A phase 1 study of buparlisib and bevacizumab in patients with metastatic renal cell carcinoma progressing on vascular endothelial growth factor‐targeted therapies

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.

[1]  K. Do,et al.  A randomized phase 2 study of MK-2206 versus everolimus in refractory renal cell carcinoma , 2017, Annals of oncology : official journal of the European Society for Medical Oncology.

[2]  Wei Zhao,et al.  Targeting Strategies for Renal Cell Carcinoma: From Renal Cancer Cells to Renal Cancer Stem Cells , 2016, Front. Pharmacol..

[3]  R. Montironi,et al.  Metabolic alterations in renal cell carcinoma. , 2015, Cancer treatment reviews.

[4]  Rodrigo Dienstmann,et al.  Tankyrase Inhibition Blocks Wnt/β-Catenin Pathway and Reverts Resistance to PI3K and AKT Inhibitors in the Treatment of Colorectal Cancer , 2015, Clinical Cancer Research.

[5]  Helen X. Chen,et al.  Multicenter Phase II Trial of Temsirolimus and Bevacizumab in Pancreatic Neuroendocrine Tumors. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  C. Baldus,et al.  Outlook on PI3K/AKT/mTOR inhibition in acute leukemia , 2015, Molecular and Cellular Therapies.

[7]  R. Yelensky,et al.  Comprehensive genomic profiling of 443 cases of renal cell carcinoma to reveal frequent clinically relevant genomic alterations. , 2015 .

[8]  J. Infante,et al.  Targeting PI3 kinase in cancer. , 2015, Pharmacology & therapeutics.

[9]  H. Pitot,et al.  Safety and activity of temsirolimus and bevacizumab in patients with advanced renal cell carcinoma previously treated with tyrosine kinase inhibitors: a phase 2 consortium study , 2015, Cancer Chemotherapy and Pharmacology.

[10]  E. Van Cutsem,et al.  A Phase Ib Dose-Escalation Study of the Oral Pan-PI3K Inhibitor Buparlisib (BKM120) in Combination with the Oral MEK1/2 Inhibitor Trametinib (GSK1120212) in Patients with Selected Advanced Solid Tumors , 2014, Clinical Cancer Research.

[11]  B. Rini,et al.  Randomized phase III trial of temsirolimus and bevacizumab versus interferon alfa and bevacizumab in metastatic renal cell carcinoma: INTORACT trial. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  D. Erdmann,et al.  Characterization of the Novel and Specific PI3Kα Inhibitor NVP-BYL719 and Development of the Patient Stratification Strategy for Clinical Trials , 2014, Molecular Cancer Therapeutics.

[13]  J. Himmelfarb,et al.  Overall Survival in Renal-Cell Carcinoma with Pazopanib versus Sunitinib , 2014 .

[14]  M. Atkins,et al.  A Phase II Study of Bevacizumab and High-dose Interleukin-2 in Patients With Metastatic Renal Cell Carcinoma: A Cytokine Working Group (CWG) Study , 2013, Journal of immunotherapy.

[15]  M. Rubin,et al.  ATLAS: randomized, double-blind, placebo-controlled, phase IIIB trial comparing bevacizumab therapy with or without erlotinib, after completion of chemotherapy, with bevacizumab for first-line treatment of advanced non-small-cell lung cancer. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[16]  Suzanne F. Jones,et al.  Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of Dalantercept, an Activin Receptor–like Kinase-1 Ligand Trap, in Patients with Advanced Cancer , 2013, Clinical Cancer Research.

[17]  J. Reeves,et al.  Pazopanib versus sunitinib in metastatic renal-cell carcinoma. , 2013, The New England journal of medicine.

[18]  A. Ravaud,et al.  Combination therapy in metastatic renal cell cancer. , 2013, Seminars in Oncology.

[19]  The Cancer Genome Atlas Research Network.  COMPREHENSIVE MOLECULAR CHARACTERIZATION OF CLEAR CELL RENAL CELL CARCINOMA , 2013, Nature.

[20]  Steven J. M. Jones,et al.  Comprehensive molecular characterization of clear cell renal cell carcinoma , 2013, Nature.

[21]  S. Srinivas,et al.  A phase II study of bevacizumab and everolimus as treatment for refractory metastatic renal cell carcinoma. , 2013, Clinical genitourinary cancer.

[22]  R. Motzer,et al.  Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial. , 2013, The Lancet. Oncology.

[23]  E. Raymond,et al.  Benchmarking effects of mTOR, PI3K, and dual PI3K/mTOR inhibitors in hepatocellular and renal cell carcinoma models developing resistance to sunitinib and sorafenib , 2013, Cancer Chemotherapy and Pharmacology.

[24]  L. Leibovici,et al.  The Impact of Bevacizumab (Avastin) on Survival in Metastatic Solid Tumors - A Meta-Analysis and Systematic Review , 2013, PloS one.

[25]  J. Lee,et al.  PIK3CA mutation H1047R is associated with response to PI3K/AKT/mTOR signaling pathway inhibitors in early-phase clinical trials. , 2013, Cancer research.

[26]  J. Dancey,et al.  Management of metabolic effects associated with anticancer agents targeting the PI3K-Akt-mTOR pathway. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[27]  M. Schlumbrecht,et al.  Sweet Response: Hyperglycemia and Hypertriglyceridemia as Biomarkers of Clinical Benefit for Everolimus in Patients with Recurrent Endometrial Cancer , 2012 .

[28]  Jordi Rodon,et al.  Phase I, dose-escalation study of BKM120, an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[29]  Nikhil Wagle,et al.  High-throughput detection of actionable genomic alterations in clinical tumor samples by targeted, massively parallel sequencing. , 2012, Cancer discovery.

[30]  Holger Gerhardt,et al.  Basic and Therapeutic Aspects of Angiogenesis , 2011, Cell.

[31]  L. Chin,et al.  Making sense of cancer genomic data. , 2011, Genes & development.

[32]  Steven J. M. Jones,et al.  Evolution of an adenocarcinoma in response to selection by targeted kinase inhibitors , 2010, Genome Biology.

[33]  S. Signoretti,et al.  The Efficacy of the Novel Dual PI3-Kinase/mTOR Inhibitor NVP-BEZ235 Compared with Rapamycin in Renal Cell Carcinoma , 2010, Clinical Cancer Research.

[34]  J. Hainsworth,et al.  Phase II trial of bevacizumab and everolimus in patients with advanced renal cell carcinoma. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[35]  L. Ellis,et al.  Resistance to Targeted Therapies: Refining Anticancer Therapy in the Era of Molecular Oncology , 2009, Clinical Cancer Research.

[36]  Keith L. Ligon,et al.  Profiling Critical Cancer Gene Mutations in Clinical Tumor Samples , 2009, PloS one.

[37]  J. Hayashi,et al.  Reactive Oxygen Species-generating Mitochondrial DNA Mutation Up-regulates Hypoxia-inducible Factor-1α Gene Transcription via Phosphatidylinositol 3-Kinase-Akt/Protein Kinase C/Histone Deacetylase Pathway* , 2009, The Journal of Biological Chemistry.

[38]  Apurva A Desai,et al.  Sorafenib for treatment of renal cell carcinoma: Final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[39]  R. Motzer,et al.  Phase I trial of bevacizumab plus escalated doses of sunitinib in patients with metastatic renal cell carcinoma. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[40]  L. Schwartz,et al.  New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). , 2009, European journal of cancer.

[41]  Bohuslav Melichar,et al.  Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial , 2007, The Lancet.

[42]  Patrick Monahan,et al.  Anxiety Disorders in Primary Care: Prevalence, Impairment, Comorbidity, and Detection , 2007, Annals of Internal Medicine.

[43]  J. Testa,et al.  Perturbations of the AKT signaling pathway in human cancer , 2005, Oncogene.

[44]  R. Spitzer,et al.  The PHQ-9: validity of a brief depression severity measure. , 2001, Journal of general internal medicine.

[45]  J. Haines,et al.  Von Hippel–Lindau disease maps to the region of chromosome 3 associated with renal cell carcinoma , 1988, Nature.