A first-in-human dose-escalation study of the oral proteasome inhibitor oprozomib in patients with advanced solid tumors
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Purpose To determine the dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), safety, and pharmacokinetic and pharmacodynamic profiles of the tripeptide epoxyketone proteasome inhibitor oprozomib in patients with advanced refractory or recurrent solid tumors. Methods Patients received escalating once daily (QD) or split doses of oprozomib on days 1–5 of 14-day cycles (C). The split-dose arm was implemented and compared in fasted (C1) and fed (C2) states. Pharmacokinetic samples were collected during C1 and C2. Proteasome inhibition was evaluated in red blood cells and peripheral blood mononuclear cells. Results Forty-four patients (QD, n = 25; split dose, n = 19) were enrolled. The most common primary tumor types were non–small cell lung cancer (18 %) and colorectal cancer (16 %). In the 180-mg QD cohort, two patients experienced DLTs: grade 3 vomiting and dehydration; grade 3 hypophosphatemia (n = 1 each). In the split-dose group, three DLTs were observed (180-mg cohort: grade 3 hypophosphatemia; 210-mg cohort: grade 5 gastrointestinal hemorrhage and grade 3 hallucinations (n = 1 each). In the QD and split-dose groups, the MTD was 150 and 180 mg, respectively. Common adverse events (all grades) included nausea (91 %), vomiting (86 %), and diarrhea (61 %). Peak concentrations and total exposure of oprozomib generally increased with the increasing dose. Oprozomib induced dose-dependent proteasome inhibition. Best response was stable disease. Conclusions While generally low-grade, clinically relevant gastrointestinal toxicities occurred frequently with this oprozomib formulation. Despite dose-dependent increases in pharmacokinetics and pharmacodynamics, single-agent oprozomib had minimal antitumor activity in this patient population with advanced solid tumors.
KeywordsProteasome inhibitor Oprozomib Dose escalation Phase 1 Carfilzomib
The authors thank all of the patients and their families and caregivers who contributed to this study; the investigators and staff from the additional participating study sites; all of the participating research nurses and data coordinators; Darrin Bomba and Tina Woo (Onyx Pharmaceuticals, Inc.) for clinical operations support; Sandra Dixon (Onyx Pharmaceuticals, Inc.) for statistical support; Ying Ou (Onyx Pharmaceuticals, Inc.) for her assistance analyzing the pharmacokinetic data; and Janet Anderl (Onyx Pharmaceuticals, Inc.) for her assistance running and analyzing the pharmacodynamic assays. This work was supported by Onyx Pharmaceuticals, Inc., an Amgen subsidiary. Editorial assistance was provided by BlueMomentum, a division of KnowledgePoint360 Group and funded by Onyx Pharmaceuticals, Inc., an Amgen subsidiary.
Compliance with ethical standards
Conflicts of interest
Jeffrey R. Infante, David S. Mendelson, Howard A. Burris III, Johanna C. Bendell, Michael S. Gordon, and KPP have no relevant conflicts of interest to disclose. Anthony W. Tolcher has received research funding from GSK. Heidi H. Gillenwater, Shirin Arastu-Kapur, and Hansen L. Wong are employed by Onyx.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Onyx Pharmaceuticals, Inc., an Amgen subsidiary, South San Francisco, California.
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