• Investigational new drugs · Apr 2016

    Multicenter Study

    A first-in-human dose-escalation study of the oral proteasome inhibitor oprozomib in patients with advanced solid tumors.

    • Jeffrey R Infante, David S Mendelson, Howard A Burris, Johanna C Bendell, Anthony W Tolcher, Michael S Gordon, Heidi H Gillenwater, Shirin Arastu-Kapur, Hansen L Wong, and Kyriakos P Papadopoulos.
    • Sarah Cannon Research Institute/Tennessee Oncology, 250 25th Avenue North, Nashville, TN, 37203, USA. jinfante@tnonc.com.
    • Invest New Drugs. 2016 Apr 1; 34 (2): 216-24.

    PurposeTo 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.MethodsPatients 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.ResultsForty-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.ConclusionsWhile 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.

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