PMID- 27198170 OWN - NLM STAT- MEDLINE DCOM- 20170518 LR - 20181113 IS - 1097-0142 (Electronic) IS - 0008-543X (Print) IS - 0008-543X (Linking) VI - 122 IP - 15 DP - 2016 Aug 1 TI - A phase 1 study of buparlisib and bevacizumab in patients with metastatic renal cell carcinoma progressing on vascular endothelial growth factor-targeted therapies. PG - 2389-98 LID - 10.1002/cncr.30056 [doi] AB - BACKGROUND: The phosphatidylinositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is dysregulated in patients with metastatic renal cell carcinoma (mRCC). Buparlisib is a pan-PI3K inhibitor with activity in advanced solid tumors. The primary objective of the current study was to determine the maximum tolerated dose (MTD) and dose-limiting toxicities of buparlisib and bevacizumab in patients with mRCC. Secondary objectives included efficacy, biomarker discovery, and additional toxicity. METHODS: This was a standard 3 + 3 dose escalation study of buparlisib (at a dose of 60-100 mg/day) and bevacizumab (at a dose of 10 mg/kg every 2 weeks). After the MTD was defined, 15 patients were accrued to the expansion cohort. RESULTS: Thirty-two patients were accrued (3 were treated at 60 mg/day, 21 were treated at 80 mg/day, 6 were treated at 100 mg/day, and 2 patients never received therapy). The majority of patients had clear cell histology (87%) and 50% had received >/=2 prior lines of therapy. The MTD of buparlisib was 80 mg/day and that of bevacizumab was 10 mg/kg every 2 weeks. A total of 28 patients discontinued therapy: 17 because of disease progression, 7 because of toxicity, and 4 for other reasons. Dose-limiting toxicities included rash/pruritis, elevated lipase/amylase, anorexia, and psychiatric disorders (suicidal ideation, depression, and cognitive disturbances). Of the 30 patients who received at least 1 dose, 13% achieved a partial response (95% confidence interval, 4%-31%). Two patients harboring activating PI3KA mutations achieved 42% and 16% maximal tumor shrinkage, respectively. CONCLUSIONS: Buparlisib at a dose of 80 mg/day with bevacizumab was found to be a tolerable regimen with preliminary activity in vascular endothelial growth factor-refractory mRCC. The benefit of this combination may be of interest for future mRCC trials, possibly in a selected patient population. Cancer 2016;122:2389-2398. (c) 2016 American Cancer Society. CI - (c) 2016 American Cancer Society. FAU - McKay, Rana R AU - McKay RR AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. FAU - De Velasco, Guillermo AU - De Velasco G AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. FAU - Werner, Lillian AU - Werner L AD - Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. FAU - Bellmunt, Joaquim AU - Bellmunt J AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. FAU - Harshman, Lauren AU - Harshman L AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. FAU - Sweeney, Christopher AU - Sweeney C AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. FAU - Rosenberg, Jonathan E AU - Rosenberg JE AD - Deparment of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York. FAU - Hirsch, Michelle AU - Hirsch M AD - Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts. FAU - Signoretti, Sabina AU - Signoretti S AD - Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts. FAU - Van Allen, Eliezer M AU - Van Allen EM AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. FAU - Walsh, Meghara AU - Walsh M AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. FAU - Vaishampayan, Ulka AU - Vaishampayan U AD - Department of Hematology/Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan. FAU - McDermott, David F AU - McDermott DF AD - Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts. FAU - Choueiri, Toni K AU - Choueiri TK AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. LA - eng GR - P30 CA008748/CA/NCI NIH HHS/United States GR - P50 CA101942/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study DEP - 20160519 PL - United States TA - Cancer JT - Cancer JID - 0374236 RN - 0 (Aminopyridines) RN - 0 (Biomarkers) RN - 0 (Morpholines) RN - 0 (NVP-BKM120) RN - 0 (Vascular Endothelial Growth Factor A) RN - 2S9ZZM9Q9V (Bevacizumab) SB - IM MH - Aminopyridines/administration & dosage MH - Antineoplastic Combined Chemotherapy Protocols/adverse effects/*therapeutic use MH - Bevacizumab/administration & dosage MH - Biomarkers MH - Carcinoma, Renal Cell/*drug therapy/*pathology MH - Female MH - Humans MH - Kidney Neoplasms/*drug therapy/*pathology MH - Male MH - Molecular Targeted Therapy MH - Morpholines/administration & dosage MH - Neoplasm Metastasis MH - Treatment Outcome MH - Vascular Endothelial Growth Factor A/antagonists & inhibitors PMC - PMC5567751 MID - NIHMS894012 OTO - NOTNLM OT - bevacizumab OT - buparlisib OT - phase 1 OT - phosphatidylinositol-3 kinase (PI3K) inhibitor OT - renal cell carcinoma EDAT- 2016/05/21 06:00 MHDA- 2017/05/19 06:00 PMCR- 2017/08/23 CRDT- 2016/05/21 06:00 PHST- 2016/02/08 00:00 [received] PHST- 2016/03/14 00:00 [revised] PHST- 2016/03/17 00:00 [accepted] PHST- 2016/05/21 06:00 [entrez] PHST- 2016/05/21 06:00 [pubmed] PHST- 2017/05/19 06:00 [medline] PHST- 2017/08/23 00:00 [pmc-release] AID - 10.1002/cncr.30056 [doi] PST - ppublish SO - Cancer. 2016 Aug 1;122(15):2389-98. doi: 10.1002/cncr.30056. Epub 2016 May 19.