- © 2013 by American Society of Clinical Oncology
Phase II Trial of the CDK4 Inhibitor PD0332991 in Patients With Advanced CDK4-Amplified Well-Differentiated or Dedifferentiated Liposarcoma
- Mark A. Dickson⇑,
- William D. Tap,
- Mary Louise Keohan,
- Sandra P. D'Angelo,
- Mrinal M. Gounder,
- Cristina R. Antonescu,
- Jonathan Landa,
- Li-Xuan Qin,
- Dustin D. Rathbone,
- Mercedes M. Condy,
- Yelena Ustoyev,
- Aimee M. Crago,
- Samuel Singer and
- Gary K. Schwartz
+ Author Affiliations
- Corresponding author: Mark A. Dickson, MD, 300 E 66th St, New York, NY 10065; e-mail: dicksonm@mskcc.org.
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Presented in part at the 48th Annual Meeting of the American Society for Clinical Oncology, Chicago, IL, June 1-5, 2012.
Abstract
Purpose 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 and 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.
Conclusion 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.
Footnotes
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Supported by Pfizer and in part by National Cancer Institute, National Institutes of Health, Soft Tissue Sarcoma Program Project Grant No. P01 CA047179 (C.R.A., S.S, G.K.S.).
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Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Clinical trial information: NCT01209598.
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