title: Phase I study of PD 0332991, a cyclin-dependent kinase inhibitor, administered in 3-week cycles (Schedule 2/1).
abstract: BACKGROUND
  This phase I, open-label, first-in-human study determined dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of PD 0332991, an oral cyclin-dependent kinase 4/6 inhibitor with potent anti-proliferative activity in vitro/vivo.
  
  
  METHODS
  A total of 33 patients with retinoblastoma protein-positive advanced solid tumours or non-Hodgkin's lymphoma refractory to standard therapy or for which no therapy was available received PD 0332991 once daily (QD) for 14 days followed by 7 days off treatment (21-day cycles; Schedule 2/1).
  
  
  RESULTS
  Six patients had DLTs (18%; four receiving 200 mg QD; two receiving 225 mg QD); the MTD was 200 mg QD. Treatment-related, non-haematological adverse events occurred in 29 patients (88%) during cycle 1 and 27 patients (82%) thereafter. Adverse events were generally mild-moderate. Of 31 evaluable patients, one with testicular cancer achieved a partial response; nine had stable disease (≥10 cycles in three cases). PD 0332991 was slowly absorbed (mean T(max) 4.2 h) and eliminated (mean half-life 26.7 h). Volume of distribution was large (mean 3241 l) with dose-proportional exposure. Using a maximum effective concentration model, neutropenia was proportional to exposure.
  
  
  CONCLUSIONS
  PD 0332991 was generally well tolerated, with DLTs related mainly to myelosuppression. The MTD, 200 mg QD, is recommended for phase II study.
authors: Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA. schwartg@mskcc.org
authors: G K
authors: GK
authors: Schwartz
authors: P M
authors: PM
authors: LoRusso
authors: M A
authors: MA
authors: Dickson
authors: S S
authors: SS
authors: Randolph
authors: M N
authors: MN
authors: Shaik
authors: K D
authors: KD
authors: Wilner
authors: R
authors: R
authors: Courtney
authors: P J
authors: PJ
authors: O'Dwyer
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