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01-12-2015 | Original Article

Phase 1 study of galunisertib, a TGF-beta receptor I kinase inhibitor, in Japanese patients with advanced solid tumors

Authors: Yutaka Fujiwara, Hiroshi Nokihara, Yasuhide Yamada, Noboru Yamamoto, Kuniko Sunami, Hirofumi Utsumi, Hiroya Asou, Osamu TakahashI, Ken Ogasawara, Ivelina Gueorguieva, Tomohide Tamura

Published in: Cancer Chemotherapy and Pharmacology | Issue 6/2015

Abstract

Purpose

Inhibition of transforming growth factor-beta receptor I (TGF-beta RI)-mediated signaling pathways blocks tumor growth and metastases in nonclinical studies. Galunisertib (LY2157299), a small molecule inhibitor of TGF-beta RI serine/threonine kinase, had antitumor effects with acceptable safety/tolerability in a first-in-human dose (FHD) study conducted mainly in Caucasian patients with glioma. In this nonrandomized, open-label, dose-escalation study, we assessed safety/tolerability, pharmacokinetics (PK), and tumor response in Japanese patients.

Methods

Patients with advanced and/or metastatic disease refractory were assigned sequentially to Cohort-1 (80 mg) or Cohort-2 (150 mg) of galunisertib, administered twice daily and treated using 2-week on, 2-week off treatment cycles. Dose escalation was guided by predefined PK criteria and dose-limiting toxicities (DLT). Safety assessments included treatment-emergent adverse events (TEAEs) and cardiac safety (ultrasound cardiography/Doppler imaging, electrocardiogram, chest computed tomography, and cardiotoxicity serum biomarkers).

Results

Twelve patients (Cohort-1, n = 3; Cohort-2, n = 9) were enrolled and the most common types of cancer were pancreatic (n = 5) and lung cancer (n = 3). Seven patients (Cohort-1, n = 2; Cohort-2, n = 5) experienced possibly galunisertib-related TEAEs. The most frequent related TEAEs were brain natriuretic peptide increased (n = 2), leukopenia (n = 2), and rash (n = 2). No cardiovascular toxicities or other DLTs were reported. PK profile of galunisertib was consistent with the FHD study. Maximum plasma concentration was reached within 2 h post-dose, and the mean elimination half-life was 9 h.

Conclusions

Galunisertib had an acceptable tolerability and safety profile in Japanese patients with advanced cancers.

ClinicaTrials.gov. Identifier

NCT01722825.

Massague J, Blain SW, Lo RS (2000) TGFbeta signaling in growth control, cancer, and heritable disorders. Cell 103:295–309. doi:10.1016/S0092-8674(00)00121-5 CrossRefPubMed

Pasche B (2001) Role of transforming growth factor beta in cancer. J Cell Physiol 186:153–168. doi:10.1002/1097-4652(200002)186:2<153:AID-JCP1016>3.0.CO;2-J CrossRefPubMed

Akhurst RJ, Hata A (2012) Targeting the TGFbeta signalling pathway in disease. Nat Rev Drug Discov 11:790–811. doi:10.1038/nrd3810 PubMedCentralCrossRefPubMed

Massague J (1998) TGF-beta signal transduction. Annu Rev Biochem 67:753–791. doi:10.1146/annurev.biochem.67.1.753 CrossRefPubMed

Roberts AB, Anzano MA, Lamb LC, Smith JM, Sporn MB (1981) New class of transforming growth factors potentiated by epidermal growth factor: isolation from non-neoplastic tissues. Proc Natl Acad Sci USA 78:5339–5343PubMedCentralCrossRefPubMed

Roberts AB, Sporn MB, Assoian RK, Smith JM, Roche NS, Wakefield LM, Heine UI, Liotta LA, Falanga V, Kehrl JH (1986) Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci USA 83:4167–4171PubMedCentralCrossRefPubMed

Zavadil J, Bottinger EP (2005) TGF-beta and epithelial-to-mesenchymal transitions. Oncogene 24:5764–5774. doi:10.1038/sj.onc.1208927 CrossRefPubMed

Bhola NE, Balko JM, Dugger TC, Kuba MG, Sanchez V, Sanders M, Stanford J, Cook RS, Arteaga CL (2013) TGF-beta inhibition enhances chemotherapy action against triple-negative breast cancer. J Clin Investig 123:1348–1358. doi:10.1172/JCI65416 PubMedCentralCrossRefPubMed

Bueno L, de Alwis DP, Pitou C, Yingling J, Lahn M, Glatt S, Trocóniz IF (2008) Semi-mechanistic modelling of the tumour growth inhibitory effects of LY2157299, a new type I receptor TGF-beta kinase antagonist, in mice. Eur J Cancer 44:142–150. doi:10.1016/j.ejca.2007.10.008 CrossRefPubMed

10.

Dituri F, Mazzocca A, Peidro FJ, Papappicco P, Fabregat I, De Santis F, Paradiso A, Sabbà C, Giannelli G (2013) Differential inhibition of the TGF-beta signaling pathway in HCC cells using the small molecule inhibitor LY2157299 and the D10 monoclonal antibody against TGF-beta receptor type II. PLoS ONE 8:e67109. doi:10.1371/journal.pone.0067109 PubMedCentralCrossRefPubMed

11.

Giannelli G, Villa E, Lahn M (2014) Transforming growth factor-beta as a therapeutic target in hepatocellular carcinoma. Cancer Res 74:1890–1894. doi:10.1158/0008-5472.CAN-14-0243 CrossRefPubMed

12.

Lahn M, Kloeker S, Berry BS (2005) TGF-beta inhibitors for the treatment of cancer. Expert Opin Investig Drugs 14:629–643. doi:10.1517/13543784.14.6.629 CrossRefPubMed

13.

Maier A, Peille AL, Vuaroqueaux V, Lahn M (2015) Anti-tumor activity of the TGF-beta receptor kinase inhibitor galunisertib (LY2157299 monohydrate) in patient-derived tumor xenografts. Cell Oncol 38:131–144. doi:10.1007/s13402-014-0210-8 CrossRef

14.

Leivonen SK, Kahari VM (2007) Transforming growth factor-beta signaling in cancer invasion and metastasis. Int J Cancer 121:2119–2124. doi:10.1002/ijc.23113 CrossRefPubMed

15.

Sawyer JS, Anderson BD, Beight DW, Campbell RM, Jones ML, Herron DK, Lampe JW, McCowan JR, McMillen WT, Mort N, Parsons S, Smith EC, Vieth M, Weir LC, Yan L, Zhang F, Yingling JM (2003) Synthesis and activity of new aryl- and heteroaryl-substituted pyrazole inhibitors of the transforming growth factor-beta type I receptor kinase domain. J Med Chem 46:3953–3956. doi:10.1021/jm0205705 CrossRefPubMed

16.

Rodon J, Carducci MA, Sepulveda-Sanchez JM, Azaro A, Calvo E, Seoane J, Braña I, Sicart E, Gueorguieva I, Cleverly AL, Pillay NS, Desaiah D, Estrem ST, Paz-Ares L, Holdhoff M, Blakeley J, Lahn MM, Baselga J (2014) First-in-human dose study of the novel transforming growth factor-beta receptor I kinase inhibitor LY2157299 monohydrate in patients with advanced cancer and glioma. Clin Cancer Res. doi:10.1158/1078-0432.CCR-14-1380 PubMedCentral

17.

Faivre SJ, Santoro A, Kelley RK, Merle P, Gane E, Douillard J-Y, Waldschmidt D, Mulcahy MF, Costentin C, Minguez B, Papappicco P, Gueorguieva I, Cleverly A, Desaiah D, Lahn MM, Ameryckx S, Benhadji KA, Raymond E, Giannelli G (2014) A phase 2 study of a novel transforming growth factor-beta (TGF-β1) receptor I kinase inhibitor, LY2157299 monohydrate (LY), in patients with advanced hepatocellular carcinoma (HCC). ASCO Gastrointestinal Cancers Symposium: J Clin Oncol 32:suppl 3; abstract LBA173

18.

Anderton MJ, Mellor HR, Bell A, Sadler C, Pass M, Powell S, Steele SJ, Roberts RR, Heier A (2011) Induction of heart valve lesions by small-molecule ALK5 inhibitors. Toxicol Pathol 39:916–924. doi:10.1177/0192623311416259 CrossRefPubMed

19.

First in human dose escalation study of TEW-7197 in subjects with advanced stage solid tumors. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02160106?term=TEW7197&rank=1. Accessed 22 March 2015

20.

Stauber AJ, Credille KM, Truex LL, Ehlhardt WJ, Young JK (2014) Nonclinical safety evaluation of a transforming growth factor b receptor I kinase inhibitor in Fischer 344 rats and beagle dogs. J Clin Toxicol. doi:10.4172/2161-0495.196

21.

Kovacs RJ, Maldonado G, Azaro A, Fernandez MS, Romero FL, Sepulveda-Sanchez JM, Corretti M, Carducci M, Dolan M, Gueorguieva I, Cleverly AL, Pillay NS, Baselga J, Lahn MM (2014) Cardiac safety of TGF-beta receptor I kinase inhibitor LY2157299 monohydrate in cancer patients in a first-in-human dose study. Cardiovasc Toxicol. doi:10.1007/s12012-014-9297-4 PubMedCentral

22.

Gueorguieva I, Cleverly AL, Stauber A, Sada Pillay N, Rodon JA, Miles CP, Yingling JM, Lahn MM (2014) Defining a therapeutic window for the novel TGF-beta inhibitor LY2157299 monohydrate based on a pharmacokinetic/pharmacodynamic model. Br J Clin Pharmacol 77:796–807. doi:10.1111/bcp.12256 PubMedCentralCrossRefPubMed

23.

Kozloff M, Carbonero R, Nadal T, Gueorguieva I, Cleverly A, Desaiah D, Lahn MMF, Pillay S, Blunt A, Josep Tabernero, Macarulla T (2013) Phase Ib study evaluating safety and pharmacokinetics (PK) of the oral transforming growth factor-beta (TGF-ss) receptor I kinase inhibitor LY2157299 monohydrate (LY) when combined with gemcitabine in patients with advanced cancer. ASCO Meet Abstr 31:2563

24.

Suarez C, Rodon J, Desjardins A, Forsyth PAJ, Gueorguieva I, Cleverly A, Burkholder T, Desaiah D, Lahn MMF, Wick W (2013) Phase Ib study evaluating safety and pharmacokinetics (PK) of the oral transforming growth factor-beta (TGF-ss) receptor I kinase inhibitor LY2157299 monohydrate (LY) when combined with chemoradiotherapy in newly diagnosed malignant gliomas. ASCO Meet Abst 31:2039

25.

A study of LY2157299 in participants with myelodysplastic syndromes. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/results/NCT02008318. Accessed 26 Feb 2015

26.

Rodon J, Carducci M, Sepulveda-Sanchez JM, Azaro A, Calvo E, Seoane J, Brana I, Sicart E, Gueorguieva I, Cleverly A, Pillay NS, Desaiah D, Estrem ST, Paz-Ares L, Holdhoff M, Blakeley J, Lahn MM, Baselga J (2015) Pharmacokinetic, pharmacodynamic and biomarker evaluation of transforming growth factor-beta receptor I kinase inhibitor, galunisertib, in phase 1 study in patients with advanced cancer. Investig New Drugs 33:357–370. doi:10.1007/s10637-014-0192-4 CrossRef

Title: Phase 1 study of galunisertib, a TGF-beta receptor I kinase inhibitor, in Japanese patients with advanced solid tumors
Authors: Yutaka Fujiwara
Hiroshi Nokihara
Yasuhide Yamada
Noboru Yamamoto
Kuniko Sunami
Hirofumi Utsumi
Hiroya Asou
Osamu TakahashI
Ken Ogasawara
Ivelina Gueorguieva
Tomohide Tamura
Publication date: 01-12-2015
Publisher: Springer Berlin Heidelberg
Published in: Cancer Chemotherapy and Pharmacology / Issue 6/2015
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-015-2895-4

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