Phase 1b/2a study of galunisertib, a small molecule inhibitor of transforming growth factor-beta receptor I, in combination with standard temozolomide-based radiochemotherapy in patients with newly diagnosed malignant glioma.
Aged
Antineoplastic Agents
/ administration & dosage
Antineoplastic Combined Chemotherapy Protocols
/ administration & dosage
Biomarkers, Tumor
/ metabolism
Brain Neoplasms
/ immunology
Chemoradiotherapy
Female
Glioma
/ immunology
Humans
Male
Middle Aged
Protein Kinase Inhibitors
/ administration & dosage
Pyrazoles
/ administration & dosage
Quinolines
/ administration & dosage
Receptor, Transforming Growth Factor-beta Type I
/ antagonists & inhibitors
T-Lymphocyte Subsets
/ drug effects
Temozolomide
/ administration & dosage
Biomarkers
Galunisertib
Glioblastoma
Radiochemotherapy
T cells
Journal
Investigational new drugs
ISSN: 1573-0646
Titre abrégé: Invest New Drugs
Pays: United States
ID NLM: 8309330
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
04
12
2019
accepted:
07
02
2020
pubmed:
7
3
2020
medline:
3
9
2021
entrez:
7
3
2020
Statut:
ppublish
Résumé
Purpose Galunisertib, a TGF-β inhibitor, has demonstrated antitumor effects in preclinical and radiographic responses in some patients with malignant glioma. This Phase 1b/2a trial investigated the clinical benefit of combining galunisertib with temozolomide-based radiochemotherapy (TMZ/RTX) in patients with newly diagnosed malignant glioma (NCT01220271). Methods This is an open-label, 2-arm Phase 1b/2a study (N = 56) of galunisertib (intermittent dosing: 14 days on/14 days off per cycle of 28 days) in combination with TMZ/RTX (n = 40), versus a control arm (TMZ/RTX, n = 16). The primary objective of Phase 1b was to determine the safe and tolerable Phase 2 dose of galunisertib. The primary objective of Phase 2a was to confirm the tolerability and pharmacodynamic profile of galunisertib with TMZ/RTX, and the secondary objectives included determining the efficacy and pharmacokinetic (PK) profile of galunisertib with TMZ/RTX in patients with glioblastoma. This study also characterized the changes in the major T-cell subsets during TMZ/RTX plus galunisertib treatment. Results In the Phase 2a study, efficacy results for patients treated with galunisertib plus TMZ/RTX or TMZ/RTX were: median overall survival (18.2 vs 17.9 months), median progression-free survival (7.6 vs 11.5 months), and disease control rate (80% [32/40] vs 56% [9/16] patients) respectively. PK profile of galunisertib plus TMZ/RTX regimen was consistent with previously published PK data of galunisertib. The overall safety profile across treatment arms was comparable. Conclusion No differences in efficacy, safety or pharmacokinetic variables were observed between the two treatment arms.
Identifiants
pubmed: 32140889
doi: 10.1007/s10637-020-00910-9
pii: 10.1007/s10637-020-00910-9
pmc: PMC7497674
doi:
Substances chimiques
Antineoplastic Agents
0
Biomarkers, Tumor
0
Protein Kinase Inhibitors
0
Pyrazoles
0
Quinolines
0
LY-2157299
700874-72-2
Receptor, Transforming Growth Factor-beta Type I
EC 2.7.11.30
TGFBR1 protein, human
EC 2.7.11.30
Temozolomide
YF1K15M17Y
Banques de données
ClinicalTrials.gov
['NCT01220271']
Types de publication
Clinical Trial, Phase I
Clinical Trial, Phase II
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1570-1579Références
Glioblastoma Facts and Figures. National Brain Tumor Society. https://braintumor.org/take-action/about-gbm/ . Accessed 17 Jan 2020
Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987–996. https://doi.org/10.1056/NEJMoa043330
doi: 10.1056/NEJMoa043330
pubmed: 15758009
Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff RO (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10(5):459–466. https://doi.org/10.1016/S1470-2045(09)70025-7
doi: 10.1016/S1470-2045(09)70025-7
pubmed: 19269895
Roszman T, Elliott L, Brooks W (1991) Modulation of T-cell function by gliomas. Immunol Today 12(10):370–374. https://doi.org/10.1016/0167-5699(91)90068-5
doi: 10.1016/0167-5699(91)90068-5
pubmed: 1958290
Wick W, Naumann U, Weller M (2006) Transforming growth factor-beta: a molecular target for the future therapy of glioblastoma. Curr Pharm Des 12(3):341–349
doi: 10.2174/138161206775201901
Gatza CE, Oh SY, Blobe GC (2010) Roles for the type III TGF-beta receptor in human cancer. Cell Signal 22(8):1163–1174. https://doi.org/10.1016/j.cellsig.2010.01.016
doi: 10.1016/j.cellsig.2010.01.016
pubmed: 20153821
pmcid: 2875339
Derynck R, Akhurst RJ, Balmain A (2001) TGF-beta signaling in tumor suppression and cancer progression. Nat Genet 29(2):117–129. https://doi.org/10.1038/ng1001-117
doi: 10.1038/ng1001-117
pubmed: 11586292
Derynck R, Zhang Y, Feng XH (1998) Smads: transcriptional activators of TGF-beta responses. Cell 95(6):737–740
doi: 10.1016/S0092-8674(00)81696-7
Shi Y, Massague J (2003) Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113(6):685–700
doi: 10.1016/S0092-8674(03)00432-X
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(19):3953–3956. https://doi.org/10.1021/jm0205705
doi: 10.1021/jm0205705
pubmed: 12954047
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 (Dordr) 38(2):131–144. https://doi.org/10.1007/s13402-014-0210-8
doi: 10.1007/s13402-014-0210-8
Herbertz S, Sawyer JS, Stauber AJ, Gueorguieva I, Driscoll KE, Estrem ST, Cleverly AL, Desaiah D, Guba SC, Benhadji KA, Slapak CA, Lahn MM (2015) Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathway. Drug Des Dev Ther 9:4479–4499. https://doi.org/10.2147/DDDT.S86621
doi: 10.2147/DDDT.S86621
Zhang M, Kleber S, Rohrich M, Timke C, Han N, Tuettenberg J, Martin-Villalba A, Debus J, Peschke P, Wirkner U, Lahn M, Huber PE (2011) Blockade of TGF-beta signaling by the TGFbetaR-I kinase inhibitor LY2109761 enhances radiation response and prolongs survival in glioblastoma. Cancer Res 71(23):7155–7167. https://doi.org/10.1158/0008-5472.CAN-11-1212
doi: 10.1158/0008-5472.CAN-11-1212
pubmed: 22006998
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(2):357–370. https://doi.org/10.1007/s10637-014-0192-4
doi: 10.1007/s10637-014-0192-4
Rodon J, Carducci MA, Sepulveda-Sanchez JM, Azaro A, Calvo E, Seoane J, Brana I, Sicart E, Gueorguieva I, Cleverly AL, Pillay NS, Desaiah D, Estrem ST, Paz-Ares L, Holdhoff M, Blakeley J, Lahn MM, Baselga J (2015) 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 21(3):553–560. https://doi.org/10.1158/1078-0432.ccr-14-1380
doi: 10.1158/1078-0432.ccr-14-1380
pubmed: 25424852
Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, Degroot J, Wick W, Gilbert MR, Lassman AB, Tsien C, Mikkelsen T, Wong ET, Chamberlain MC, Stupp R, Lamborn KR, Vogelbaum MA, van den Bent MJ, Chang SM (2010) Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 28(11):1963–1972. https://doi.org/10.1200/JCO.2009.26.3541
doi: 10.1200/JCO.2009.26.3541
pubmed: 20231676
Capper D, von Deimling A, Brandes AA, Carpentier AF, Kesari S, Sepulveda-Sanchez JM, Wheeler HR, Chinot O, Cher L, Steinbach JP, Specenier P, Rodon J, Cleverly A, Smith C, Gueorguieva I, Miles C, Guba SC, Desaiah D, Estrem ST, Lahn MM, Wick W (2017) Biomarker and histopathology evaluation of patients with recurrent Glioblastoma treated with Galunisertib, Lomustine, or the combination of Galunisertib and Lomustine. Int J Mol Sci 18(5). https://doi.org/10.3390/ijms18050995
Grossman SA, Ye X, Lesser G, Sloan A, Carraway H, Desideri S, Piantadosi S, Consortium NC (2011) Immunosuppression in patients with high-grade gliomas treated with radiation and temozolomide. Clin Cancer Res 17(16):5473–5480. https://doi.org/10.1158/1078-0432.CCR-11-0774
doi: 10.1158/1078-0432.CCR-11-0774
pubmed: 21737504
pmcid: 3156964
Gessler F, Zappi J, Konczalla J, Bernstock JD, Forster MT, Wagner M, Mittelbronn M, Seifert V, Senft C (2017) Secondary Glioblastoma: molecular and clinical factors that affect outcome after malignant progression of a lower grade tumor. World Neurosurg 102:49–55. https://doi.org/10.1016/j.wneu.2017.02.104
doi: 10.1016/j.wneu.2017.02.104
pubmed: 28263929
Kourelis TV, Buckner JC, Gangat N, Patnaik MM (2015) Temozolomide induced bone marrow suppression--a single institution outcome analysis and review of the literature. Am J Hematol 90(9):E183–E184. https://doi.org/10.1002/ajh.24066
doi: 10.1002/ajh.24066
pubmed: 26010271
Stauber AJ, Credille KM, Truex LL, Ehlhardt WJ, Young JK (2014) Nonclinical safety evaluation of a transforming growth factor ß receptor I kinase inhibitor in Fischer 344 rats and beagle dogs. J Clin Toxicol 4(3):1–10. https://doi.org/10.4172/2161-0495.196
doi: 10.4172/2161-0495.196
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 (2015) Cardiac safety of TGF-beta receptor I kinase inhibitor LY2157299 monohydrate in Cancer patients in a first-in-human dose study. Cardiovasc Toxicol 15(4):309–323. https://doi.org/10.1007/s12012-014-9297-4
doi: 10.1007/s12012-014-9297-4
pubmed: 25488804
Ellsworth S, Balmanoukian A, Kos F, Nirschl CJ, Nirschl TR, Grossman SA, Luznik L, Drake CG (2014) Sustained CD4+ T cell-driven lymphopenia without a compensatory IL-7/IL-15 response among high-grade glioma patients treated with radiation and temozolomide. Oncoimmunology 3(1):e27357. https://doi.org/10.4161/onci.27357
doi: 10.4161/onci.27357
pubmed: 24790790
pmcid: 4004618
Fadul CE, Fisher JL, Gui J, Hampton TH, Cote AL, Ernstoff MS (2011) Immune modulation effects of concomitant temozolomide and radiation therapy on peripheral blood mononuclear cells in patients with glioblastoma multiforme. Neuro-Oncology 13(4):393–400. https://doi.org/10.1093/neuonc/noq204
doi: 10.1093/neuonc/noq204
pubmed: 21339188
pmcid: 3064696
McCoy MJ, Lake RA, van der Most RG, Dick IM, Nowak AK (2012) Post-chemotherapy T-cell recovery is a marker of improved survival in patients with advanced thoracic malignancies. Br J Cancer 107(7):1107–1115. https://doi.org/10.1038/bjc.2012.362
doi: 10.1038/bjc.2012.362
pubmed: 22910319
pmcid: 3461157
Brandes AA, Carpentier AF, Kesari S, Sepulveda-Sanchez JM, Wheeler HR, Chinot O, Cher L, Steinbach JP, Capper D, Specenier P, Rodon J, Cleverly A, Smith C, Gueorguieva I, Miles C, Guba SC, Desaiah D, Lahn MM, Wick W (2016) A phase II randomized study of galunisertib monotherapy or galunisertib plus lomustine compared with lomustine monotherapy in patients with recurrent glioblastoma. Neuro-Oncology 18(8):1146–1156. https://doi.org/10.1093/neuonc/now009
doi: 10.1093/neuonc/now009
pubmed: 26902851
pmcid: 4933481
Han J, Alvarez-Breckenridge CA, Wang QE, Yu J (2015) TGF-beta signaling and its targeting for glioma treatment. Am J Cancer Res 5(3):945–955
pubmed: 26045979
pmcid: 4449428
de Gramont A, Faivre S, Raymond E (2017) Novel TGF-beta inhibitors ready for prime time in onco-immunology. Oncoimmunology 6(1):e1257453. https://doi.org/10.1080/2162402x.2016.1257453
doi: 10.1080/2162402x.2016.1257453
pubmed: 28197376
Melisi D, Hollebecque A, Oh D-Y, Calvo E, Varghese AM, Borazanci EH, Mercade TM, Simionato F, Park JO, Bendell JC, Faivre SJ, Zhao Y, Gueorguieva I, Man M, Estrem S, Benhadji KA, Lanasa M, Guba SC, Garcia-Carbonero R (2019) A phase Ib dose-escalation and cohort-expansion study of safety and activity of the transforming growth factor (TGF) β receptor I kinase inhibitor galunisertib plus the anti-PD-L1 antibody durvalumab in metastatic pancreatic cancer [abstract]. J Clin Oncol 37(15_suppl):4124–4124. https://doi.org/10.1200/JCO.2019.37.15_suppl.4124
doi: 10.1200/JCO.2019.37.15_suppl.4124
Nadal E, Saleh MN, Aix SP, Olza MOd, Patel SP, Antonia SJ, Zhao Y, Gueorguieva I, Man M, Estrem ST, Avsar E, Lin WH, Benhadji K, Guba S, Diaz IA A Phase 1b/2 study of galunisertib in combination with nivolumab in solid tumors and NSCLC [abstract]. In: SITC 2019, National Harbor, Maryland, Nov 6–10 2019. p P413
Kelley RK, Gane E, Assenat E, Siebler J, Galle PR, Merle P, Hourmand IO, Cleverly A, Zhao Y, Gueorguieva I, Lahn M, Faivre S, Benhadji KA, Giannelli G (2019) A phase 2 study of Galunisertib (TGF-beta1 receptor type I inhibitor) and Sorafenib in patients with advanced hepatocellular carcinoma. Clin Transl Gastroenterol 10(7):e00056. https://doi.org/10.14309/ctg.0000000000000056
doi: 10.14309/ctg.0000000000000056
pubmed: 31295152
pmcid: 6708671
Melisi D, Garcia-Carbonero R, Macarulla T, Pezet D, Deplanque G, Fuchs M, Trojan J, Oettle H, Kozloff M, Cleverly A, Smith C, Estrem ST, Gueorguieva I, Lahn MMF, Blunt A, Benhadji KA, Tabernero J (2018) Galunisertib plus gemcitabine vs. gemcitabine for first-line treatment of patients with unresectable pancreatic cancer. Br J Cancer 119(10):1208–1214. https://doi.org/10.1038/s41416-018-0246-z
doi: 10.1038/s41416-018-0246-z
pubmed: 30318515
pmcid: 6251034
Faivre S, Santoro A, Kelley RK, Gane E, Costentin CE, Gueorguieva I, Smith C, Cleverly A, Lahn MM, Raymond E, Benhadji KA, Giannelli G (2019) Novel transforming growth factor beta receptor I kinase inhibitor galunisertib (LY2157299) in advanced hepatocellular carcinoma. Liver Int 39(8):1468–1477. https://doi.org/10.1111/liv.14113
doi: 10.1111/liv.14113
pubmed: 30963691
Lilly puts two-thirds of midphase cancer pipeline up for sale in major shake-up of R&D priorities [news release]. FierceBiotech; https://www.fiercebiotech.com/biotech/lilly-puts-two-thirds-mid-phase-cancer-pipeline-up-for-sale-major-shake-up-r-d-priorities . Accessed 17 Jan 2020
Yap T, Baldini C, Massard C, Gueorguieva I, Zhao Y, Schmidt S, Man M, Estrem S, Benhadji K, Vieito M (2018) First-in-human phase 1 dose-escalation trial of the potent and selective next generation transforming growth factor-β receptor type 1 (TGF-βR1) inhibitor LY3200882 in patients with advanced cancers [abstract]. J Immunother Cancer 6(Suppl1):O30
Keedy VL, Bauer TM, Clarke JM, Hurwitz H, Baek I, Ha I, Ock C-Y, Nam SY, Kim M, Park N, Kim JY, Kim S-J (2018) Association of TGF-β responsive signature with anti-tumor effect of vactosertib, a potent, oral TGF-β receptor type I (TGFBRI) inhibitor in patients with advanced solid tumors. J Clin Oncol 36(15_suppl):3031–3031. https://doi.org/10.1200/JCO.2018.36.15_suppl.3031
doi: 10.1200/JCO.2018.36.15_suppl.3031
ClinicalTrials.gov . M7824 versus pembrolizumab as a first-line (1L) treatment in participants with programmed death ligand 1 (PD-L1) expressing advanced non-small cell lung cancer (NSCLC). https://clinicaltrials.gov/ct2/show/NCT03631706