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Invest New Drugs. 2016 Apr;34(2):216-24. doi: 10.1007/s10637-016-0327-x. Epub 2016 Feb 29.

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

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Sarah Cannon Research Institute/Tennessee Oncology, 250 25th Avenue North, Nashville, TN, 37203, USA.
Pinnacle Oncology Hematology, Scottsdale, AZ, USA.
Sarah Cannon Research Institute/Tennessee Oncology, 250 25th Avenue North, Nashville, TN, 37203, USA.
South Texas Accelerated Research Therapeutics (START), San Antonio, TX, USA.
Onyx Pharmaceuticals, Inc., an Amgen Subsidiary, South San Francisco, CA, USA.



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.


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.


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.


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.


Carfilzomib; Dose escalation; Oprozomib; Phase 1; Proteasome inhibitor

[Indexed for MEDLINE]

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