title: A phase I/II study of carfilzomib 2-10-min infusion in patients with advanced solid tumors.
abstract: OBJECTIVE
  Tolerability, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of carfilzomib, a selective proteasome inhibitor, administered twice weekly by 2-10-min intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 in 28-day cycles, were assessed in patients with advanced solid tumors in this phase I/II study.
  
  
  METHODS
  Adult patients with solid tumors progressing after ≥1 prior therapies were enrolled. The dose was 20 mg/m(2) in week 1 of cycle 1 and 20, 27, or 36 mg/m(2) thereafter. The maximum tolerated dose or protocol-defined maximum planned dose (MPD) identified during dose escalation was administered to an expansion cohort and to patients with small cell lung, non-small cell lung, ovarian, and renal cancer in phase II tumor-specific cohorts.
  
  
  RESULTS
  Fourteen patients received carfilzomib during dose escalation. The single dose-limiting toxicity at 20/36 mg/m(2) was grade 3 fatigue, establishing the MPD as the expansion and phase II dose. Sixty-five additional patients received carfilzomib at the MPD. Adverse events included fatigue, nausea, anorexia, and dyspnea. Carfilzomib PK was dose proportional with a half-life <1 h. All doses resulted in at least 80 % proteasome inhibition in blood. Partial responses occurred in two patients in phase I, with 21.5 % stable disease after four cycles in evaluable patients in the expansion and phase II cohorts.
  
  
  CONCLUSIONS
  Carfilzomib 20/36 mg/m(2) was well tolerated when administered twice weekly by 2-10-min IV infusion. At this dose and infusion rate, carfilzomib inhibited the proteasome in blood but demonstrated limited antitumor activity in patients with advanced solid tumors.
authors: South Texas Accelerated Research Therapeutics (START), 4383 Medical Dr, Room 4042, San Antonio, TX, 78229, USA, kyri.papadopoulos@start.stoh.com.
authors: Kyriakos P
authors: KP
authors: Papadopoulos
authors: Howard A
authors: HA
authors: Burris
authors: Michael
authors: M
authors: Gordon
authors: Peter
authors: P
authors: Lee
authors: Edward A
authors: EA
authors: Sausville
authors: Peter J
authors: PJ
authors: Rosen
authors: Amita
authors: A
authors: Patnaik
authors: Richard E
authors: RE
authors: Cutler
authors: Zhengping
authors: Z
authors: Wang
authors: Susan
authors: S
authors: Lee
authors: Suzanne F
authors: SF
authors: Jones
authors: Jeffery R
authors: JR
authors: Infante
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009842:Oligopeptides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D009842:Oligopeptides; D061988:Proteasome Inhibitors; C524865:carfilzomib; D046988:Proteasome Endopeptidase Complex
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