title: A first-in-human dose-escalation study of the oral proteasome inhibitor oprozomib in patients with advanced solid tumors.
abstract: OBJECTIVE
  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.
authors.affiliation: Sarah Cannon Research Institute/Tennessee Oncology, 250 25th Avenue North, Nashville, TN, 37203, USA. jinfante@tnonc.com.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
authors.affiliation: Pinnacle Oncology Hematology, Scottsdale, AZ, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Mendelson
authors.affiliation: Sarah Cannon Research Institute/Tennessee Oncology, 250 25th Avenue North, Nashville, TN, 37203, USA.
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
authors.affiliation: Sarah Cannon Research Institute/Tennessee Oncology, 250 25th Avenue North, Nashville, TN, 37203, USA.
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Bendell
authors.affiliation: South Texas Accelerated Research Therapeutics (START), San Antonio, TX, USA.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Tolcher
authors.affiliation: Pinnacle Oncology Hematology, Scottsdale, AZ, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Gordon
authors.affiliation: Onyx Pharmaceuticals, Inc., an Amgen Subsidiary, South San Francisco, CA, USA.
authors.forename: Heidi H
authors.initials: HH
authors.lastname: Gillenwater
authors.affiliation: Onyx Pharmaceuticals, Inc., an Amgen Subsidiary, South San Francisco, CA, USA.
authors.forename: Shirin
authors.initials: S
authors.lastname: Arastu-Kapur
authors.affiliation: Onyx Pharmaceuticals, Inc., an Amgen Subsidiary, South San Francisco, CA, USA.
authors.forename: Hansen L
authors.initials: HL
authors.lastname: Wong
authors.affiliation: South Texas Accelerated Research Therapeutics (START), San Antonio, TX, USA.
authors.forename: Kyriakos P
authors.initials: KP
authors.lastname: Papadopoulos
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D009842:Oligopeptides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D061988:Proteasome Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; C554738:ONX 0912; D009842:Oligopeptides; D061988:Proteasome Inhibitors
keywords: Carfilzomib; Dose escalation; Oprozomib; Phase 1; Proteasome inhibitor