Top

Published in:

01-08-2019 | Nausea | Original Article

Phase I study of BGT226, a pan-PI3K and mTOR inhibitor, in Japanese patients with advanced solid cancers

Authors: Hironobu Minami, Yutaka Fujiwara, Kei Muro, Masahiko Sato, Atsuko Moriya

Published in: Cancer Chemotherapy and Pharmacology | Issue 2/2019

Abstract

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.

Wickenden JA, Watson CJ (2010) Key signalling nodes in mammary gland development and cancer. Signalling downstream of PI3Kinase in mammary epithelium: a play in 3 Akts. Breast Cancer Res 12(2):202. https://doi.org/10.1186/bcr2558 CrossRefPubMedPubMedCentral

Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD (2001) Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annu Rev Cell Dev Biol 17:615–675. https://doi.org/10.1146/annurev.cellbio.17.1.615 CrossRefPubMed

Fry MJ (2001) Phosphoinositide 3-kinase signalling in breast cancer: how big a role might it play? Breast Cancer Res 3(5):304–312CrossRefPubMedPubMedCentral

Liu P, Cheng H, Roberts TM, Zhao JJ (2009) Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 8(8):627–644. https://doi.org/10.1038/nrd2926 CrossRefPubMedPubMedCentral

Engelman JA (2009) Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 9(8):550–562. https://doi.org/10.1038/nrc2664 CrossRefPubMed

Courtney KD, Corcoran RB, Engelman JA (2010) The PI3K pathway as drug target in human cancer. J Clin Oncol 28(6):1075–1083. https://doi.org/10.1200/JCO.2009.25.3641 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

Valkov A, Kilvaer TK, Sorbye SW, Donnem T, Smeland E, Bremnes RM, Busund LT (2011) The prognostic impact of Akt isoforms, PI3K and PTEN related to female steroid hormone receptors in soft tissue sarcomas. J Transl Med 9:200. https://doi.org/10.1186/1479-5876-9-200 CrossRefPubMedPubMedCentral

Mukohara T (2015) PI3K mutations in breast cancer: prognostic and therapeutic implications. Breast Cancer (Dove Medical Press) 7:111–123. https://doi.org/10.2147/bctt.S60696 CrossRef

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 CrossRefPubMed

11.

Baumann P, Schneider L, Mandl-Weber S, Oduncu F, Schmidmaier R (2012) Simultaneous targeting of PI3K and mTOR with NVP-BGT226 is highly effective in multiple myeloma. Anticancer Drugs 23(1):131–138. https://doi.org/10.1097/CAD.0b013e32834c8683 CrossRefPubMed

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 CrossRefPubMed

13.

Markham A (2017) Copanlisib: first global approval. Drugs 77(18):2057–2062. https://doi.org/10.1007/s40265-017-0838-6 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

16.

Toyoda M, Watanabe K, Amagasaki T, Natsume K, Takeuchi H, Quadt C, Shirao K, Minami H (2018) A phase I study of single-agent BEZ235 special delivery system sachet in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol. https://doi.org/10.1007/s00280-018-3725-2 CrossRefPubMedPubMedCentral

17.

Miller TW, Rexer BN, Garrett JT, Arteaga CL (2011) Mutations in the phosphatidylinositol 3-kinase pathway: role in tumor progression and therapeutic implications in breast cancer. Breast Cancer Res 13(6):224. https://doi.org/10.1186/bcr3039 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 LBA3

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 LBA1006

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 CrossRefPubMedPubMedCentral

Title: Phase I study of BGT226, a pan-PI3K and mTOR inhibitor, in Japanese patients with advanced solid cancers
Authors: Hironobu Minami
Yutaka Fujiwara
Kei Muro
Masahiko Sato
Atsuko Moriya
Publication date: 01-08-2019
Publisher: Springer Berlin Heidelberg
Keywords: Nausea
Pharmacodynamics
Pharmacokinetics
Diarrhea
Diarrhea
Published in: Cancer Chemotherapy and Pharmacology / Issue 2/2019
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-019-03883-6

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2019

A panel of serum exosomal microRNAs as predictive markers for chemoresistance in advanced colorectal cancer

Postoperative chemotherapy as adjuvant treatment for endometrioid adenocarcinoma: early stage vs late stage

SN-38, the active metabolite of irinotecan, inhibits the acute inflammatory response by targeting toll-like receptor 4

CNS penetration of the CDK4/6 inhibitor ribociclib in non-tumor bearing mice and mice bearing pediatric brain tumors

Phase I study of ipatasertib as a single agent and in combination with abiraterone plus prednisolone in Japanese patients with advanced solid tumors

Cancer immunotherapy: the art of targeting the tumor immune microenvironment

Keynote webinar | Spotlight on antibody–drug conjugates in cancer