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

David C. Smith,T. Kalebic,J. Infante,L. Siu,D. Sullivan,G. Vlahović,J. Kauh,F. Gao,A. Berger,S. Tirrell,N. Gupta,A. Di Bacco,D. Berg,Guohui Liu,Jianchang Lin,A. Hui,John A Thompson

Published 2015 in Investigational new drugs

ABSTRACT

SummaryPurpose 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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