Phase I study of BGT226, a pan-PI3K and mTOR inhibitor, in Japanese patients with advanced solid cancers
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The phosphatidylinositol 3-kinase (PI3K) pathway is a promising therapeutic target for various cancers. BGT226 is a pan-PI3K and mammalian target of rapamycin (mTOR) inhibitor. The tolerability and pharmacokinetics/pharmacodynamics of BGT226 were investigated in a phase I study in Japanese patients with advanced solid cancers. BGT226 was orally administered on days 1, 3, and 5 of each week. The initial dose of 10 mg was subsequently escalated to 20, 40, 80, and 100 mg in a cohort of three patients. Pharmacokinetics and pharmacodynamics were investigated using plasma, normal skin, and tumor samples. A total of 18 patients were enrolled and evaluated. The most frequently reported toxicities were diarrhea, nausea, decreased appetite, vomiting, and fatigue. They were all grade 1 or 2, and no dose-limiting toxicity was observed. However, all six patients treated at 100 mg experienced diarrhea and nausea, while two experienced a dose reduction and/or interruptions during the study. Two of five patients who exhibited stable disease continued the study treatment for ≥ 16 weeks. The absorption of BGT226 was rapid, and systemic exposure increased in a dose-dependent manner. Treatment with BGT226 did not change any of the biomarkers in neither normal skin nor tumor tissues. BGT226 was tolerated up to 100 mg three times a week in Japanese patients with solid cancers, without difference in toxicity profiles and pharmacokinetics compared to Western patients.
KeywordsPI3K mTOR Pharmacokinetics Pharmacodynamics BGT226
This study was supported by Novartis Pharma K.K.
Compliance with ethical standards
Conflict of interest
Hironobu Minami has received research funding from Asahi-Kasei, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eizai, Exelixis, Fuji, Kowa, Kyowa-Kirin, Lilly, Nihon Shinyaku, Novartis, Ono, Otsuka, Pfizer, Sanofi, Shire Japan, Taiho, and Takeda, and speaker honoraria from Bayer, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eizai, Exelixis, Kowa, Kyowa-Kirin, Lilly, Novartis, Ono, Otsuka, Pfizer, Sanofi, Shire Japan, Taiho, and Takeda. Yutaka Fujiwara has received research funding from AbbVie, AstraZeneca, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, Incyte, Merck Serono, MSD, and Novartis, and speaker honoraria from Bristol-Myers Squibb, MSD, ONO, and Taiho.
- 7.Bellmunt J, Werner L, Leow JJ, Mullane SA, Fay AP, Riester M, Van Hummelen P, Taplin ME, Choueiri TK, Van Allen E, Rosenberg J (2015) Somatic copy number abnormalities and mutations in PI3K/AKT/mTOR pathway have prognostic significance for overall survival in platinum treated locally advanced or metastatic urothelial tumors. PLoS One 10(6):e0124711. https://doi.org/10.1371/journal.pone.0124711 CrossRefGoogle Scholar
- 10.Chang KY, Tsai SY, Wu CM, Yen CJ, Chuang BF, Chang JY (2011) Novel phosphoinositide 3-kinase/mTOR dual inhibitor, NVP-BGT226, displays potent growth-inhibitory activity against human head and neck cancer cells in vitro and in vivo. Clin Cancer Res 17(22):7116–7126. https://doi.org/10.1158/1078-0432.Ccr-11-0796 CrossRefGoogle Scholar
- 12.Markman B, Tabernero J, Krop I, Shapiro GI, Siu L, Chen LC, Mita M, Melendez Cuero M, Stutvoet S, Birle D, Anak O, Hackl W, Baselga J (2012) Phase I safety, pharmacokinetic, and pharmacodynamic study of the oral phosphatidylinositol-3-kinase and mTOR inhibitor BGT226 in patients with advanced solid tumors. Ann Oncol 23(9):2399–2408. https://doi.org/10.1093/annonc/mds011 CrossRefGoogle Scholar
- 14.Flinn IW, O’Brien S, Kahl B, Patel M, Oki Y, Foss FF, Porcu P, Jones J, Burger JA, Jain N, Kelly VM, Allen K, Douglas M, Sweeney J, Kelly P, Horwitz S (2018) Duvelisib, a novel oral dual inhibitor of PI3K-delta, gamma, is clinically active in advanced hematologic malignancies. Blood 131(8):877–887. https://doi.org/10.1182/blood-2017-05-786566 CrossRefGoogle Scholar
- 15.Bendell JC, Kurkjian C, Infante JR, Bauer TM, Burris HA 3rd, Greco FA, Shih KC, Thompson DS, Lane CM, Finney LH, Jones SF (2015) A phase 1 study of the sachet formulation of the oral dual PI3K/mTOR inhibitor BEZ235 given twice daily (BID) in patients with advanced solid tumors. Invest New Drugs 33(2):463–471. https://doi.org/10.1007/s10637-015-0218-6 CrossRefGoogle Scholar
- 18.Janku F, Hong DS, Fu S, Piha-Paul SA, Naing A, Falchook GS, Tsimberidou AM, Stepanek VM, Moulder SL, Lee JJ, Luthra R, Zinner RG, Broaddus RR, Wheler JJ, Kurzrock R (2014) Assessing PIK3CA and PTEN in early-phase trials with PI3K/AKT/mTOR inhibitors. Cell Rep 6(2):377–387. https://doi.org/10.1016/j.celrep.2013.12.035 CrossRefGoogle Scholar
- 19.F André, E M Ciruelos, G Rubovszky, M Campone, S Loibl, H S Rugo, H Iwata, P Conte, I A Mayer, B Kaufman, T Yamashita, Y -S Lu, K Inoue, M Takahashi, Z Pápai, A-S Longin, D Mills, C Wilke, S Hirawat, Juric D (2018) Alpelisib (ALP) + fulvestrant (FUL) for advanced breast cancer (ABC): results of the phase III SOLAR-1 trial. Ann Oncol 29(suppl 8). Abstract Number LBA3Google Scholar
- 20.Jose Baselga SFD, Javier Cortés, Young-Hyuck Im, Véronique Diéras, Nadia Harbeck, Ian E. Krop, Sunil Verma, Timothy R. Wilson, Huan Jin, Lijia Wang, Frauke Schimmoller, Jerry Y. Hsu, Jing He, Michelino DeLaurentiis, Pamela Drullinsky, William Jacot (2018) Phase III study of taselisib (GDC-0032) + fulvestrant (FULV) v FULV in patients (pts) with estrogen receptor (ER)-positive, PIK3CA-mutant (MUT), locally advanced or metastatic breast cancer (MBC): primary analysis from SANDPIPER. Am Soc Clin Oncol LBA1006Google Scholar
- 21.Baselga J, Im SA, Iwata H, Cortes J, De Laurentiis M, Jiang Z, Arteaga CL, Jonat W, Clemons M, Ito Y, Awada A, Chia S, Jagiello-Gruszfeld A, Pistilli B, Tseng LM, Hurvitz S, Masuda N, Takahashi M, Vuylsteke P, Hachemi S, Dharan B, Di Tomaso E, Urban P, Massacesi C, Campone M (2017) Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 18(7):904–916. https://doi.org/10.1016/S1470-2045(17)30376-5 CrossRefGoogle Scholar