Top

Published in:

01-12-2015 | PHASE I STUDIES

A first-in-human phase I dose-escalation, pharmacokinetic, and pharmacodynamic evaluation of intravenous LY2090314, a glycogen synthase kinase 3 inhibitor, administered in combination with pemetrexed and carboplatin

Authors: Jhanelle E. Gray, Jeffrey R. Infante, Les H. Brail, George R. Simon, Jennifer F. Cooksey, Suzanne F. Jones, Daphne L. Farrington, Adeline Yeo, Kimberley A. Jackson, Kay H. Chow, Maciej J. Zamek-Gliszczynski, Howard A. Burris III

Published in: Investigational New Drugs | Issue 6/2015

Summary

Purpose LY2090314 (LY) is a glycogen synthase kinase 3 inhibitor with preclinical efficacy in xenograft models when combined with platinum regimens. A first-in-human phase 1 dose-escalation study evaluated the combination of LY with pemetrexed/carboplatin. Patients and Methods Forty-one patients with advanced solid tumors received single-dose LY monotherapy lead-in and 37 patients received LY (10–120 mg) plus pemetrexed/carboplatin (500 mg/m² and 5–6 AUC, respectively) across 8 dose levels every 21 days. Primary objective was maximum tolerated dose (MTD) determination; secondary endpoints included safety, antitumor activity, pharmacokinetics, and beta-catenin pharmacodynamics. Results MTD of LY with pemetrexed/carboplatin was 40 mg. Eleven dose-limiting toxicities (DLTs) occurred in ten patients. DLTs during LY monotherapy occurred at ≥40 mg: grade 2 visual disturbance (n = 1) and grade 3/4 peri-infusional thoracic pain during or shortly post infusion (n = 4; chest, upper abdominal, and back pain). Ranitidine was added after de-escalation to 80 mg LY to minimize peri-infusional thoracic pain. Following LY with pemetrexed/carboplatin therapy, DLTs included grade 3/4 thrombocytopenia (n = 4) and grade 4 neutropenia (n = 1). Best overall response by RECIST included 5 confirmed partial responses (non-small cell lung cancer [n = 3], mesothelioma, and breast cancer) and 19 patients having stable disease. Systemic LY exposure was approximately linear over dose range studied. Transient upregulation of beta-catenin measured in peripheral blood mononuclear cells (PBMCs) occurred at 40 mg LY. Conclusions The initial safety profile of LY2090314 was established. MTD LY dose with pemetrexed/carboplatin is 40 mg IV every 3 weeks plus ranitidine. Efficacy of LY plus pemetrexed/carboplatin requires confirmation in randomized trials.

Doble BW, Woodgett JR (2003) GSK-3: tricks of the trade for a multi-tasking kinase. J Cell Sci 116:1175–1186PubMedCentralCrossRefPubMed

Cohen P, Goedert M (2004) GSK3 inhibitors: development and therapeutic potential. Nat Rev Drug Discov 3:479–487CrossRefPubMed

Derksen PW, Tjin E, Meijer HP, Klok MD, MacGillavry HD, van Oers MH, Lokhorst HM, Bloem AC, Clevers H, Nusse R, van der Neut R, Spaargaren M, Pals ST (2004) Illegitimate WNT signaling promotes proliferation of multiple myeloma cells. Proc Natl Acad Sci 101:6122–6127PubMedCentralCrossRefPubMed

Tan J, Zhuang L, Leong HS, Iyer NG, Liu ET, Yu Q (2005) Pharmacologic modulation of glycogen synthase kinase-3beta promotes p53-dependent apoptosis through a direct Bax-mediated mitochondrial pathway in colorectal cancer cells. Cancer Res 65:9012–9020CrossRefPubMed

Shimura T, Kakuda S, Ochiai Y, Kuwahara Y, Takai Y, Fukumoto M (2011) Targeting the AKT/GSK3β/cyclin D1/Cdk4 survival signaling pathway for eradication of tumor radioresistance acquired by fractionated radiotherapy. Int J Radiat Oncol Biol Phys 80:540–548CrossRefPubMed

Kho PS, Wang Z, Zhuang L, Li Y, Chew J-L, Ng H-H, Liu ET, Yu Q (2004) p53-regulated transcriptional program associated with genotoxic stress-induced apoptosis. J Biol Chem 279:21183–21192CrossRefPubMed

Ghosh JC, Altieri DC (2005) Activation of p53-dependent apoptosis by acute ablation of glycogen synthase kinase-3β in colorectal cancer cells. Clin Cancer Res 1:4580–4588CrossRef

Zamek-Gliszczynski MJ, Abraham TL, Alberts JJ, Kulanthaivel P, Jackson KA, Chow KH, McCann DJ, Hu H, Anderson S, Furr NA, Barbuch RJ, Cassidy KC (2013) Pharmacokinetics, metabolism, and excretion of the GSK-3 inhibitor LY2090314 in rats, dogs, and humans: a case study in rapid clearance by extensive metabolism with low circulating metabolite exposures. Drug Metab Dispos 41:714–726CrossRefPubMed

Alimta® pemetrexed for injection Product Information, Lilly USA, LLC, January 2013

10.

Paraplatin (carboplatin aqueous solution) Injection. Bristol-Myers Squibb Company, July, 2010

11.

Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216CrossRefPubMed

12.

Byrne MJ, Nowak AK (2004) Modified RECIST criteria for assessment of response in malignant pleural mesothelioma. Ann Oncol 15:257–260CrossRefPubMed

13.

Kumar A, Hou X, Lee C, Li Y, Maminishkis A, Tang Z, Zhang F, Langer HF, Arjunan P, Dong L, Wu Z, Zhu LY, Wang L, Min W, Colosi P, Chavakis T, Li X (2010) Platelet-derived growth factor-DD targeting arrests pathological angiogenesis by modulating glycogen synthase kinase-3beta phosphorylation. J Biol Chem 285:15500–15510PubMedCentralCrossRefPubMed

14.

Hoang MV, Smith LE, Senger DR (2010) Moderate GSK-3β inhibition improves neovascular architecture, reduces vascular leakage, and reduces retinal hypoxia in a model of ischemic retinopathy. Angiogenesis 13:269–277PubMedCentralCrossRefPubMed

15.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Malignant pleural mesothelioma. Version 1: 2013. National Comprehensive Cancer Network, Inc. Available at http://www.nccn.com. Accessed 01 April 2015

16.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Non-small cell lung cancer. Version 2: 2013. National Comprehensive Cancer Network, Inc. Available at http://www.nccn.com. Accessed 01 April 2015

17.

Naito S, Bilim V, Yuuki K, Ugolkov A, Motoyama T, Nagaoka A, Kato T, Tomita Y (2010) Glycogen synthase kinase-3beta: a prognostic marker and a potential therapeutic target in human bladder cancer. Clin Cancer Res 16:5124–5132CrossRefPubMed

18.

Manning BD, Cantley LC (2007) AKT/PKB signaling: navigating downstream. Cell 129:1261–1274PubMedCentralCrossRefPubMed

19.

Wong KK, Engelman JA, Cantley LC (2010) Targeting the PI3K signaling pathway in cancer. Curr Opin Genet Dev 20:87–90PubMedCentralCrossRefPubMed

20.

David O, Jett J, LeBeau H, Dy G, Hughes J, Friedman M, Brody AR (2004) Phospho-Akt overexpression in non-small cell lung cancer confers significant stage-independent survival disadvantage. Clin Cancer Res 10:6865–6871CrossRefPubMed

21.

Kim D, Dan HC, Park S, Yang L, Liu Q, Kaneko S, Ning J, He L, Yang H, Sun M, Nicosia SV, Cheng JQ (2005) AKT/PKB signaling mechanisms in cancer and chemoresistance. Front Biosci 10:975–987CrossRefPubMed

22.

Abedini MR, Muller EJ, Bergeron R, Gray DA, Tsang BK (2010) Akt promotes chemoresistance in human ovarian cancer cells by modulating cisplatin-induced, p53-dependent ubiquitination of FLICE-like inhibitory protein. Oncogene 29:11–25CrossRefPubMed

23.

Girouard J, Lafleur MJ, Parent S, Leblanc V, Asselin E (2013) Involvement of Akt isoforms in chemoresistance of endometrial carcinoma cells. Gynecol Oncol 128:335–343CrossRefPubMed

24.

Bachelder RE, Yoon SO, Franci C, de Herreros AG, Mercurio AM (2005) Glycogen synthase kinase-3 is an endogenous inhibitor of Snail transcription: implications for the epithelial-mesenchymal transition. J Cell Biol 168:29–33PubMedCentralCrossRefPubMed

25.

Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M, Hung MC (2004) Dual regulation of Snail by GSK-3 beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol 6:931–940CrossRefPubMed

Title: A first-in-human phase I dose-escalation, pharmacokinetic, and pharmacodynamic evaluation of intravenous LY2090314, a glycogen synthase kinase 3 inhibitor, administered in combination with pemetrexed and carboplatin
Authors: Jhanelle E. Gray
Jeffrey R. Infante
Les H. Brail
George R. Simon
Jennifer F. Cooksey
Suzanne F. Jones
Daphne L. Farrington
Adeline Yeo
Kimberley A. Jackson
Kay H. Chow
Maciej J. Zamek-Gliszczynski
Howard A. Burris III
Publication date: 01-12-2015
Publisher: Springer US
Published in: Investigational New Drugs / Issue 6/2015
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-015-0278-7

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 medication adherence

Springer Medicine

Summary

Please log in to get access to this content

Other articles of this Issue 6/2015

Identification of a novel compound (β-sesquiphellandrene) from turmeric (Curcuma longa) with anticancer potential: comparison with curcumin

Erratum to: A Phase 1 dose-escalation study of the safety and pharmacokinetics of once-daily oral foretinib, a multi-kinase inhibitor, in patients with solid tumors

Phase I and pharmacological trial of lapatinib in combination with gemcitabine in patients with advanced breast cancer

Fibrin gels loaded with cisplatin and cisplatin-hyaluronate complexes tested in a subcutaneous human melanoma model

Histone deacetylase inhibitors and epigenetic regulation in lymphoid malignancies

A phase I trial of mFOLFOX6 combined with the oral PI3K inhibitor BKM120 in patients with advanced refractory solid tumors

Keynote webinar | Spotlight on antibody–drug conjugates in cancer