Mark A Dickson1, Gary K Schwartz2, Mary Louise Keohan1, Sandra P D'Angelo1, Mrinal M Gounder1, Ping Chi1, Cristina R Antonescu3, Jonathan Landa4, Li-Xuan Qin5, Aimee M Crago6, Samuel Singer6, Andrew Koff7, William D Tap1. 1. Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York8Weill Cornell Medical College, New York, New York. 2. Columbia University Medical Center, New York, New York. 3. Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York. 4. Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York8Weill Cornell Medical College, New York, New York. 5. Department of Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York. 6. Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York8Weill Cornell Medical College, New York, New York. 7. Department of Cell Biology, Memorial Sloan-Kettering Cancer Center, New York, New York.
Abstract
IMPORTANCE: More than 90% of well-differentiated or dedifferentiated liposarcomas (WD/DDLS) have CDK4 amplification. The selective CDK4 and CDK6 inhibitor palbociclib inhibits growth and induces senescence in liposarcoma cell lines and xenografts. Our prior phase 2 study demonstrated that treatment with palbociclib (200 mg daily for 14 days every 21 days) resulted in clinical benefit in WD/DDLS but moderate hematologic toxic effects. It is important to understand whether palbociclib at a new dose and schedule-125 mg daily for 21 days every 28 days-results in clinical benefit and manageable toxic effects. OBJECTIVE: To determine the progression-free survival (PFS) at 12 weeks of patients with WD/DDLS treated with palbociclib (PD0332991). DESIGN, SETTING, AND PARTICIPANTS: In this phase 2, nonrandomized, open-label clinical trial conducted at the Memorial Sloan Kettering Cancer Center, 60 patients 18 years and older with advanced WD/DDLS and measurable disease by RECIST 1.1 were enrolled from December 2011 to January 2014 and followed to March 2015. Patients received oral palbociclib at 125 mg daily for 21 days in 28-day cycles. MAIN OUTCOMES AND MEASURES: Primary end point was PFS. Secondary end points included response rate and toxic effects. RESULTS: Overall, 30 patients were enrolled in the initial cohort and 30 more in an expansion cohort. Median (range) age was 61.5 (35-87) years; 31 patients (52%) were male; median (range) Eastern Cooperative Oncology Group score was 0 (0-1). Progression-free survival at 12 weeks was 57.2% (2-sided 95% CI, 42.4%-68.8%), and the median PFS was 17.9 weeks (2-sided 95% CI, 11.9-24.0 weeks). There was 1 complete response. Toxic effects were primarily hematologic and included neutropenia (grade 3, n = 20 [33%]; grade 4, n = 2 [3%]) but no neutropenic fever. CONCLUSIONS AND RELEVANCE: In patients with advanced WD/DDLS, treatment with palbociclib was associated with a favorable PFS and occasional tumor response. This dose and schedule appears active and may have less toxic effects than 200 mg for 14 days. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01209598.
IMPORTANCE: More than 90% of well-differentiated or dedifferentiated liposarcomas (WD/DDLS) have CDK4 amplification. The selective CDK4 and CDK6 inhibitor palbociclib inhibits growth and induces senescence in liposarcoma cell lines and xenografts. Our prior phase 2 study demonstrated that treatment with palbociclib (200 mg daily for 14 days every 21 days) resulted in clinical benefit in WD/DDLS but moderate hematologic toxic effects. It is important to understand whether palbociclib at a new dose and schedule-125 mg daily for 21 days every 28 days-results in clinical benefit and manageable toxic effects. OBJECTIVE: To determine the progression-free survival (PFS) at 12 weeks of patients with WD/DDLS treated with palbociclib (PD0332991). DESIGN, SETTING, AND PARTICIPANTS: In this phase 2, nonrandomized, open-label clinical trial conducted at the Memorial Sloan Kettering Cancer Center, 60 patients 18 years and older with advanced WD/DDLS and measurable disease by RECIST 1.1 were enrolled from December 2011 to January 2014 and followed to March 2015. Patients received oral palbociclib at 125 mg daily for 21 days in 28-day cycles. MAIN OUTCOMES AND MEASURES: Primary end point was PFS. Secondary end points included response rate and toxic effects. RESULTS: Overall, 30 patients were enrolled in the initial cohort and 30 more in an expansion cohort. Median (range) age was 61.5 (35-87) years; 31 patients (52%) were male; median (range) Eastern Cooperative Oncology Group score was 0 (0-1). Progression-free survival at 12 weeks was 57.2% (2-sided 95% CI, 42.4%-68.8%), and the median PFS was 17.9 weeks (2-sided 95% CI, 11.9-24.0 weeks). There was 1 complete response. Toxic effects were primarily hematologic and included neutropenia (grade 3, n = 20 [33%]; grade 4, n = 2 [3%]) but no neutropenic fever. CONCLUSIONS AND RELEVANCE: In patients with advanced WD/DDLS, treatment with palbociclib was associated with a favorable PFS and occasional tumor response. This dose and schedule appears active and may have less toxic effects than 200 mg for 14 days. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01209598.
Authors: William D Tap; Fritz C Eilber; Charles Ginther; Sarah M Dry; Nicholas Reese; Kate Barzan-Smith; Hsiao-Wang Chen; Hong Wu; Frederick R Eilber; Dennis J Slamon; Lee Anderson Journal: Genes Chromosomes Cancer Date: 2011-02 Impact factor: 5.006
Authors: Jordi Barretina; Barry S Taylor; Shantanu Banerji; Alexis H Ramos; Mariana Lagos-Quintana; Penelope L Decarolis; Kinjal Shah; Nicholas D Socci; Barbara A Weir; Alan Ho; Derek Y Chiang; Boris Reva; Craig H Mermel; Gad Getz; Yevgenyi Antipin; Rameen Beroukhim; John E Major; Charles Hatton; Richard Nicoletti; Megan Hanna; Ted Sharpe; Tim J Fennell; Kristian Cibulskis; Robert C Onofrio; Tsuyoshi Saito; Neerav Shukla; Christopher Lau; Sven Nelander; Serena J Silver; Carrie Sougnez; Agnes Viale; Wendy Winckler; Robert G Maki; Levi A Garraway; Alex Lash; Heidi Greulich; David E Root; William R Sellers; Gary K Schwartz; Cristina R Antonescu; Eric S Lander; Harold E Varmus; Marc Ladanyi; Chris Sander; Matthew Meyerson; Samuel Singer Journal: Nat Genet Date: 2010-07-04 Impact factor: 38.330
Authors: E A Eisenhauer; P Therasse; J Bogaerts; L H Schwartz; D Sargent; R Ford; J Dancey; S Arbuck; S Gwyther; M Mooney; L Rubinstein; L Shankar; L Dodd; R Kaplan; D Lacombe; J Verweij Journal: Eur J Cancer Date: 2009-01 Impact factor: 9.162
Authors: 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; Gary K Schwartz Journal: J Clin Oncol Date: 2013-04-08 Impact factor: 44.544
Authors: Samuel Singer; Nicholas D Socci; Grazia Ambrosini; Elliot Sambol; Penelope Decarolis; Yuhsin Wu; Rachael O'Connor; Robert Maki; Agnes Viale; Chris Sander; Gary K Schwartz; Cristina R Antonescu Journal: Cancer Res Date: 2007-07-15 Impact factor: 12.701
Authors: David W Fry; Patricia J Harvey; Paul R Keller; William L Elliott; Maryanne Meade; Erin Trachet; Mudher Albassam; XianXian Zheng; Wilbur R Leopold; Nancy K Pryer; Peter L Toogood Journal: Mol Cancer Ther Date: 2004-11 Impact factor: 6.261
Authors: Marta Kovatcheva; David D Liu; Mark A Dickson; Mary E Klein; Rachael O'Connor; Fatima O Wilder; Nicholas D Socci; William D Tap; Gary K Schwartz; Samuel Singer; Aimee M Crago; Andrew Koff Journal: Oncotarget Date: 2015-04-10
Authors: Zachary Benson; Saeed H Manjili; Mehran Habibi; Georgi Guruli; Amir A Toor; Kyle K Payne; Masoud H Manjili Journal: Biochem Pharmacol Date: 2017-08-10 Impact factor: 5.858
Authors: Leanne C Sayles; Marcus R Breese; Amanda L Koehne; Stanley G Leung; Alex G Lee; Heng-Yi Liu; Aviv Spillinger; Avanthi T Shah; Bogdan Tanasa; Krystal Straessler; Florette K Hazard; Sheri L Spunt; Neyssa Marina; Grace E Kim; Soo-Jin Cho; Raffi S Avedian; David G Mohler; Mi-Ok Kim; Steven G DuBois; Douglas S Hawkins; E Alejandro Sweet-Cordero Journal: Cancer Discov Date: 2018-09-28 Impact factor: 39.397
Authors: Andrew J Wagner; Udai Banerji; Amit Mahipal; Neeta Somaiah; Heather Hirsch; Craig Fancourt; Amy O Johnson-Levonas; Raymond Lam; Amy K Meister; Giuseppe Russo; Clayton D Knox; Shelonitda Rose; David S Hong Journal: J Clin Oncol Date: 2017-02-27 Impact factor: 44.544
Authors: Ali Amin-Mansour; Suzanne George; Stefano Sioletic; Scott L Carter; Mara Rosenberg; Amaro Taylor-Weiner; Chip Stewart; Aaron Chevalier; Sara Seepo; Adam Tracy; Gad Getz; Jason L Hornick; Marisa R Nucci; Bradley Quade; George D Demetri; Chandrajit P Raut; Levi A Garraway; Eliezer M Van Allen; Andrew J Wagner Journal: Clin Cancer Res Date: 2019-06-04 Impact factor: 12.531
Authors: Thomas Benjamin Karasic; Mark H O'Hara; Ursina R Teitelbaum; Nevena Damjanov; Bruce J Giantonio; Tracy S d'Entremont; Maryann Gallagher; Paul J Zhang; Peter J O'Dwyer Journal: Oncologist Date: 2020-08-08