First-in-human dose study of the novel transforming growth factor-β receptor I kinase inhibitor LY2157299 monohydrate in patients with advanced cancer and glioma

Clinical Cancer Research

Volumn 21, Issue 3, 2015, Pages 553-560

  Rodon, Jordi ^a   Carducci, Michael A ^b   Sepulveda Sánchez, Juan M ^c   Azaro, Analia ^a   Calvo, Emiliano ^a,g   Seoane, Joan ^a   Braña, Irene ^a   Sicart, Elisabet ^a   Gueorguieva, Ivelina ^d   Cleverly, Ann L ^d   Pillay, N Sokalingum ^d   Desaiah, Durisala ^d   Estrem, Shawn T ^d   Paz Ares, Luis ^e   Holdhoff, Matthias ^b   Blakeley, Jaishri ^f   Lahn, Michael M ^d   Baselga, Jose ^a  

^a HOSPITAL UNIVERSITARI VALL D HEBRON   (Spain)

^b JOHNS HOPKINS UNIVERSITY   (United States)

^c HOSPITAL UNIVERSITARIO 12 DE OCTUBRE   (Spain)

^d ELI LILLY AND COMPANY   (United States)

^e HOSPITAL UNIVERSITARIO VIRGEN DEL ROCÍO   (Spain)

^f JOHNS HOPKINS UNIVERSITY   (United States)

^g START   (Spain)

Author keywords

[No Author keywords available]

Indexed keywords

BEVACIZUMAB; BRAIN NATRIURETIC PEPTIDE; DEXAMETHASONE; ETIRACETAM; GALUNISERTIB; LOMUSTINE; OMEPRAZOLE; PARACETAMOL; TEMOZOLOMIDE; TRANSFORMING GROWTH FACTOR BETA; TRANSFORMING GROWTH FACTOR BETA RECEPTOR 1; TROPONIN I; ANTINEOPLASTIC AGENT; LY-2157299; PROTEIN KINASE INHIBITOR; PROTEIN SERINE THREONINE KINASE; PYRAZOLE DERIVATIVE; QUINOLINE DERIVATIVE; TGF-BETA TYPE I RECEPTOR; TRANSFORMING GROWTH FACTOR BETA RECEPTOR;

ADULT; ADVANCED CANCER; AGED; ANTINEOPLASTIC ACTIVITY; ARTICLE; BRAIN ISCHEMIA; CANCER COMBINATION CHEMOTHERAPY; CANCER GRADING; CANCER MORTALITY; CANCER REGRESSION; DISEASE DURATION; DOPPLER ECHOGRAPHY; DRUG DETERMINATION; DRUG DOSE ESCALATION; DRUG EFFICACY; DRUG INTERMITTENT THERAPY; DRUG RESPONSE; DRUG SAFETY; DRUG WITHDRAWAL; DYSPNEA; ECHOCARDIOGRAPHY; EMBOLISM; EVENING DOSAGE; FATIGUE; FEBRILE NEUTROPENIA; FEMALE; GLIOMA; HUMAN; HUMAN TISSUE; LEUKOPENIA; LYMPHOCYTOPENIA; MAJOR CLINICAL STUDY; MALE; MAXIMUM TOLERATED DOSE; MONOTHERAPY; MORNING DOSAGE; MULTICENTER STUDY; MULTIPLE CYCLE TREATMENT; NEUTROPENIA; OPEN STUDY; PHASE 1 CLINICAL TRIAL; PROTEIN BLOOD LEVEL; THROMBOCYTOPENIA; THROMBOSIS; TREATMENT DURATION; TUMOR GROWTH; ANTAGONISTS AND INHIBITORS; CANCER STAGING; CLINICAL TRIAL; MIDDLE AGED; NEOPLASMS; NUCLEAR MAGNETIC RESONANCE IMAGING; PATHOLOGY; TREATMENT OUTCOME; YOUNG ADULT;

ADULT; AGED; ANTINEOPLASTIC AGENTS; FEMALE; GLIOMA; HUMANS; MAGNETIC RESONANCE IMAGING; MALE; MIDDLE AGED; NEOPLASM GRADING; NEOPLASM STAGING; NEOPLASMS; PROTEIN KINASE INHIBITORS; PROTEIN-SERINE-THREONINE KINASES; PYRAZOLES; QUINOLINES; RECEPTORS, TRANSFORMING GROWTH FACTOR BETA; TREATMENT OUTCOME; YOUNG ADULT;

EID: 84961288435     PISSN: 10780432     EISSN: 15573265     Source Type: Journal    
DOI: 10.1158/1078-0432.CCR-14-1380     Document Type: Article

References (34)

1. Roberts AB, Anzano MA, Lamb LC, Smith JM, Sporn MB. New class of transforming growth factors potentiated by epidermal growth factor: isolation from non-neoplastic tissues. Proc Natl Acad Sci U S A 1981;78:5339-43.
2. Massagué J, Blain SW, Lo RS. TGFbeta signaling in growth control, cancer, and heritable disorders. Cell 2000;103:295-309.
3. Cheifetz S, Weatherbee JA, Tsang MLST, Anderson JK, Mole JE, Lucas R, et al. The transforming growth factor-B system, a complex pattern of cross-reactive ligands and receptors. Cell 1987;48:409-15.
4. Miyazono K, Ehata S, Koinuma D. Tumor-promoting functions of transforming growth factor-b in progression of cancer. Ups J Med Sci 2012;117:143-52.
5. Thomas DA, Massagué. TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. J Cancer Cell 2005;8:369-80.
6. Bruna A, Greenwood W, LeQuesne J, Teschendorff A, Miranda-Saavedra D, Rueda OM, et al. TGFb induces the formation of tumour-initiating cells in claudinlow breast cancer. Nat Commun 2012;3:1055.
7. Anido J, Sáez-Borderías A, Gonzàlez-Juncà A, Rodón L, Folch G, Carmona MA, et al. TGF-beta receptor Inhibitors target the CD44(high)/Id1(high) glioma-initiating cell population in human glioblastoma. Cancer Cell 2010;18:655-68.
8. Viñals F, Pouysségur J. Transforming growth factor β1 (TGF-β1) promotes endothelial cell survival during in vitro angiogenesis via an autocrine mechanism implicating TGF-α signaling. Mol Cell Biol 2001;21:7218-30.
9. Hawinkels LJ, Paauwe M, Verspaget HW, Wiercinska E, van der Zon JM, van der Ploeg K, et al. Interaction with colon cancer cells hyperactivates TGF-β signaling in cancer-associated fibroblasts. Oncogene 2014;33: 97-107.
10. Calon A, Espinet E, Palomo-Ponce S, Tauriello DVF, Iglesias M, Cespedes MV, et al. Dependency of colorectal cancer on a TGF-β-driven program in stromal cells for metastasis initiation. Cancer Cell 2012;22:571-84.
11. Schneider T, Sailer M, Ansorge S, Firsching R, Reinhold D. Increased concentrations of transforming growth factor beta1 and beta2 in the plasma of patients with glioblastoma. J Neuro Oncol 2006;79:61-5.
12. Bruna A, Darken RS, Rojo F, Ocaña A, Peñuelas S, Arias A, et al. High TGFbeta-Smad activity confers poor prognosis in glioma patients and promotes cell proliferation depending on the methylation of the PDGFB gene. Cancer Cell 2007;11:147-60.
13. Peñuelas S, Anido J, Prieto-Sánchez RM, Folch G, Barba I, Cuartas I, et al. TGF-beta increases glioma-initiating cell self-renewal through the induction of LIF in human glioblastoma. Cancer Cell 2009;15:315-27.
14. Tritschler I, Gramatzki D, Capper D, Mittelbronn M, Meyermann R, Saharinen J, et al. Modulation of TGF-beta activity by latent TGF-beta-binding protein 1 in human malignant glioma cells. Int J Cancer 2009; 125:530-40.
15. Fransvea E, Angelotti U, Antonaci S, Giannelli G. Blocking transforming growth factor-beta up-regulates E-cadherin and reduces migration and invasion of hepatocellular carcinoma cells. Hepatology 2008;47:1557-66.
16. Melisi D, Ishiyama S, Sclabas GM, Fleming JB, Xia Q, Tortora G, et al. LY2109761, a novel transforming growth factor beta receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis. Mol Cancer Ther 2008;7:829-40.
17. Zhou L, McMahon C, Bhagat T, Alencar C, Yu Y, Fazzari M, et al. Reduced SMAD7 leads to over activation of TGF-beta signaling in MDS that can be reversed by a specific inhibitor of TGF-beta receptor I kinase. Cancer Res 2011;71:955-63.
18. Anderton MJ, Mellor HR, Bell A, Sadler C, Pass M, Powell S, et al. Induction of heart valve lesions by small-molecule ALK5 inhibitors. Toxicol Pathol 2011;39:916-24.
19. Stauber AJ, Credille KM, Truex LL, Ehlhardt WJ, Young JK. Nonclinical safety evaluation of a transforming growth factor b receptor I kinase inhibitor in Fischer 344 rats and beagle dogs. J Clin Toxicol 2014;4:196.
20. Bueno L, de Alwis DP, Pitou C, Yingling J, Lahn M, Glatt S, et al. 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 2008;44:142-50.
21. Gueorguieva I, Cleverly AL, Stauber A, Pillay NS, Rodon JA, Miles CP, et al. Defining a therapeutic window for the novel TGF-β inhibitor LY2157299 monohydrate based on a pharmacokinetic/pharmacodynamics (PK/PD) model. Br J Clin Pharmacol 2013;77:796-807.
22. Macdonald DR, Cascino TL, Schold SC Jr, Cairncross JG. Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 1990;8:1277-80.
23. Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, et al. An integrated genomic analysis of human glioblastoma multiforme. Science 2008;321:1807-12.
24. Frampton GM, Fichtenholtz A, Otto GA, Wang K, Downing SR, He J, et al. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol 2013;31:1023-31.
25. Sawyer JS, Beight DW, Britt KS, Anderson BD, Campbell RM, Goodson T Jr, et al. Synthesis and activity of new aryl- and heteroaryl-substituted 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole inhibitors of the transforming growth factor-beta type I receptor kinase domain. Bioorg Med Chem Lett 2004;14:3581-4.
26. Derynck R, Akhurst RJ, Balmain A. TGF-beta signaling in tumor suppression and cancer progression. Nat Genet 2001;29:117-29.
27. Bao W, Bussel JB, Heck S, He W, Karpoff M, Boulad N, et al. Improved regulatory T cell activity in patients with chronic immune thrombocytopenia treated with thrombopoietic agents. Blood 2010;116:4639-45.
28. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients withmetastatic melanoma. N Engl J Med 2010;363:711-23.
29. Parsons S, Sawyer S, Yan L, Foreman R, Weir S, Lahn M, et al. The combination of the small molecule TGFβR1 inhibitor, LY2157299 monohydrate, with CCNU substantially blocks SMAD phosphorylation and significantly suppresses human glioblastoma xenograft growth [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, California; Abstract C201.
30. Carpentier A, Brandes B, Kesari S, Sepulveda J, Wheeler H, Chinot O, et al. Safety interim data from a 3-arm phase 2 study evaluating safety and pharmacokinetics of the oral transforming growth factor-beta (TGF-β) receptor I kinase inhibitor LY2157299 monohydrate in patients with glioblastoma at first progression. J Clin Oncol 2013;31 (abstr 2061).
31. Bogdahn U, Hau P, Stockhammer G, Venkataramana NK, Mahapatra AK, Suri A, et al. Targeted therapy for high-grade glioma with the TGF-beta2 inhibitor trabedersen: results of a randomized and controlled phase IIb study. Neuro Oncol 2011;13:132-42.
32. Sasaki M, Knobbe CB, Munger JC, Lind EF, Brenner D, Brüstle A, et al. IDH1 (R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature 2012;488:656-9.
33. Grassian AR, Lin F, Barrett R, Liu Y, Jiang W, Korpal M, et al. Isocitrate dehydrogenase (IDH) mutations promote a reversible ZEB1/MicroRNA (miR)-200-dependent epithelial-mesenchymal transition (EMT). J Biol Chem 2012;287:42180-94.
34. Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 2010;17:98-110.