ3 integrin effectively prevents metastatic colonization of the bone . Clinical trials using neutralizing antibodies and small molecule inhibitors against αvβ3 have shown promise; however, these have not specifically focused on bone metastasis . Microenvironmental factors such as TGFβ and VEGF have also been identified as potential therapeutic targets to prevent bone metastasis .…”