PMID- 29198055 OWN - NLM STAT- MEDLINE DCOM- 20190319 LR - 20201230 IS - 1573-7217 (Electronic) IS - 0167-6806 (Print) IS - 0167-6806 (Linking) VI - 168 IP - 2 DP - 2018 Apr TI - Phase II study of buparlisib (BKM120) and trastuzumab in patients with HER2+ locally advanced or metastatic breast cancer resistant to trastuzumab-based therapy. PG - 357-364 LID - 10.1007/s10549-017-4596-7 [doi] AB - PURPOSE: A Phase Ib study in patients with trastuzumab-resistant, human epidermal growth factor receptor-2- (HER2)-positive advanced breast cancer defined the recommended Phase II dose of buparlisib as 100 mg/day in combination with 2 mg/kg weekly trastuzumab, and reported preliminary signs of clinical activity. Here we present results from the Phase II portion. METHODS: Patients with trastuzumab-resistant, HER2-positive advanced breast cancer received buparlisib plus trastuzumab. Study endpoints included safety/tolerability and antitumour activity. The study was extended to include a Phase Ib dose-escalation phase, in which patients with progressive brain metastases also received capecitabine. RESULTS: In the Phase II portion, of 50 patients treated with buparlisib and trastuzumab, the most common (>/= 30%) all-grade adverse events (AEs) were diarrhoea (54%), nausea (48%), decreased appetite, increased alanine aminotransferase (36% each), increased aspartate aminotransferase (34%), fatigue, rash (32% each), cough and hyperglycemia (30% each). One (2%) patient achieved complete response and four (8%) patients had confirmed partial responses [PR; including two patients with phosphatidylinositol 3-kinase (PI3 K) pathway-activated tumours]. Overall response rate (ORR) was 10%: the primary endpoint (ORR >/= 25%) was therefore not met. In the Phase Ib portion, all patients with measurable brain lesions at baseline showed tumour shrinkage to some degree; due to low enrollment, maximum tolerated dose of buparlisib in combination with trastuzumab and capecitabine was not determined. CONCLUSION: Buparlisib plus trastuzumab, as a chemotherapy-free regimen, demonstrated an acceptable safety profile but limited efficacy in patients with heavily pretreated, trastuzumab-resistant HER2-positive breast cancer, and in patients with progressive brain metastases also receiving capecitabine. FAU - Pistilli, B AU - Pistilli B AUID- ORCID: 0000-0002-9184-7199 AD - Breast Cancer Unit, Institut Gustave Roussy, 114 Rue Edouard-Vaillant, 94800, Villejuif, France. barbara.pistilli@gustaveroussy.fr. AD - Macerata Hospital, Macerata, Italy. barbara.pistilli@gustaveroussy.fr. FAU - Pluard, T AU - Pluard T AD - Saint Luke's Health System, Kansas City, MO, USA. FAU - Urruticoechea, A AU - Urruticoechea A AD - Onkologikoa Foundation, San Sebastian, Spain. AD - Catalan Institute of Oncology, Barcelona, Spain. FAU - Farci, D AU - Farci D AD - Ospedale Oncologico, Cagliari, Italy. FAU - Kong, A AU - Kong A AD - University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK. AD - University of Oxford and Oxford University Hospitals NHS Trust, Oxford, UK. FAU - Bachelot, T AU - Bachelot T AD - Centre Leon Berard et Inserm U1052, Lyon, France. FAU - Chan, S AU - Chan S AD - Nottingham University Hospitals NHS Trust, Nottingham, UK. FAU - Han, H S AU - Han HS AD - Moffitt Cancer Center, Tampa, FL, USA. FAU - Jerusalem, G AU - Jerusalem G AD - CHU Sart Tilman Liege and University of Liege, Liege, Belgium. FAU - Urban, P AU - Urban P AD - Novartis Pharma AG, Basel, Switzerland. FAU - Robinson, D AU - Robinson D AD - Novartis Institutes for BioMedical Research, Cambridge, MA, USA. FAU - Mouhaer, S L AU - Mouhaer SL AD - Novartis Pharmaceuticals Corporation, Rueil-Malmaison, France. FAU - Tomaso, E D AU - Tomaso ED AD - Novartis Institutes for BioMedical Research, Cambridge, MA, USA. AD - Syros Pharmaceuticals, Watertown, MA, USA. FAU - Massacesi, C AU - Massacesi C AD - Novartis Pharmaceuticals Corporation, Rueil-Malmaison, France. FAU - Saura, C AU - Saura C AD - Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. LA - eng GR - P30 CA076292/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase I PT - Clinical Trial, Phase II PT - Journal Article DEP - 20171202 PL - Netherlands TA - Breast Cancer Res Treat JT - Breast cancer research and treatment JID - 8111104 RN - 0 (Aminopyridines) RN - 0 (Biomarkers, Tumor) RN - 0 (Morpholines) RN - 0 (NVP-BKM120) RN - 6804DJ8Z9U (Capecitabine) RN - EC 2.7.10.1 (ERBB2 protein, human) RN - EC 2.7.10.1 (Receptor, ErbB-2) RN - P188ANX8CK (Trastuzumab) SB - IM MH - Adult MH - Aged MH - Aminopyridines/administration & dosage/*adverse effects MH - Antineoplastic Combined Chemotherapy Protocols/administration & dosage/*adverse effects MH - Biomarkers, Tumor/analysis MH - Brain Neoplasms/*drug therapy/secondary MH - Breast Neoplasms/*drug therapy/pathology MH - Capecitabine/administration & dosage/adverse effects MH - Disease Progression MH - Drug Resistance, Neoplasm/drug effects MH - Female MH - Humans MH - Maximum Tolerated Dose MH - Middle Aged MH - Morpholines/administration & dosage/*adverse effects MH - Receptor, ErbB-2/metabolism MH - Response Evaluation Criteria in Solid Tumors MH - Trastuzumab/administration & dosage/*adverse effects PMC - PMC7771343 MID - NIHMS1653819 OTO - NOTNLM OT - Advanced/metastatic breast cancer OT - Brain metastases OT - Buparlisib OT - HER2-positive OT - Herceptin OT - Trastuzumab pretreated EDAT- 2017/12/05 06:00 MHDA- 2019/03/20 06:00 PMCR- 2020/12/29 CRDT- 2017/12/04 06:00 PHST- 2017/05/14 00:00 [received] PHST- 2017/11/22 00:00 [accepted] PHST- 2017/12/05 06:00 [pubmed] PHST- 2019/03/20 06:00 [medline] PHST- 2017/12/04 06:00 [entrez] PHST- 2020/12/29 00:00 [pmc-release] AID - 10.1007/s10549-017-4596-7 [pii] AID - 10.1007/s10549-017-4596-7 [doi] PST - ppublish SO - Breast Cancer Res Treat. 2018 Apr;168(2):357-364. doi: 10.1007/s10549-017-4596-7. Epub 2017 Dec 2.