Phase I dose-escalation study evaluating safety, tolerability and pharmacokinetics of MEDI-573, a dual IGF-I/II neutralizing antibody, in Japanese patients with advanced solid tumours

Iguchi, Haruo; Nishina, Tomohiro; Nogami, Naoyuki; Kozuki, Toshiyuki; Yamagiwa, Yumiko; Yagawa, Katsuro

doi:10.1007/s10637-014-0170-x

Cited by 26 publications

(23 citation statements)

References 11 publications

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“…These findings are consistent with two phase 1 studies of dusigitumab, which reported SD in Caucasian (US) and Asian (Japanese) patients. 9,10 The results of the BLRM, integrating biomarkers (plateau in total IGF-1; inhibition of IGF bioactivity), and efficacy data from patients in both studies, provided further confirmation of the RBD. In the BLRM model, the estimated probability of having reached the RBD with a dose of 1000 mg was 87%, indicating that saturation of total IGF-1 biomarker, inhibition of IGF bioactivity, and disease control would plateau around this dose.…”

Section: Discussionmentioning

confidence: 71%

“…1 The finding that drug-related hyperglycaemia was rare with xentuzumab (no patients in study 1280.1 and two patients in study 1280.2 [grade 1 and grade 3]) is consistent with clinical studies of another IGF-ligand blocking mAb, dusigitumab (MEDI-573). 9,10 The low incidence of hyperglycaemia with xentuzumab suggests that the anti-ligand mechanism of action may be more favourable than IGF-1R-targeted therapies with regard to hyperglycaemia. The immunogenic reaction to xentuzumab was low; however, no firm conclusions on ADA incidence and prevalence could be made in either study due to a high frequency of samples being deemed ADA inconclusive.…”

Section: Discussionmentioning

confidence: 99%

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Two first-in-human studies of xentuzumab, a humanised insulin-like growth factor (IGF)-neutralising antibody, in patients with advanced solid tumours

et al. 2020

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BACKGROUND: Xentuzumab, an insulin-like growth factor (IGF)-1/IGF-2-neutralising antibody, binds IGF-1 and IGF-2, inhibiting their growth-promoting signalling. Two first-inhuman trials assessed the maximum-tolerated/relevant biological dose (MTD/RBD), safety, pharmacokinetics, pharmacodynamics, and activity of xentuzumab in advanced/metastatic solid cancers. METHODS: These phase 1, open-label trials comprised dose-finding (part I; 3 + 3 design) and expansion cohorts (part II; selected tumours; RBD [weekly dosing]). Primary endpoints were MTD/RBD. RESULTS: Study 1280.1 involved 61 patients (part I: xentuzumab 10-1800 mg weekly, n = 48; part II: 1000 mg weekly, n = 13); study 1280.2, 64 patients (part I: 10-3600 mg three-weekly, n = 33; part II: 1000 mg weekly, n = 31). One dose-limiting toxicity occurred; the MTD was not reached for either schedule. Adverse events were generally grade 1/2, mostly gastrointestinal. Xentuzumab showed dose-proportional pharmacokinetics. Total plasma IGF-1 increased dose dependently, plateauing at~1000 mg/week; at ≥450 mg/week, IGF bioactivity was almost undetectable. Two partial responses occurred (poorly differentiated nasopharyngeal carcinoma and peripheral primitive neuroectodermal tumour). Integration of biomarker and response data by Bayesian Logistic Regression Modeling (BLRM) confirmed the RBD. CONCLUSIONS: Xentuzumab was well tolerated; MTD was not reached. RBD was 1000 mg weekly, confirmed by BLRM. Xentuzumab showed preliminary anti-tumour activity.

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Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Two first-in-human studies of xentuzumab, a humanised insulin-like growth factor (IGF)-neutralising antibody, in patients with advanced solid tumours

et al. 2020

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“…Currently two IGF ligand-capturing antibodies are evaluated in phase I clinical trials, MEDI-573 and BI 836845 respectively [94,95]. Phase I dose-escalation and safety studies show MEDI-573 to be well tolerated (NCT01340040) [96]. For BI 836845a phase I trial has been completed but no results have been published so far (NCT01403974).…”

Section: Targeting Igf-i and Igf-iimentioning

confidence: 99%

IGF system targeted therapy: Therapeutic opportunities for ovarian cancer

Liefers-Visser

Meijering

Reyners

et al. 2017

Cancer Treatment Reviews

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The insulin-like growth factor (IGF) system comprises multiple growth factor receptors, including insulin-like growth factor 1 receptor (IGF-1R), insulin receptor (IR) -A and -B. These receptors are activated upon binding to their respective growth factor ligands, IGF-I, IGF-II and insulin, and play an important role in development, maintenance, progression, survival and chemotherapeutic response of ovarian cancer. In many pre-clinical studies anti-IGF-1R/IR targeted strategies proved effective in reducing growth of ovarian cancer models. In addition, anti-IGF-1R targeted strategies potentiated the efficacy of platinum based chemotherapy. Despite the vast amount of encouraging and promising pre-clinical data, anti-IGF-1R/IR targeted strategies lacked efficacy in the clinic. The question is whether targeting the IGF-1R/IR signaling pathway still holds therapeutic potential. In this review we address the complexity of the IGF-1R/IR signaling pathway, including receptor heterodimerization within and outside the IGF system and downstream signaling. Further, we discuss the implications of this complexity on current targeted strategies and indicate therapeutic opportunities for successful targeting of the IGF-1R/IR signaling pathway in ovarian cancer. Multiple-targeted approaches circumventing bidirectional receptor tyrosine kinase (RTK) compensation and prevention of system rewiring are expected to have more therapeutic potential.

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“…In a phase I trial MEDI-573 was well tolerated but failed to achieve partial or complete responses in HCC patients[51]. A study in Japanese patients with advanced solid tumors produced similar results[52]. EM164 is a humanized anti-IGF-1R antibody that inhibits signaling through IGF-1R.…”

Section: Signaling Disruptionmentioning

confidence: 99%

Mechanisms of action of therapeutic antibodies for cancer

Redman

Hill

Aldeghaither

et al. 2015

Molecular Immunology

144

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The therapeutic utility of antibodies and their derivatives is achieved by various means. The FDA has approved several targeted antibodies that disrupt signaling of various growth factor receptors for the treatment of a number of cancers. Rituximab, and other anti-CD20 monoclonal antibodies are active in B cell malignancies. As more experience has been gained with anti-CD20 monoclonal antibodies, the multifactorial nature of their anti-tumor mechanisms has emerged. Other targeted antibodies function to dampen inhibitory checkpoints. These checkpoint inhibitors have recently achieved dramatic results in several cancers, including melanoma. These and related antibodies continue to be investigated in the clinical and pre-clinical settings. Novel antibody structures that target two or more antigens have also made their way into clinical use. Tumor targeted antibodies can also be conjugated to chemo- or radiotherapeutic agents, or catalytic toxins, as a means to deliver toxic payloads to cancer cells. Here we provide a review of these mechanisms and a discussion of their relevance to current and future clinical applications.

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Phase I dose-escalation study evaluating safety, tolerability and pharmacokinetics of MEDI-573, a dual IGF-I/II neutralizing antibody, in Japanese patients with advanced solid tumours

Abstract: MEDI-573 is well tolerated at the doses investigated.

Cited by 26 publications

References 11 publications

Two first-in-human studies of xentuzumab, a humanised insulin-like growth factor (IGF)-neutralising antibody, in patients with advanced solid tumours

Two first-in-human studies of xentuzumab, a humanised insulin-like growth factor (IGF)-neutralising antibody, in patients with advanced solid tumours

IGF system targeted therapy: Therapeutic opportunities for ovarian cancer

Mechanisms of action of therapeutic antibodies for cancer

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