Purpose Ixazomib is an investigational proteasome\ninhibitor with demonstrated antitumor activity in xenograft\nmodels of multiple myeloma (MM), lymphoma, and\nsolid tumors. This open-label, phase 1 study investigated intravenous\n(IV) ixazomib, in adult patients with advanced nonhematologic\nmalignancies. Methods Patients received IV\nixazomib twice-weekly for up to twelve 21-day cycles. The\n0.125 mg/m2 starting dose was doubled (one patient/dose)\nuntil 1.0 mg/m2 based on dose-limiting toxicities (DLTs) in\ncycle 1. This was followed by 3+3 dose-escalation and expansion\nat the maximum tolerated dose (MTD). Primary objectives\nincluded safety and MTD assessment. Secondary objectives\nincluded assessment of pharmacokinetics, pharmacodynamics,\nand disease response. Results Ixazomib was escalated\nfrom 0.125 to 2.34 mg/m2 to determine the MTD (n=\n23); patients were then enrolled to MTD expansion (n=73)\nand pharmacodynamic (n=20) cohorts. Five patients experienced\nDLTs (1.0 and 1.76 mg/m2: grade 3 pruritic rash;\n2.34 mg/m2: grade 3 and 4 thrombocytopenia, and grade 3\nacute renal failure); thus, the MTD was 1.76 mg/m2. Drugrelated\ngrade ?3 adverse events (AEs) included thrombocytopenia\n(23 %), skin and subcutaneous (SC) tissue disorders\n(16 %), and fatigue (9 %). Among 92 evaluable patients,\none (head and neck cancer) had a partial response and\n30 had stable disease. Ixazomib terminal half-life was\n3.8ââ?¬â??7.2 days; plasma exposures increased dose proportionally\nand drug was distributed to tumors. Inhibition\nof whole-blood 20S proteasome activity and upregulation\nof ATF-3 in tumor biopsies demonstrated target\nengagement. Conclusions In patients with solid tumors,\nixazomib was associated with a manageable safety\nprofile, limited antitumor activity, and evidence of\ndownstream proteasome inhibition effects.
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