Advertisement

Journal of Neuro-Oncology

, Volume 111, Issue 2, pp 205–212 | Cite as

Phase II open-label study of nintedanib in patients with recurrent glioblastoma multiforme

  • Aida Muhic
  • Hans Skovgaard Poulsen
  • Morten Sorensen
  • Kirsten Grunnet
  • Ulrik Lassen
Clinical Study

Abstract

Nintedanib (BIBF 1120) is a small, orally available, triple angiokinase inhibitor in phase III development (various indications) that targets VEGFR 1–3, FGFR 1–3, and PDGFR-α/β. This open-label, uncontrolled, phase II study assessed the efficacy and safety of nintedanib in patients with recurrent glioblastoma multiforme (GBM) who had previously failed radiotherapy plus temozolomide as first-line therapy (STUPP), or the same regimen with subsequent bevacizumab-based therapy as second-line treatment (BEV). Patients with a performance status of 0–1, histologically proven GBM, and measurable disease (by RANO) were enrolled. Nintedanib was given orally at a dose of 200 mg twice daily (bid), with magnetic resonance imaging undertaken every 8 weeks. The primary endpoint was objective response rate. The study was stopped prematurely following a preplanned futility analysis after inclusion of 13 patients in the STUPP arm and 12 in the BEV arm. Best response was stable disease (SD) in three patients (12 %); all other patients progressed within the first four 28-day cycles. One patient in the BEV arm has had SD for 17+ months. Median progression-free survival was 1 month and median overall survival was 6 months. Nintedanib had an acceptable safety profile, with no CTCAE grade 3–4 adverse events. Common adverse events were CTCAE grade 1–2 fatigue, loss of appetite, diarrhea, and nausea. Single-agent nintedanib (200 mg bid) demonstrated limited, but clinically non-relevant antitumor activity in patients with recurrent GBM who had failed 1–2 prior lines of therapy.

Keywords

Glioblastoma Nintedanib (BIBF 1120) Angiogenesis inhibitors Phase II clinical trial 

Notes

Acknowledgments

Medical writing support, funded by Boehringer Ingelheim, was provided by Duncan Campbell of GeoMed in the production of this manuscript. This investigator-initiated study was supported by a research grant from Boehringer Ingelheim, Germany, who also provided the study medication.

Conflicts of interest

No authors have conflicts of interest.

References

  1. 1.
    Bruce J, Kennedy B. (2012) Glioblastoma Multiforme http://emedicine.medscape.com/article/283252-overview
  2. 2.
    Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996PubMedCrossRefGoogle Scholar
  3. 3.
    National Comprehensive Cancer Network (NCCN) (2012) Clinical Practice Guidelines in Oncology: Central Nervous System Cancers, Version 2.2012Google Scholar
  4. 4.
    Wen PY, Kesari S (2008) Malignant gliomas in adults. N Engl J Med 359:492–507PubMedCrossRefGoogle Scholar
  5. 5.
    Wong ET, Hess KR, Gleason MJ, Jaeckle KA, Kyritsis AP, Prados MD, Levin VA, Yung WK (1999) Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol 17:2572–2578PubMedGoogle Scholar
  6. 6.
    Takano S, Yoshii Y, Kondo S, Suzuki H, Maruno T, Shirai S, Nose T (1996) Concentration of vascular endothelial growth factor in the serum and tumor tissue of brain tumor patients. Cancer Res 56:2185–2190PubMedGoogle Scholar
  7. 7.
    Smith JS, Tachibana I, Passe SM, Huntley BK, Borell TJ, Iturria N, O’Fallon JR, Schaefer PL, Scheithauer BW, James CD, Buckner JC, Jenkins RB (2001) PTEN mutation, EGFR amplification, and outcome in patients with anaplastic astrocytoma and glioblastoma multiforme. J Natl Cancer Inst 93:1246–1256PubMedCrossRefGoogle Scholar
  8. 8.
    Hesselager G, Uhrbom L, Westermark B, Nister M (2003) Complementary effects of platelet-derived growth factor autocrine stimulation and p53 or Ink4a-Arf deletion in a mouse glioma model. Cancer Res 63:4305–4309PubMedGoogle Scholar
  9. 9.
    Iacob G, Dinca EB (2009) Current data and strategy in glioblastoma multiforme. J Med Life 2:386–393PubMedGoogle Scholar
  10. 10.
    Morrison RS, Yamaguchi F, Bruner JM, Tang M, McKeehan W, Berger MS (1994) Fibroblast growth factor receptor gene expression and immunoreactivity are elevated in human glioblastoma multiforme. Cancer Res 54:2794–2799PubMedGoogle Scholar
  11. 11.
    Kita D, Yonekawa Y, Weller M, Ohgaki H (2007) PIK3CA alterations in primary (de novo) and secondary glioblastomas. Acta Neuropathol 113:295–302PubMedCrossRefGoogle Scholar
  12. 12.
    Cao H, Zhang H, Zheng X, Gao D (2007) 3D QSAR studies on a series of potent and high selective inhibitors for three kinases of RTK family. J Mol Graph Model 26:236–245PubMedCrossRefGoogle Scholar
  13. 13.
    Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, Yung WK, Paleologos N, Nicholas MK, Jensen R, Vredenburgh J, Huang J, Zheng M, Cloughesy T (2009) Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 27:4733–4740PubMedCrossRefGoogle Scholar
  14. 14.
    Jakobsen JN, Hasselbalch B, Stockhausen MT, Lassen U, Poulsen HS (2011) Irinotecan and bevacizumab in recurrent glioblastoma multiforme. Expert Opin Pharmacother 12:825–833PubMedCrossRefGoogle Scholar
  15. 15.
    Vredenburgh JJ, Desjardins A, Herndon JE, Marcello J, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Sampson J, Wagner M, Bailey L, Bigner DD, Friedman AH, Friedman HS (2007) Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 25:4722–4729PubMedCrossRefGoogle Scholar
  16. 16.
    Hilberg F, Roth GJ, Krssak M, Kautschitsch S, Sommergruber W, Tontsch-Grunt U, Garin-Chesa P, Bader G, Zoephel A, Quant J, Heckel A, Rettig WJ (2008) BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res 68:4774–4782PubMedCrossRefGoogle Scholar
  17. 17.
    Mross K, Stefanic M, Gmehling D, Frost A, Baas F, Unger C, Strecker R, Henning J, Gaschler-Markefski B, Stopfer P, de   RL, Kaiser R (2010) Phase I study of the angiogenesis inhibitor BIBF 1120 in patients with advanced solid tumors. Clin Cancer Res 16:311–319PubMedCrossRefGoogle Scholar
  18. 18.
    Ledermann JA, Hackshaw A, Kaye S, Jayson G, Gabra H, McNeish I, Earl H, Perren T, Gore M, Persic M, Adams M, James L, Temple G, Merger M, Rustin G (2011) Randomized phase II placebo-controlled trial of maintenance therapy using the oral triple angiokinase inhibitor BIBF 1120 after chemotherapy for relapsed ovarian cancer. J Clin Oncol 29:3798–3804PubMedCrossRefGoogle Scholar
  19. 19.
    Reck M, Kaiser R, Eschbach C, Stefanic M, Love J, Gatzemeier U, Stopfer P, von   PJ (2011) A phase II double-blind study to investigate efficacy and safety of two doses of the triple angiokinase inhibitor BIBF 1120 in patients with relapsed advanced non-small-cell lung cancer. Ann Oncol 22:1374–1381PubMedCrossRefGoogle Scholar
  20. 20.
    Richeldi L, Costabel U, Selman M, Kim DS, Hansell DM, Nicholson AG, Brown KK, Flaherty KR, Noble PW, Raghu G, Brun M, Gupta A, Juhel N, Kluglich M, du Bois RM (2011) Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med 365:1079–1087PubMedCrossRefGoogle Scholar
  21. 21.
    Okamoto I, Kaneda H, Satoh T, Okamoto W, Miyazaki M, Morinaga R, Ueda S, Terashima M, Tsuya A, Sarashina A, Konishi K, Arao T, Nishio K, Kaiser R, Nakagawa K (2010) Phase I safety, pharmacokinetic, and biomarker study of BIBF 1120, an oral triple tyrosine kinase inhibitor in patients with advanced solid tumors. Mol Cancer Ther 9:2825–2833PubMedCrossRefGoogle Scholar
  22. 22.
    Quant EC, Wen PY (2011) Response assessment in neuro-oncology. Curr Oncol Rep 13:50–56PubMedCrossRefGoogle Scholar
  23. 23.
    U.S.Department of Health and Human Services, National Institutes of Health, National Cancer Institute (2009) Common Terminology Criteria for Adverse Events (CTCAE) version 4.02Google Scholar
  24. 24.
    Santos ES, Gomez JE, Raez LE (2012) Targeting angiogenesis from multiple pathways simultaneously: BIBF 1120, an investigational novel triple angiokinase inhibitor. Invest New Drugs 30:1261–1269PubMedCrossRefGoogle Scholar
  25. 25.
    Baeriswyl V, Christofori G (2009) The angiogenic switch in carcinogenesis. Semin Cancer Biol 19:329–337PubMedCrossRefGoogle Scholar
  26. 26.
    Stommel JM, Kimmelman AC, Ying H, Nabioullin R, Ponugoti AH, Wiedemeyer R, Stegh AH, Bradner JE, Ligon KL, Brennan C, Chin L, DePinho RA (2007) Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science 318:287–290PubMedCrossRefGoogle Scholar
  27. 27.
    Batchelor T, Mulholland P, Neyns B, Nabors LB, Campone M, Wick A, Mason W, Mikkelsen T, Phuphanich S, Ashby LS, et al (2010) The efficacy of cediranib as monotherapy and in combination with lomustine compared to lomustine alone in patients with recurrent glioblastoma: a phase III randomized study. Neuro-Oncol 12:iv69–iv78Google Scholar
  28. 28.
    Conrad C, Friedman H, Reardon D, Provenzale J, Jackson E, Serajuddin H, Laurent D, Chen B, Yung WKA (2004) A phase I/II trial of single-agent PTK 787/ZK 222584 (PTK/ZK), a novel, oral angiogenesis inhibitor, in patients with recurrent glioblastoma multiforme (GBM). ASCO 22:1512Google Scholar
  29. 29.
    Iwamoto FM, Lamborn KR, Robins HI, Mehta MP, Chang SM, Butowski NA, Deangelis LM, Abrey LE, Zhang WT, Prados MD, Fine HA (2010) Phase II trial of pazopanib (GW786034), an oral multi-targeted angiogenesis inhibitor, for adults with recurrent glioblastoma (North American Brain Tumor Consortium Study 06–02). Neuro Oncol 12:855–861PubMedCrossRefGoogle Scholar
  30. 30.
    Pan E, Yu D, Yue B, Potthast L, Chowdhary S, Smith P, Chamberlain M (2012) A prospective phase II single-institution trial of sunitinib for recurrent malignant glioma. J Neurooncol 110(1):111–118PubMedCrossRefGoogle Scholar
  31. 31.
    Reardon DA, Vredenburgh JJ, Desjardins A, Peters K, Gururangan S, Sampson JH, Marcello J, Herndon JE, McLendon RE, Janney D, Friedman AH, Bigner DD, Friedman HS (2011) Effect of CYP3A-inducing anti-epileptics on sorafenib exposure: results of a phase II study of sorafenib plus daily temozolomide in adults with recurrent glioblastoma. J Neurooncol 101:57–66PubMedCrossRefGoogle Scholar
  32. 32.
    Scott BJ, Quant EC, McNamara MB, Ryg PA, Batchelor TT, Wen PY (2010) Bevacizumab salvage therapy following progression in high-grade glioma patients treated with VEGF receptor tyrosine kinase inhibitors. Neuro Oncol 12:603–607PubMedCrossRefGoogle Scholar
  33. 33.
    Agarwal S, Sane R, Gallardo JL, Ohlfest JR, Elmquist WF (2010) Distribution of gefitinib to the brain is limited by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2)-mediated active efflux. J Pharmacol Exp Ther 334:147–155PubMedCrossRefGoogle Scholar
  34. 34.
    Kodaira H, Kusuhara H, Ushiki J, Fuse E, Sugiyama Y (2010) Kinetic analysis of the cooperation of P-glycoprotein (P-gp/Abcb1) and breast cancer resistance protein (Bcrp/Abcg2) in limiting the brain and testis penetration of erlotinib, flavopiridol, and mitoxantrone. J Pharmacol Exp Ther 333:788–796PubMedCrossRefGoogle Scholar
  35. 35.
    Polli JW, Olson KL, Chism JP, John-Williams LS, Yeager RL, Woodard SM, Otto V, Castellino S, Demby VE (2009) An unexpected synergist role of P-glycoprotein and breast cancer resistance protein on the central nervous system penetration of the tyrosine kinase inhibitor lapatinib (N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; GW572016). Drug Metab Dispos 37:439–442PubMedCrossRefGoogle Scholar
  36. 36.
    Wang T, Agarwal S, Elmquist WF (2012) Brain distribution of cediranib is limited by active efflux at the blood-brain barrier. J Pharmacol Exp Ther 341:386–395PubMedCrossRefGoogle Scholar
  37. 37.
    Agarwal S, Sane R, Oberoi R, Ohlfest JR, Elmquist WF (2011) Delivery of molecularly targeted therapy to malignant glioma, a disease of the whole brain. Expert Rev Mol Med 13:e17PubMedCrossRefGoogle Scholar
  38. 38.
    Chi AS, Sorensen AG, Jain RK, Batchelor TT (2009) Angiogenesis as a therapeutic target in malignant gliomas. Oncologist 14:621–636PubMedCrossRefGoogle Scholar
  39. 39.
    Chowdhary S, Wong ET (2008) Bevacizumab combined with irinotecan for recurrent glioblastoma multiforme–improvement over available therapy? Nat Clin Pract Neurol 4:242–243PubMedCrossRefGoogle Scholar
  40. 40.
    Reardon DA, Desjardins A, Peters KB, Gururangan S, Sampson JH, McLendon RE, Herndon JE, Bulusu A, Threatt S, Friedman AH, Vredenburgh JJ, Friedman HS (2012) Phase II study of carboplatin, irinotecan, and bevacizumab for bevacizumab naive, recurrent glioblastoma. J Neurooncol 107:155–164PubMedCrossRefGoogle Scholar
  41. 41.
    Shirai K, Siedow MR, Chakravarti A (2012) Antiangiogenic therapy for patients with recurrent and newly diagnosed malignant gliomas. J Oncol 2012:193436PubMedCrossRefGoogle Scholar
  42. 42.
    Bergers G, Hanahan D (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8:592–603PubMedCrossRefGoogle Scholar
  43. 43.
    Wick W, Weller M, Weiler M, Batchelor T, Yung AW, Platten M (2011) Pathway inhibition: emerging molecular targets for treating glioblastoma. Neuro Oncol 13:566–579PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Aida Muhic
    • 1
  • Hans Skovgaard Poulsen
    • 1
    • 2
  • Morten Sorensen
    • 1
  • Kirsten Grunnet
    • 1
    • 2
  • Ulrik Lassen
    • 1
  1. 1.Department of Oncology 5073, Section for Neuro-oncology and Phase I UnitCopenhagenDenmark
  2. 2.Department of Radiation BiologyCopenhagenDenmark

Personalised recommendations