title: Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma.
abstract: OBJECTIVE
  CDK4 is amplified in > 90% of well-differentiated (WDLS) and dedifferentiated liposarcomas (DDLS). The selective cyclin-dependent kinase 4 (CDK4)/CDK6 inhibitor PD0332991 inhibits growth and induces senescence in cell lines and xenografts. In a phase I trial of PD0332991, several patients with WDLS or DDLS experienced prolonged stable disease. We performed an open-label phase II study to determine the safety and efficacy of PD0332991 in patients with advanced WDLS/DDLS.
  
  
  METHODS
  Patients age ≥ 18 years experiencing disease progression while receiving systemic therapy before enrollment received PD0332991 200 mg orally once per day for 14 consecutive days in 21-day cycles. All were required to have CDK4 amplification by fluorescence in situ hybridization and retinoblastoma protein (RB) expression by immunohistochemistry (≥ 1+). The primary end point was progression-free survival (PFS) at 12 weeks, with 12-week PFS of ≥ 40% considered promising and ≤ 20% not promising. If ≥ nine of 28 patients were progression free at 12 weeks, PD0332991 would be considered active.
  
  
  RESULTS
  We screened 48 patients (44 of 48 had CDK4 amplification; 41 of 44 were RB positive). Of those, 30 were enrolled, and 29 were evaluable for the primary end point. Grade 3 to 4 events included anemia (17%), thrombocytopenia (30%), neutropenia (50%), and febrile neutropenia (3%). At 12 weeks, PFS was 66% (90% CI, 51% to 100%), significantly exceeding the primary end point. The median PFS was 18 weeks. There was one partial response.
  
  
  CONCLUSIONS
  Treatment with the CDK4 inhibitor PD0332991 was associated with a favorable progression-free rate in patients with CDK4-amplified and RB-expressing WDLS/DDLS who had progressive disease despite systemic therapy.
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY, USA. dicksonm@mskcc.org
authors.forename: Mark A
authors.initials: MA
authors.lastname: Dickson
authors.forename: William D
authors.initials: WD
authors.lastname: Tap
authors.forename: Mary Louise
authors.initials: ML
authors.lastname: Keohan
authors.forename: Sandra P
authors.initials: SP
authors.lastname: D'Angelo
authors.forename: Mrinal M
authors.initials: MM
authors.lastname: Gounder
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Antonescu
authors.forename: Jonathan
authors.initials: J
authors.lastname: Landa
authors.forename: Li-Xuan
authors.initials: LX
authors.lastname: Qin
authors.forename: Dustin D
authors.initials: DD
authors.lastname: Rathbone
authors.forename: Mercedes M
authors.initials: MM
authors.lastname: Condy
authors.forename: Yelena
authors.initials: Y
authors.lastname: Ustoyev
authors.forename: Aimee M
authors.initials: AM
authors.lastname: Crago
authors.forename: Samuel
authors.initials: S
authors.lastname: Singer
authors.forename: Gary K
authors.initials: GK
authors.lastname: Schwartz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis*; D002454:Cell Differentiation / Q000187:drug effects; D051358:Cyclin-Dependent Kinase 4 / Q000032:analysis* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008080:Liposarcoma / Q000737:chemistry / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D016160:Retinoblastoma Protein / Q000032:analysis; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D010879:Piperazines; D011725:Pyridines; D016160:Retinoblastoma Protein; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; C500026:palbociclib