A Multicenter Phase 1 Study of EMD 525797 (DI17E6), a Novel Humanized Monoclonal Antibody Targeting αv Integrins, in Progressive Castration-resistant Prostate Cancer with Bone Metastases After Chemotherapy

Wirth, Manfred; Heidenreich, Axel; Gschwend, J.; Gil, Thierry; Zastrow, Stefan; Laniado, Michael; Gerloff, J.; Zühlsdorf, M.; Mordenti, Giacomo; Uhl, Wolfgang; Lannert, H.

doi:10.1016/j.eururo.2013.05.051

Cited by 36 publications

(34 citation statements)

References 26 publications

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“…There were no observable doserelated trends or clinically relevant changes in any vital signs parameters. The pharmacokinetics of EMD-525797 was driven by nonlinear elimination [176]. A phase I trial conducted to investigate the safety, tolerability, and pharmacokinetics in healthy individuals showed that ascending single doses of EMD-525797 were safe and well tolerated and no safety concerns were identified, which supported the ongoing investigation of EMD-525797 [177].…”

Section: Integrins As Therapeutic Targetsmentioning

confidence: 88%

Integrins

Sun

Gao

2014

Anti-Cancer Drugs

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Integrins are a large family of cell surface receptors that bind extracellular matrix proteins. The interaction of integrins with extracellular matrix activates a number of intracellular signaling pathways involved in cell proliferation, differentiation, motility, and other essential cell functions. Integrins are critically important to both health and disease. In this review, we first describe the structure, functions, and signaling characteristics of integrins. We then discuss the roles of integrins in cancer progression. Finally, we recapitulate the laboratory and clinical efforts of targeting integrins as effective means of cancer therapy and diagnosis. This comprehensive review could help scientists and clinicians gain a complete understanding of integrins. It could also contribute toward the development of new drugs, new methods of diagnostics, and new treatment of cancers to benefit the patients in clinical practice.

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Section: Integrins As Therapeutic Targetsmentioning

confidence: 88%

Integrins

Sun

Gao

2014

Anti-Cancer Drugs

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“…No DLTs and dose dependent relationship in TEAEs were observed. But there was significant decrease in primary tumor only in one patient and over all the treatment with EMD 525797 was well tolerated and it appeared to be safe in metastatic CRPC patients [52]. In another Phase-I, first-in-human study with 54 subjects studied observed the EMD 525797 elimination from serum with t ½ of 13 fold difference to 1500 mg dose group.…”

Section: Integrin Antagonists In Tumor and Angiogenesis Inhibitionmentioning

confidence: 92%

“…The results demonstrated that the pharmacokinetics of EMD 525797 was dose-dependent with dose proportion increase of Cmax values and treatment was well tolerated with ascending doses of EMD 525797 (35 mg to 1500 mg) [53]. A Phase-II randomized, double-blind placebo controlled in mCRPC patients was ongoing with 750 mg and 1500 mg of EMD 525797 [52]. Over all these results suggest EMD 525797 as a potent single agent inhibitor but further evaluation of predictive markers and controlled randomized trials are necessary to evaluate the efficacy of the EMD 52579.…”

Section: Integrin Antagonists In Tumor and Angiogenesis Inhibitionmentioning

confidence: 97%

Pharmacological and Clinical Importance of Integrin Antagonists in Treatment of Cancer

Santhosh¹

2014

J Cell Sci Ther

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Integrins are heterodimeric molecules that are composed of 18 α-subunits and 8 β-subunits. They exist in 24 distinctive shapes based on combination of these sub-units and are mainly responsible for the adhesion of extracellular matrix (ECM) and immunoglobulin family molecules. Integrins mediate adhesion of epithelial cells to the basement membrane and also help in the migration, proliferation and survival of tumor cells. Studies also reveal that certain integrins act as markers for tumor cells and they also assist in both tumor progression and apoptosis. Studies reveal that unligated integrins in association with caspase 8 result in inhibition of ECM adhesion might result and integrin mediated death (IMD) on the other hand integrins in association with oncogenes or receptor tyrosine kinases can result in enhanced tumorigenesis. Among several types of integrins, αvβ3 and α 5 β 1 have gained importance in anti-angiogenesis studies.Hence the role of antiangiogenesis antagonists has come into light. These include a variety of monoclonal antibodies and peptides. Each one of them has their own mechanism of action and antiangiogenesis activity. Current review aims at studying the phase 1 and 2 trails of these antagonists for anti-angiogenic function.

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“…Two dose levels of abituzumab were selected in this trial to achieve different levels of target saturation over 3 weeks, because no firm dose recommendation could be made based on an earlier phase I study (24). Pharmacokinetic guidance from this study suggested that abituzumab 750 mg every 3 weeks was likely to achieve serum trough concentrations above the 95% inhibitory concentration (IC 95 ) and to peak at the 99% inhibitory concentration (IC 99 ).…”

Section: Study Design and Treatmentmentioning

confidence: 99%

“…Preclinical studies confirmed that abituzumab inhibits xenograft tumor growth (23). In a phase I study, single-agent abituzumab had activity in patients with CRPC and bone metastases (24): 18 of 26 patients did not have disease progression (PD) for !18 weeks and 2 patients had clinically significant reductions in PSA and pain relief. One of these patients had a confirmed partial response (PR; ref.…”

Section: Introductionmentioning

confidence: 99%

Differential Effect on Bone Lesions of Targeting Integrins: Randomized Phase II Trial of Abituzumab in Patients with Metastatic Castration-Resistant Prostate Cancer

Hussain

Moulec

Gimmi

et al. 2016

Clinical Cancer Research

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on behalf of the PERSEUS Study Group Abstract Purpose: Integrins play a critical role in the progression of prostate cancer and its bone metastases. We investigated the use of the pan-av integrin inhibitor abituzumab in chemotherapy-na€ ve patients with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer.Experimental Design: PERSEUS (NCT01360840) was a randomized, double-blind phase II study. Men with pathologically confirmed prostate cancer and radiologic progression of bone lesions in the 28 days prior to randomization were assigned to receive abituzumab 750 mg or 1,500 mg or placebo (1:1:1) every 3 weeks in combination with luteinizing hormone-releasing hormone agonist/antagonist therapy. The primary endpoint was progression-free survival (PFS).Results: The intent-to-treat population comprised 180 patients, 60 in each arm. The primary endpoint of PFS was not significantly different with abituzumab-based therapy compared with placebo [abituzumab 750 mg, 3.4 months, HR ¼ 0.89; 95% confidence interval (CI), 0.57-1.39; abituzumab 1,500 mg, 4.3 months, HR ¼ 0.81; 95% CI, 0.52-1.26; placebo, 3.3 months], but the cumulative incidence of bone lesion progression was lower with abituzumab than with placebo for up to 24 months (cumulative incidence 23.6% vs. 41.1% at 6 months, 26.1% vs. 45.4% at 12 months). Two partial tumor responses were observed (1 abituzumab 1,500 mg and 1 placebo). Approximately 85% to 90% of patients experienced at least one treatment-emergent adverse event (TEAE) in the different arms, but the incidences of serious TEAEs and TEAEs with fatal outcome were similar in the three arms.Conclusions: Although PFS was not significantly extended, abituzumab appears to have specific activity in prostate cancerassociated bone lesions that warrants further investigation. Clin Cancer Res; 22(13); 3192-200. Ó2016 AACR.

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A Multicenter Phase 1 Study of EMD 525797 (DI17E6), a Novel Humanized Monoclonal Antibody Targeting αv Integrins, in Progressive Castration-resistant Prostate Cancer with Bone Metastases After Chemotherapy

Cited by 36 publications

References 26 publications

Integrins

Integrins

Pharmacological and Clinical Importance of Integrin Antagonists in Treatment of Cancer

Differential Effect on Bone Lesions of Targeting Integrins: Randomized Phase II Trial of Abituzumab in Patients with Metastatic Castration-Resistant Prostate Cancer

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