A Phase II randomized study of galunisertib monotherapy or galunisertib plus lomustine compared with lomustine monotherapy in patients with recurrent glioblastoma
Open accessAbstract
BACKGROUND: The combination of galunisertib, a transforming growth factor (TGF)-β receptor (R)1 kinase inhibitor, and lomustine was found to have antitumor activity in murine models of glioblastoma. METHODS: Galunisertib (300 mg/day) was given orally 14 days on/14 days off (intermittent dosing). Lomustine was given as approved. Patients were randomized in a 2:1:1 ratio to galunisertib + lomustine, galunisertib monotherapy, or placebo + lomustine. The primary objective was overall survival (OS); secondary objectives were safety, pharmacokinetics (PKs), and antitumor activity. RESULTS: One hundred fifty-eight patients were randomized: galunisertib + lomustine (N = 79), galunisertib (N = 39), and placebo + lomustine (N = 40). Baseline characteristics were: male (64.6%), white (75.3%), median age 58 years, ECOG performance status (PS) 1 (63.3%), and primary glioblastoma (93.7%). The PKs of galunisertib were not altered with lomustine, and galunisertib had a median half-life of ∼8 hours. Median OS in months (95% credible interval [CrI]) for galunisertib + lomustine was 6.7 (range: 5.3-8.5), 8.0 (range: 5.7-11.7) for galunisertib alone, and 7.5 (range: 5.6-10.3) for placebo + lomustine. There was no difference in OS for patients treated with galunisertib + lomustine compared with placebo + lomustine [P (HR < 1) = 26%]. Median progression-free survival of ∼2 months was observed in all 3 arms. Among 8 patients with IDH1 mutation, 7 patients were treated with galunisertib (monotherapy or with lomustine); OS ranged from 4 to 17 months. Patients treated with galunisertib alone had fewer drug-related grade 3/4 adverse events (n = 34) compared with lomustine-treated patients (10% vs 26%). Baseline PS, post-discontinuation of bevacizumab, tumor size, and baseline levels of MDC/CCL22 were correlated with OS. CONCLUSIONS: Galunisertib + lomustine failed to demonstrate improved OS relative to placebo + lomustine. Efficacy outcomes were similar in all 3 arms. CLINICAL TRIAL REGISTRATION: NCT01582269, ClinicalTrials.gov.
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These inhibitors may also inhibit other kinases, such as p38 MAPK.
“and may also inhibit other kinases, such as p38 MAPK292,294.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [294]
Cites
Benedict, R. H. B., Schretlen, D., Groninger, L., & Brandt, J. (1998) · The Clinical Neuropsychologist · doi:10.1076/clin.12.1.43.1726 · Cited by 1,597 · see citing works
Microglia and inflammation-mediated neurodegeneration: Multiple triggers with a common mechanism
Block, M. L., & Hong, J.-S. (2005) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2005.06.004 · Cited by 1,557 · see citing works
High-grade glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
Stupp, R., Brada, M., van den Bent, M. J., Tonn, J.-C., & Pentheroudakis, G. E. (2014) · Annals of Oncology · doi:10.1093/annonc/mdu050 · Cited by 773 · see citing works
Baron, U., Floess, S., Wieczorek, G., Baumann, K., Grützkau, A., Dong, J., Thiel, A., Boeld, T. J., Hoffmann, P., Edinger, M., et al. (2007) · European Journal of Immunology · doi:10.1002/eji.200737594 · Cited by 694 · see citing works
Chen, D. S., Irving, B. A., & Hodi, F. S. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-1362 · Cited by 648 · see citing works
PD-L1 and PD-L2 are differentially regulated by Th1 and Th2 cells
Loke, P., & Allison, J. P. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0931259100 · Cited by 630 · see citing works
Benton controlled oral word association test: Reliability and updated norms
Ruff, R. M., Light, R. H., Parker, S. B., & Levin, H. S. (1996) · Archives of Clinical Neuropsychology · doi:10.1093/arclin/11.4.329 · Cited by 618 · see citing works
Fecci, P. E., Mitchell, D. A., Whitesides, J. F., Xie, W., Friedman, A. H., Archer, G. E., Herndon, J. E., Bigner, D. D., Dranoff, G., & Sampson, J. H. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-3773 · Cited by 618 · see citing works
Batchelor, T. T., Mulholland, P. J., Neyns, B., Nabors, B., Campone, M., Wick, A., Mason, W. P., Mikkelsen, T., Phuphanich, S., Ashby, L. S., et al. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2012.47.2464 · Cited by 610 · see citing works
Self-citationThe role of human glioma-infiltrating microglia/macrophages in mediating antitumor immune responses1
Hussain, S. F., Yang, D., Suki, D., Aldape, K., Grimm, E., & Heimberger, A. B. (2006) · Neuro-Oncology · doi:10.1215/15228517-2006-008 · Cited by 592 · see citing works
Anido, J., Sáez‐Borderías, A., Gonzàlez-Juncà, A., Rodón, L., Folch, G., Carmona, M. A., Prieto-Sánchez, R. M., Barba, I., Martínez-Sáez, E. A., Prudkin, L., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.10.023 · Cited by 571 · see citing works
Self-citationLahn, M. M. F., Herbertz, S., Sawyer, J. S., Stauber, A. J., Gueorguieva, I., Driscoll, K. E., Estrem, S. T., Cleverly, A., Desaiah, D., Guba, S. C., et al. (2015) · Drug Design Development and Therapy · doi:10.2147/dddt.s86621 · Cited by 558 · see citing works
Self-citationPeñuelas, S., Anido, J., Prieto-Sánchez, R. M., Folch, G., Barba, I., Cuartas, I., David Garcia-dorado, A., Poca, M. A., Sahuquillo, J., Baselga, J. M., et al. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.02.011 · Cited by 527 · see citing works
Wick, W., Puduvalli, V. K., Chamberlain, M. C., van den Bent, M. J., Carpentier, A. F., Cher, L., Mason, W. P., Weller, M., Hong, S., Musib, L. C., et al. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2009.23.2595 · Cited by 518 · see citing works
Self-citationBruna, A., Darken, R. S., Rojo, F., Ocaña, A., Peñuelas, S., Arias, A., Parı́s, R., Tortosa, A., Mora, J., Baselga, J. M., et al. (2007) · Cancer Cell · doi:10.1016/j.ccr.2006.11.023 · Cited by 472 · see citing works
Uhl, M., Aulwurm, S., Wischhusen, J., Weiler, M., Jing, Y., Almirez, R. G., Mangadu, R., Liu, Y.-W., Platten, M., Herrlinger, U., et al. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-1013 · Cited by 414 · see citing works
Self-citationRole and Relevance of Neurocognitive Assessment in Clinical Trials of Patients With CNS Tumors
Meyers, C. A., & Brown, P. D. (2006) · Journal of Clinical Oncology · doi:10.1200/jco.2005.04.6086 · Cited by 350 · see citing works
Brandes, A. A., Tosoni, A., Spagnolli, F., Frezza, G., Leonardi, M., Calbucci, F., & Franceschi, E. (2008) · Neuro-Oncology · doi:10.1215/15228517-2008-008 · Cited by 280 · see citing works
Self-citationValidation of the M.D. Anderson Symptom Inventory Brain Tumor Module (MDASI-BT)
Armstrong, T. S., Mendoza, T. R., Gring, I., Coco, C., Cohen, M. Z., Eriksen, L. R., Hsu, M.-A., Gilbert, M. R., & Cleeland, C. S. (2006) · Journal of Neuro-Oncology · doi:10.1007/s11060-006-9135-z · Cited by 278 · see citing works
Agnihotri, S., Burrell, K. E., Wolf, A., Jalali, S., Hawkins, C. E., Rutka, J. T., & Zadeh, G. M. (2012) · Archivum Immunologiae et Therapiae Experimentalis · doi:10.1007/s00005-012-0203-0 · Cited by 272 · see citing works
Kanner, A. A., Marchi, N., Fazio, V. J., et al. (2003) · Cancer · doi:10.1002/cncr.11409 · Cited by 269 · see citing works
Lactate promotes glioma migration by TGF-β2–dependent regulation of matrix metalloproteinase-2
Baumann, F., Leukel, P., Doerfelt, A., Beier, C. P., Dettmer, K., Oefner, P. J., Kastenberger, M., Kreutz, M. P., Nickl‐Jockschat, T., Bogdahn, U., et al. (2008) · Neuro-Oncology · doi:10.1215/15228517-2008-106 · Cited by 256 · see citing works
Rodon, J. A., Carducci, M. A., Sepúlveda-Sánchez, J. M., Azaro, A., Calvo, E., Seoane, J., Braña, I., Sicart, E., Gueorguieva, I., Cleverly, A., et al. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-1380 · Cited by 235 · see citing works
Self-citationBambury, R. M., Teo, M. Y., Power, D., Yusuf, A., Murray, S. L., Battley, J. E., Drake, C., O’Dea, P., Bermingham, N., Keohane, C., et al. (2013) · Journal of Neuro-Oncology · doi:10.1007/s11060-013-1164-9 · Cited by 215 · see citing works
Macrophage-derived chemokine (MDC)
Mantovani, A., Gray, P. A., Damme, J. V., & Sozzani, S. (2000) · Journal of Leukocyte Biology · doi:10.1189/jlb.68.3.400 · Cited by 186 · see citing works
Validation of the M.D. Anderson Symptom Inventory Brain Tumor Module (MDASI-BT)
Armstrong, T. S., Mendoza, T. R., Gning, I., Coco, C., Cohen, M. Z., Eriksen, L. R., Hsu, M., Gilbert, M. R., & Cleeland, C. S. (2006) · Journal of Neuro-Oncology · doi:10.1007/s11060-006-9228-8 · Cited by 168 · see citing works
Bevacizumab for Recurrent Glioblastoma Multiforme: A Meta-Analysis
Wong, E. T., Gautam, S., Malchow, C., et al. (2011) · Journal of the National Comprehensive Cancer Network · doi:10.6004/jnccn.2011.0037 · Cited by 143 · see citing works
Molecular determinants of glioma cell migration and invasion
Wild-Bode, C., Weller, M., & Wick, W. (2001) · Journal of Neurosurgery · doi:10.3171/jns.2001.94.6.0978 · Cited by 130 · see citing works
Self-citationRandomization by minimization for unbalanced treatment allocation
Han, B., Enas, N. H., & McEntegart, D. (2009) · Statistics in Medicine · doi:10.1002/sim.3710 · Cited by 112 · see citing works
Neurocognitive function in patients with recurrent glioblastoma treated with bevacizumab
Wefel, J. S., Cloughesy, T. F., Zazzali, J. L., Zheng, M., Prados, M., Wen, P. Y., Mikkelsen, T., Schiff, D., Abrey, L. E., Yung, W. K. A., et al. (2011) · Neuro-Oncology · doi:10.1093/neuonc/nor024 · Cited by 112 · see citing works
Rodon, J. A., Carducci, M. A., Sepúlveda-Sánchez, J. M., Azaro, A., Calvo, E., Seoane, J., Braña, I., Sicart, E., Gueorguieva, I., Cleverly, A., et al. (2014) · Investigational New Drugs · doi:10.1007/s10637-014-0192-4 · Cited by 108 · see citing works
Self-citationInhibiting TGF-β signaling restores immune surveillance in the SMA-560 glioma model
Tran, T.-T., Uhl, M., Jing, Y., et al. (2007) · Neuro-Oncology · doi:10.1215/15228517-2007-010 · Cited by 96 · see citing works
TGF-β, Neuronal Stem Cells and Glioblastoma
Golestaneh, N., & Mishra, B. (2005) · Oncogene · doi:10.1038/sj.onc.1208925 · Cited by 90 · see citing works
Wick, W., Brandes, A., Gorlia, T., Bendszus, M., Sahm, F., Taal, W., TAPHOORN, M. J. B., Dômont, J., Idbaïh, A., Campone, M., et al. (2015) · Neuro-Oncology · doi:10.1093/neuonc/nov306 · Cited by 80 · see citing works
Self-citationGueorguieva, I., Cleverly, A., Stauber, A. J., Pillay, N. S., Rodon, J. A., Miles, C., Yingling, J. M., & Lahn, M. M. F. (2013) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.12256 · Cited by 77 · see citing works
Self-citationSchneider, T. L., Sailer, M., Ansorge, S., et al. (2006) · Journal of Neuro-Oncology · doi:10.1007/s11060-005-9116-7 · Cited by 65 · see citing works
Repetition priming with nonverbal stimuli in patients with dementia of the Alzheimer type.
Heindel, W. C., Salmon, D. P., Fennema‐Notestine, C., et al. (1998) · Neuropsychology · doi:10.1037/0894-4105.12.1.43 · Cited by 62 · see citing works
Modulation of TGF‐β activity by latent TGF‐β‐binding protein 1 in human malignant glioma cells
Tritschler, I., Gramatzki, D., Capper, D., Mittelbronn, M. G. A., Meyermann, R., Saharinen, J., Wick, W., Keski‐Oja, J., & Weller, M. (2009) · International Journal of Cancer · doi:10.1002/ijc.24443 · Cited by 61 · see citing works
Self-citationESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of malignant glioma
Stupp, R., Pavlidis, N. A., & Jelić, S. (2005) · Annals of Oncology · doi:10.1093/annonc/mdi834 · Cited by 60 · see citing works
Preusser, M., Capper, D., & Hartmann, C. J. (2011) · Clinical Neuropathology · doi:10.5414/np300422 · Cited by 59 · see citing works
Self-citationZhou, M., Bracci, P. M., Mccoy, L. S., et al. (2015) · International Journal of Cancer · doi:10.1002/ijc.29441 · Cited by 45 · see citing works
Tahara, H., Sato, M., Thurin, M., Wang, E., Butterfield, L. H., Disis, M. L., Fox, B. A., Lee, P. P., Khleif, S. N., Wigginton, J. M., et al. (2009) · Journal of Translational Medicine · doi:10.1186/1479-5876-7-45 · Cited by 44 · see citing works
Clarke, J., Ennis, M. M., Lamborn, K. R., et al. (2010) · Neuro-Oncology · doi:10.1093/neuonc/noq116.s9 · Cited by 22 · see citing works
Giannelli, G., Faivre, S. J., Santoro, A., et al. (2014) · Journal of Hepatology · doi:10.1016/s0168-8278(14)60128-8 · Cited by 6 · see citing works
Parsons, S. H., Sawyer, S., Yan, L., et al. (2011) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.targ-11-c201 · Cited by 5 · see citing works
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Wen, P. Y., Weller, M., Lee, E. Q., Alexander, B. M., Barnholtz-Sloan, J. S., Barthel, F. P., Batchelor, T. T., Bindra, R. S., Chang, S. M., Chiocca, E. A., et al. (2020) · Neuro-Oncology · doi:10.1093/neuonc/noaa106 · Cited by 1,168 · see citing works
Self-citationTargeting TGF-β Signaling in Cancer
Colak, S., & ten Dijke, P. (2017) · Trends in cancer · doi:10.1016/j.trecan.2016.11.008 · Cited by 1,003 · see citing works
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Derynck, R., Turley, S. J., & Akhurst, R. J. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-020-0403-1 · Cited by 944 · see citing works
Targeting Cancer Stemness in the Clinic: From Hype to Hope
Saygin, C., Matei, D., Majeti, R., Reizes, O., & Lathia, J. D. (2019) · Cell Stem Cell · doi:10.1016/j.stem.2018.11.017 · Cited by 517 · see citing works
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Liu, T., Zhou, L., Li, D., Andl, T., & Zhang, Y. (2019) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2019.00060 · Cited by 446 · see citing works
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Liu, S., Ren, J., & ten Dijke, P. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00436-9 · Cited by 413 · see citing works
“However, in a phase 2 study of patients with recurrent glioblastoma, this inhibitor failed to improve the overall survival.(217) Vactosertib (TEW-7197) is another orally bioavailable kinase inhibitor of TβRI that revealed promising antitumor function in a mouse model of myeloma.”
BackgroundLind, H., Gameiro, S. R., Jochems, C., Donahue, R. N., Strauss, J., Gulley, J. L., Palena, C., & Schlom, J. (2020) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2019-000433 · Cited by 247 · see citing works
Martin, C. J., Datta, A., Littlefield, C., Kalra, A., Chapron, C., Wawersik, S., Dagbay, K. B., Brueckner, C. T., Nikiforov, A., Danehy, F. T., et al. (2020) · Science Translational Medicine · doi:10.1126/scitranslmed.aay8456 · Cited by 224 · see citing works
Yingling, J. M., McMillen, W. T., Yan, L., Huang, H., Sawyer, J. S., Graff, J., Clawson, D. K., Britt, K. S., Anderson, B. D., Beight, D. W., et al. (2018) · Oncotarget · doi:10.18632/oncotarget.23795 · Cited by 187 · see citing works
Self-citationIkeda, M., Morimoto, M., Tajimi, M., Inoue, K., Benhadji, K. A., Lahn, M. M. F., & Sakai, D. (2019) · Investigational New Drugs · doi:10.1007/s10637-018-0636-3 · Cited by 46 · see citing works
- Authors
- Brandes, A. A., Carpentier, A. F., Kesari, S., Sepulveda-Sanchez, J. M., Wheeler, H. R., Chinot, O., Cher, L., Steinbach, J. P., Capper, D., Specenier, P., Rodon, J., Cleverly, A., Smith, C., Gueorguieva, I., Miles, C., Guba, S. C., Desaiah, D., Lahn, M. M., & Wick, W.
- Affiliations
- Universitat Autònoma de Barcelona (ES)
- Corresponding author
- Brandes, Alba A.
- ORCID
- Venue
- Neuro-Oncology
- Publisher
- Oxford University Press (OUP)
- Published
- 2016-02-21
- Volume
- 18
- Issue
- 8
- Pages
- 1146-1156
- ISSN
- 1522-8517 (ISSN-L)
- 1523-5866
- PMC
- PMC4933481
- OpenAlex
- W2344682920
- Cited by
- 273
- References
- 45
- Citations by year
- 2026: 15 · 2025: 29 · 2024: 31 · 2023: 29 · 2022: 26 · 2021: 43 · 2020: 32 · 2019: 19 · 2018: 21 · 2017: 18 · 2016: 10
- FWCI
- 16.45
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neuro-Oncology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Eli Lilly and Company
- American Society of Clinical Oncology
- Topics
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Health Sciences › Medicine › Reproductive Medicine › Ovarian cancer diagnosis and treatment
- Health Sciences › Medicine › Oncology › Cancer survivorship and care
- Keywords
- galunisertib, lomustine, recurrent glioblastoma, combination therapy, overall survival, pharmacokinetics, drug safety, IDH1 mutation, progression-free survival, intermittent dosing, oral chemotherapy, anticancer activity, brain metastases
- MeSH terms
- Brain Neoplasms, Drug Therapy, Combination, Female, Glioblastoma, Humans, Lomustine, Male, Middle Aged, Pyrazoles, Quinolines, Treatment Outcome, Disease-Free Survival, Antineoplastic Agents, Alkylating, Kaplan-Meier Estimate
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