PMID- 30979737 OWN - NLM STAT- MEDLINE DCOM- 20200914 LR - 20200914 IS - 1557-3265 (Electronic) IS - 1078-0432 (Linking) VI - 25 IP - 15 DP - 2019 Aug 1 TI - Activity and Safety of Palbociclib in Patients with Advanced Gastrointestinal Stromal Tumors Refractory to Imatinib and Sunitinib: A Biomarker-driven Phase II Study. PG - 4611-4615 LID - 10.1158/1078-0432.CCR-18-3127 [doi] AB - PURPOSE: CDKN2A loss is frequent in gastrointestinal stromal tumors (GISTs) and associated with aggressive outcome. Palbociclib is a CDK4 inhibitor with preclinical antitumor efficacy in tumors with P16/CDKN2A loss. PATIENTS AND METHODS: This is a multicenter single-arm phase II clinical trial assessing safety and efficacy of palbociclib in patients with advanced GIST bearing CDKN2A gene loss. Adults with unresectable locally advanced or metastatic, refractory to at least imatinib and sunitinib, measurable and documented progressive disease (PD) as per RECIST 1.1, and CDKN2A deletion centrally assessed were eligible. Patients received palbociclib 125 mg orally daily on a 21 days on/7 days off dosing schedule, until PD or unacceptable toxicity. The primary endpoint was 4-month non-PD rate according to RECIST 1.1. RESULTS: As of May 2017, 71 patients had been included in the study, and 29 patients (40.3%) met the molecular eligibility requirement. Twenty-five patients (86.2%) had grade 1-2 adverse events (AEs) and 12 patients (41.4%) grade 3-4 AEs possibly related to the drug. The planned interim statistical analysis performed after central histologic and radiological review showed that 19 (86.4%) out of the first 22 evaluable patients had PD at 4 months. CDKN2A status had no impact either on overall survival or outcome on previous standard lines of treatment. Translational analysis suggested upregulation of CCNE1 or downregulation of CDKN1A/P21 or LRRC3B as potential mechanisms of resistance. CONCLUSIONS: Palbociclib has no significant clinical activity as a single agent in P16/CDKN2A -deleted GIST refractory to imatinib and sunitinib. CI - (c)2019 American Association for Cancer Research. FAU - Toulmonde, Maud AU - Toulmonde M AD - Department of Medical Oncology, Institut Bergonie, Bordeaux, France. FAU - Blay, Jean-Yves AU - Blay JY AUID- ORCID: 0000-0001-7926-4671 AD - Department of Medical Oncology, Centre Leon Berard, Lyon, France. FAU - Bouche, Olivier AU - Bouche O AD - Department of Digestive Oncology, Hopital Robert Debre, Reims, France. FAU - Mir, Olivier AU - Mir O AD - Department of Ambulatory Care, Gustave Roussy, Villejuif, France. FAU - Penel, Nicolas AU - Penel N AD - Department of Medical Oncology, Centre Oscar Lambret, and Lille University Hospital, Lille, France. FAU - Isambert, Nicolas AU - Isambert N AD - Department of Medical Oncology, Centre Georges Francois Leclerc, Dijon, France. FAU - Duffaud, Florence AU - Duffaud F AD - Department of Medical Oncology, Hopital La Timone, Marseille, France. FAU - Bompas, Emmanuelle AU - Bompas E AD - Department of Medical Oncology, Institut de Cancerologie de l'Ouest, Nantes, France. FAU - Esnaud, Thomas AU - Esnaud T AD - Department of Epidemiology and Clinical Research, Institut Bergonie, Bordeaux, France. FAU - Boidot, Romain AU - Boidot R AUID- ORCID: 0000-0001-9956-1737 AD - Department of Tumor Biology, Centre Georges-Francois Leclerc, Dijon, France. FAU - Geneste, Damien AU - Geneste D AD - Department of Boinformatics, Institut Bergonie, Bordeaux, France. FAU - Ghiringhelli, Francois AU - Ghiringhelli F AD - Department of Tumor Biology, Centre Georges-Francois Leclerc, Dijon, France. FAU - Lucchesi, Carlo AU - Lucchesi C AUID- ORCID: 0000-0001-6657-2341 AD - Department of Boinformatics, Institut Bergonie, Bordeaux, France. FAU - Bellera, Carine A AU - Bellera CA AD - Department of Epidemiology and Clinical Research, Institut Bergonie, Bordeaux, France. FAU - Le Loarer, Francois AU - Le Loarer F AD - Department of Pathology, Institut Bergonie, Bordeaux, France. FAU - Italiano, Antoine AU - Italiano A AD - Department of Medical Oncology, Institut Bergonie, Bordeaux, France. a.italiano@bordeaux.unicancer.fr. LA - eng SI - ClinicalTrials.gov/NCT01907607 PT - Clinical Trial, Phase II PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't DEP - 20190412 PL - United States TA - Clin Cancer Res JT - Clinical cancer research : an official journal of the American Association for Cancer Research JID - 9502500 RN - 0 (Biomarkers, Tumor) RN - 0 (CDKN2A protein, human) RN - 0 (Cyclin-Dependent Kinase Inhibitor p16) RN - 0 (Piperazines) RN - 0 (Pyridines) RN - 8A1O1M485B (Imatinib Mesylate) RN - G9ZF61LE7G (palbociclib) RN - V99T50803M (Sunitinib) SB - IM EIN - Clin Cancer Res. 2019 Aug 1;25(15):4859. PMID: 31371309 MH - Adult MH - Aged MH - Aged, 80 and over MH - Antineoplastic Combined Chemotherapy Protocols/*therapeutic use MH - Biomarkers, Tumor/*analysis MH - Cyclin-Dependent Kinase Inhibitor p16/genetics MH - Drug Resistance, Neoplasm/*drug effects MH - Female MH - Gastrointestinal Neoplasms/*drug therapy/genetics/pathology MH - Gastrointestinal Stromal Tumors/*drug therapy/genetics/pathology MH - Gene Deletion MH - Humans MH - Imatinib Mesylate/administration & dosage MH - Male MH - Middle Aged MH - Patient Safety MH - Piperazines/administration & dosage MH - Pyridines/administration & dosage MH - Sunitinib/administration & dosage MH - Survival Rate MH - Treatment Outcome EDAT- 2019/04/14 06:00 MHDA- 2020/09/15 06:00 CRDT- 2019/04/14 06:00 PHST- 2018/10/01 00:00 [received] PHST- 2018/11/15 00:00 [revised] PHST- 2019/04/02 00:00 [accepted] PHST- 2019/04/14 06:00 [pubmed] PHST- 2020/09/15 06:00 [medline] PHST- 2019/04/14 06:00 [entrez] AID - 1078-0432.CCR-18-3127 [pii] AID - 10.1158/1078-0432.CCR-18-3127 [doi] PST - ppublish SO - Clin Cancer Res. 2019 Aug 1;25(15):4611-4615. doi: 10.1158/1078-0432.CCR-18-3127. Epub 2019 Apr 12.