PMID- 30293995 OWN - NLM STAT- MEDLINE DCOM- 20190826 LR - 20200225 IS - 1532-1827 (Electronic) IS - 0007-0920 (Print) IS - 0007-0920 (Linking) VI - 119 IP - 7 DP - 2018 Oct TI - Phase II trial of palbociclib in patients with metastatic urothelial cancer after failure of first-line chemotherapy. PG - 801-807 LID - 10.1038/s41416-018-0229-0 [doi] AB - BACKGROUND: The majority of urothelial cancers (UC) harbor alterations in retinoblastoma (Rb) pathway genes that can lead to loss of Rb tumour suppressor function. Palbociclib is an oral, selective inhibitor of CDK 4/6 that restores Rb function and promotes cell cycle arrest. METHODS: In this phase II trial, patients with metastatic platinum-refractory UC molecularly selected for p16 loss and intact Rb by tumour immunohistochemistry received palbociclib 125 mg p.o. daily for 21 days of a 28-day cycle. Primary endpoint was progression-free survival at 4 months (PFS4) using a Simon's two-stage design. Next-generation sequencing including Rb pathway alterations was conducted. RESULTS: Twelve patients were enrolled and two patients (17%) achieved PFS4 with insufficient activity to advance to stage 2. No responses were seen. Median PFS was 1.9 months (95% CI 1.8-3.7 months) and median overall survival was 6.3 months (95% CI 2.2-12.6 months). Fifty-eight percent of patients had grade >/=3 hematologic toxicity. There were no CDKN2A alterations found and no correlation of Rb pathway alterations with clinical outcome. CONCLUSIONS: Palbociclib did not demonstrate meaningful activity in selected patients with platinum-refractory metastatic UC. Further development of palbociclib should only be considered with improved integral biomarker selection or in rational combination with other therapies. FAU - Rose, Tracy L AU - Rose TL AD - Division of Hematology/Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. FAU - Chism, David D AU - Chism DD AD - Division of Hematology and Oncology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA. FAU - Alva, Ajjai S AU - Alva AS AD - Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI, USA. FAU - Deal, Allison M AU - Deal AM AD - Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. FAU - Maygarden, Susan J AU - Maygarden SJ AD - Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. FAU - Whang, Young E AU - Whang YE AD - Division of Hematology/Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. FAU - Kardos, Jordan AU - Kardos J AD - Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. FAU - Drier, Anthony AU - Drier A AD - Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. FAU - Basch, Ethan AU - Basch E AD - Division of Hematology/Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. FAU - Godley, Paul A AU - Godley PA AD - Division of Hematology/Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. FAU - Dunn, Mary W AU - Dunn MW AD - Division of Hematology/Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. FAU - Kim, William Y AU - Kim WY AD - Division of Hematology/Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. FAU - Milowsky, Matthew I AU - Milowsky MI AD - Division of Hematology/Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. matt_milowsky@med.unc.edu. LA - eng GR - K12 CA120780/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase II PT - Journal Article PT - Multicenter Study PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20181008 PL - England TA - Br J Cancer JT - British journal of cancer JID - 0370635 RN - 0 (CDKN2A protein, human) RN - 0 (Cyclin-Dependent Kinase Inhibitor p16) RN - 0 (Piperazines) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyridines) RN - G9ZF61LE7G (palbociclib) MH - Aged MH - Aged, 80 and over MH - Carcinoma, Transitional Cell/*drug therapy/genetics MH - Cyclin-Dependent Kinase Inhibitor p16/*genetics MH - Disease-Free Survival MH - Drug Administration Schedule MH - Female MH - High-Throughput Nucleotide Sequencing MH - Humans MH - Male MH - Middle Aged MH - Mutation MH - Piperazines/*administration & dosage/adverse effects MH - Protein Kinase Inhibitors/*administration & dosage/adverse effects MH - Pyridines/*administration & dosage/adverse effects MH - Sequence Analysis, DNA MH - Treatment Outcome MH - Urologic Neoplasms/*drug therapy/genetics PMC - PMC6189143 COIS- W.Y.K. has research funding from GeneCentric and IBM. D.D.C. has a scientific advisory role for Karyopharm Inc. and Exelixis. Y.E.W. has research funding from Astellas Pharma, Innocrin Pharmaceuticals, Inovio Pharmaceuticals, and Tokai Pharmaceuticals. M.I.M. receives research funding from Merck, BMS, and Genentech. The other authors declare no competing interests. EDAT- 2018/10/09 06:00 MHDA- 2019/08/27 06:00 PMCR- 2019/10/08 CRDT- 2018/10/09 06:00 PHST- 2018/03/27 00:00 [received] PHST- 2018/07/19 00:00 [accepted] PHST- 2018/07/09 00:00 [revised] PHST- 2018/10/09 06:00 [pubmed] PHST- 2019/08/27 06:00 [medline] PHST- 2018/10/09 06:00 [entrez] PHST- 2019/10/08 00:00 [pmc-release] AID - 10.1038/s41416-018-0229-0 [pii] AID - 229 [pii] AID - 10.1038/s41416-018-0229-0 [doi] PST - ppublish SO - Br J Cancer. 2018 Oct;119(7):801-807. doi: 10.1038/s41416-018-0229-0. Epub 2018 Oct 8.