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Open Access 01-06-2015 | PHASE I STUDIES

Phase 1 study of ixazomib, an investigational proteasome inhibitor, in advanced non-hematologic malignancies

Authors: David C. Smith, Thea Kalebic, Jeffrey R. Infante, Lillian L. Siu, Daniel Sullivan, Gordana Vlahovic, John S. Kauh, Feng Gao, Allison J. Berger, Stephen Tirrell, Neeraj Gupta, Alessandra Di Bacco, Deborah Berg, Guohui Liu, Jianchang Lin, Ai-Min Hui, John A. Thompson

Published in: Investigational New Drugs | Issue 3/2015

Summary

Purpose Ixazomib is an investigational proteasome inhibitor with demonstrated antitumor activity in xenograft models of multiple myeloma (MM), lymphoma, and solid tumors. This open-label, phase 1 study investigated intravenous (IV) ixazomib, in adult patients with advanced non-hematologic malignancies. Methods Patients received IV ixazomib twice-weekly for up to twelve 21-day cycles. The 0.125 mg/m² starting dose was doubled (one patient/dose) until 1.0 mg/m² based on dose-limiting toxicities (DLTs) in cycle 1. This was followed by 3 + 3 dose-escalation and expansion at the maximum tolerated dose (MTD). Primary objectives included safety and MTD assessment. Secondary objectives included assessment of pharmacokinetics, pharmacodynamics, and disease response. Results Ixazomib was escalated from 0.125 to 2.34 mg/m² to determine the MTD (n = 23); patients were then enrolled to MTD expansion (n = 73) and pharmacodynamic (n = 20) cohorts. Five patients experienced DLTs (1.0 and 1.76 mg/m²: grade 3 pruritic rash; 2.34 mg/m²: grade 3 and 4 thrombocytopenia, and grade 3 acute renal failure); thus, the MTD was 1.76 mg/m². Drug-related grade ≥3 adverse events (AEs) included thrombocytopenia (23 %), skin and subcutaneous (SC) tissue disorders (16 %), and fatigue (9 %). Among 92 evaluable patients, one (head and neck cancer) had a partial response and 30 had stable disease. Ixazomib terminal half-life was 3.8–7.2 days; plasma exposures increased dose-proportionally and drug was distributed to tumors. Inhibition of whole-blood 20S proteasome activity and upregulation of ATF-3 in tumor biopsies demonstrated target engagement. Conclusions In patients with solid tumors, ixazomib was associated with a manageable safety profile, limited antitumor activity, and evidence of downstream proteasome inhibition effects.

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Title: Phase 1 study of ixazomib, an investigational proteasome inhibitor, in advanced non-hematologic malignancies
Authors: David C. Smith
Thea Kalebic
Jeffrey R. Infante
Lillian L. Siu
Daniel Sullivan
Gordana Vlahovic
John S. Kauh
Feng Gao
Allison J. Berger
Stephen Tirrell
Neeraj Gupta
Alessandra Di Bacco
Deborah Berg
Guohui Liu
Jianchang Lin
Ai-Min Hui
John A. Thompson
Publication date: 01-06-2015
Publisher: Springer US
Published in: Investigational New Drugs / Issue 3/2015
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-015-0230-x

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