| Abstract: |
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. 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. 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. 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. |
| Keywords: |
immunohistochemistry; adult; treatment outcome; aged; aged, 80 and over; disease-free survival; middle aged; antineoplastic agents; pyridines; disease free survival; antineoplastic agent; metabolism; in situ hybridization, fluorescence; phase 2 clinical trial; tumor markers, biological; cell differentiation; drug effect; pathology; tumor marker; chemistry; drug antagonism; fluorescence in situ hybridization; piperazines; kaplan meier method; piperazine derivative; retinoblastoma protein; liposarcoma; cyclin dependent kinase 4; pyridine derivative; cyclin-dependent kinase 4; kaplan-meier estimate; very elderly; 6 acetyl 8 cyclopentyl 5 methyl 2 (5 piperazin 1 ylpyridin 2 ylamino) 8h pyrido(2,3 d)pyrimidin 7 one; 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-ylpyridin-2-ylamino)-8h-pyrido(2,3-d)pyrimidin-7-one; cdk4 protein, human
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