title: Phase I, dose-escalation trial of the oral cyclin-dependent kinase 4/6 inhibitor PD 0332991, administered using a 21-day schedule in patients with advanced cancer.
abstract: OBJECTIVE
  To identify the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of the first-in-class, oral CDK4/6 inhibitor PD 0332991 administered once daily for 21 of 28 days (3/1 schedule) in patients with retinoblastoma protein (Rb)-positive advanced solid tumors and to describe pharmacokinetic-pharmacodynamic relationships relative to drug effects.
  
  
  METHODS
  This open-label phase I study (NCT00141297) enrolled patients who received PD 0332991 orally in six dose-escalation cohorts in a standard 3 + 3 design.
  
  
  RESULTS
  Forty-one patients were enrolled. DLTs were observed in five patients (12%) overall; at the 75, 125, and 150 mg once daily dose levels. The MTD and recommended phase II dose of PD 0332991 was 125 mg once daily. Neutropenia was the only dose-limiting effect. After cycle 1, grade 3 neutropenia, anemia, and leukopenia occurred in five (12%), three (7%), and one (2%) patient(s), respectively. The most common non-hematologic adverse events included fatigue, nausea, and diarrhea. Thirty-seven patients were evaluable for tumor response; 10 (27%) had stable disease for ≥4 cycles of whom six derived prolonged benefit (≥10 cycles). PD 0332991 was slowly absorbed (median T(max), 5.5 hours), and slowly eliminated (mean half-life was 25.9 hours) with a large volume of distribution (mean, 2,793 L). The area under the concentration-time curve increased linearly with dose. Using an E(max) model, neutropenia was shown to be proportional to exposure.
  
  
  CONCLUSIONS
  PD 0332991 warrants phase II testing at 125 mg once daily, at which dose neutropenia was the sole significant toxicity.
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Lorusso
authors.forename: Angela
authors.initials: A
authors.lastname: Demichele
authors.forename: Vandana G
authors.initials: VG
authors.lastname: Abramson
authors.forename: Rachel
authors.initials: R
authors.lastname: Courtney
authors.forename: Sophia S
authors.initials: SS
authors.lastname: Randolph
authors.forename: M Naveed
authors.initials: MN
authors.lastname: Shaik
authors.forename: Keith D
authors.initials: KD
authors.lastname: Wilner
authors.forename: Peter J
authors.initials: PJ
authors.lastname: O'Dwyer
authors.forename: Gary K
authors.initials: GK
authors.lastname: Schwartz
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D019540:Area Under Curve; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced; D010879:Piperazines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D011725:Pyridines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D010879:Piperazines; D011725:Pyridines; D018844:Cyclin-Dependent Kinases; C500026:palbociclib