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Journal of Neuro-Oncology

, Volume 136, Issue 1, pp 115–125 | Cite as

Randomized phase II trial comparing axitinib with the combination of axitinib and lomustine in patients with recurrent glioblastoma

  • J. DuerinckEmail author
  • S. Du Four
  • F. Bouttens
  • C. Andre
  • V. Verschaeve
  • F. Van Fraeyenhove
  • C. Chaskis
  • N. D’Haene
  • M. Le Mercier
  • A. Rogiers
  • A. Michotte
  • I. Salmon
  • B. Neyns
Clinical Study

Abstract

Axitinib is a small molecule tyrosine kinase inhibitor with high affinity and specificity for the family of vascular endothelial growth factor receptors. It has previously demonstrated anti-tumor activity in a small cohort of patients with recurrent glioblastoma (rGB). We conducted a non-comparative randomized phase II clinical trial investigating axitinib monotherapy versus axitinib plus lomustine (LOM) in patients with rGB. Primary endpoint was 6 month progression-free survival (6mPFS). Patients who progressed on axitinib-monotherapy were allowed to cross-over. Between August 2011 and July 2015, 79 patients were randomized and initiated axitinib monotherapy (n = 50; AXI) or axitinib plus lomustine (n = 29; AXILOM). Median age was 55y [range 18–80], 50M/28F. Baseline characteristics were well balanced between study arms. Nineteen patients in the AXI-arm crossed-over at the time of progression. Treatment was generally well tolerated. AXILOM patients were at higher risk for grade 3/4 neutropenia (0 vs. 21%) and thrombocytopenia (4 vs. 29%). Best Overall Response Rate (BORR) in the AXI-arm was 28 vs. 38% in the AXILOM-arm. 6mPFS was 26% (95% CI 14–38) versus 17% (95% CI 2–32) for patients treated in the AXI versus AXILOM-arms, respectively. Median overall survival was 29 weeks (95% CI 20–38) in the AXI-arm and 27.4 weeks (95% CI 18.4–36.5) in the AXILOM-arm. MGMT-promoter hypermethylation and steroid treatment at baseline correlated significantly with PFS and OS. We conclude from these results that axitinib improves response rate and progression-free survival in patients with rGB compared to historical controls. There is no indication that upfront combination of axitinib with LOM improves results (European Clinical Trials Database (EudraCT) Study Number: 2011-000900-16).

Keywords

Glioblastoma Recurrent Axitinib Lomustine 

Notes

Acknowledgements

We would like to acknowledge the patients who consented to participate in this study, their families and professional health care providers. Pfizer Belgium for the provision of axitinib study medication and a research grant. We would also like to thank the data manager Katrien Van den Bossche and Kathleen Mooren (UZ Brussel) for their help with the data collection and analysis, and Ludwig Van den Hove, PhD (Pfizer Belgium), for his support and critical review of the manuscript.

Supplementary material

11060_2017_2629_MOESM1_ESM.docx (21 kb)
Supplementary material 1 (DOCX 21 KB)

References

  1. 1.
    De Angelis LM (2001) Brain tumors. N Engl J Med 344:114–123. doi: 10.1056/NEJM200101113440207 CrossRefGoogle Scholar
  2. 2.
    Stupp R, Hegi ME, Mason WP et al (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 10:459–466. doi: 10.1016/S1470-2045(09)70025-7 CrossRefPubMedGoogle Scholar
  3. 3.
    Wong ET, Hess KR, Gleason MJ et al (1999) Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol 17:2572–2578CrossRefPubMedGoogle Scholar
  4. 4.
    Lamborn KR, Yung WKA, Chang SM et al (2008) Progression-free survival: an important end point in evaluating therapy for recurrent high-grade gliomas. Neuro Oncol 10:162–170. doi: 10.1215/15228517-2007-062 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Puputti M, Tynninen O, Sihto H et al (2006) Amplification of KIT, PDGFRA, VEGFR2, and EGFR in gliomas. Mol Cancer Res 4:927–934. doi: 10.1158/1541-7786.MCR-06-0085 CrossRefPubMedGoogle Scholar
  6. 6.
    Reardon DA, Turner S, Peters KB et al (2011) A review of VEGF/VEGFR-targeted therapeutics for recurrent glioblastoma. J Natl Compr Canc Netw 9:414–427. doi: 10.6004/jnccn.2011.0038 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Friedman HS, Prados MD, Wen PY et al (2009) Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 27:4733–4740. doi: 10.1200/JCO.2008.19.8721 CrossRefPubMedGoogle Scholar
  8. 8.
    Kreisl TN, Kim L, Moore K et al (2009) Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 27:740–745. doi: 10.1200/JCO.2008.16.3055 CrossRefPubMedGoogle Scholar
  9. 9.
    Taal W, Oosterkamp HM, Walenkamp AME et al (2014) Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial. Lancet Oncol 15:943–953. doi: 10.1016/S1470-2045(14)70314-6 CrossRefPubMedGoogle Scholar
  10. 10.
    Wick W, Brandes A, Gorlia T, Al E (2015) Phase III trial exploring the combination of bevacizumab and lomustine in patients with first recurrence of a glioblastoma: the EORTC 26101 trial. Neuro Oncol 17 (suppl 5):v1CrossRefGoogle Scholar
  11. 11.
    Escudier B, Gore M (2011) Axitinib for the management of metastatic renal cell carcinoma. Drugs R D 11:113–126. doi: 10.2165/11591240-000000000-00000 CrossRefPubMedGoogle Scholar
  12. 12.
    Albiges L, Gizzi M, Carton E, Escudier B (2015) Axitinib in metastatic renal cell carcinoma. Expert Rev Anticancer Ther 15:499–507. doi: 10.1586/14737140.2015.1033408 CrossRefPubMedGoogle Scholar
  13. 13.
    Lu L, Saha D, Martuza RL et al (2014) Single agent efficacy of the VEGFR kinase inhibitor axitinib in preclinical models of glioblastoma. J Neurooncol 121:91–100. doi: 10.1007/s11060-014-1612-1 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Kratzsch T, Gruenwald V, Vajkoczy P, Kuhn S (2013) Use of axitinib, a new-generation tyrosine kinase inhibitor, to decrease glioblastoma growth despite primary resistance to the VEGF-antibody bevacizumab. ASCO Meeting Abstracts 2013; 31 2077Google Scholar
  15. 15.
    Duerinck J, Du Four S, Vandervorst F et al (2016) Randomized phase II study of axitinib versus physicians best alternative choice of therapy in patients with recurrent glioblastoma. J Neurooncol 128:147–155. doi: 10.1007/s11060-016-2092-2 CrossRefPubMedGoogle Scholar
  16. 16.
    Fleming TR (1982) One-sample multiple testing procedure for phase II clinical trials. Biometrics 38:143–151CrossRefPubMedGoogle Scholar
  17. 17.
    Moher D, Schulz KF, Altman DG (2001) The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomised trials. The Lancet 357:1191–1194. doi: 10.1016/S0140-6736(00)04337-3 CrossRefGoogle Scholar
  18. 18.
    Rugo HS, Herbst RS, Liu G et al (2005) Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: pharmacokinetic and clinical results. J Clin Oncol 23:5474–5483. doi: 10.1200/JCO.2005.04.192 CrossRefPubMedGoogle Scholar
  19. 19.
    Wen PY, Macdonald DR, Reardon D a et al (2010) Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 28:1963–1972. doi: 10.1200/JCO.2009.26.3541 CrossRefPubMedGoogle Scholar
  20. 20.
    National Cancer Institute (2009) Common terminology criteria for adverse events (CTCAE) v4.0Google Scholar
  21. 21.
    Eads CA, Danenberg KD, Kawakami K et al (2000) MethyLight: a high-throughput assay to measure DNA methylation. Nucleic Acids Res 28:E32. doi: 10.1093/nar/28.8.e32 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    D’Haene N, Le Mercier M, De Nève N et al (2015) Clinical validation of targeted next generation sequencing for colon and lung cancers. PLoS ONE 10:e0138245. doi: 10.1371/journal.pone.0138245 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Le Mercier M, D’Haene N, De Nève N et al (2015) Next-generation sequencing improves the diagnosis of thyroid FNA specimens with indeterminate cytology. Histopathology 66:215–224. doi: 10.1111/his.12461 CrossRefPubMedGoogle Scholar
  24. 24.
    Raizer JJ, Grimm S, Chamberlain MC et al (2010) A phase 2 trial of single-agent bevacizumab given in an every-3-week schedule for patients with recurrent high-grade gliomas. Cancer 116:5297–5305. doi: 10.1002/cncr.25462 CrossRefPubMedGoogle Scholar
  25. 25.
    Duerinck J, Clement P, Bouttens F et al (2015) Patient outcome in the Belgian medical need program on bevacizumab for recurrent glioblastoma. J Neurol 262:742–751. doi: 10.1007/s00415-014-7633-z
  26. 26.
    Hutterer M, Nowosielski M, Haybaeck J et al (2014) A single-arm phase II Austrian/German multicenter trial on continuous daily sunitinib in primary glioblastoma at first recurrence (SURGE 01–07). Neuro Oncol 16:92–102. doi: 10.1093/neuonc/not161 CrossRefPubMedGoogle Scholar
  27. 27.
    Iwamoto FM, Lamborn KR, Robins HI et al (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 12:855–861. doi: 10.1093/neuonc/noq025 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Batchelor TT, Mulholland P, Neyns B et al (2013) Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. J Clin Oncol 31:3212–3218. doi: 10.1200/JCO.2012.47.2464 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    de Groot JF, Lamborn KR, Chang SM et al (2011) Phase II study of aflibercept in recurrent malignant glioma: A North American Brain Tumor Consortium Study. J Clin Oncol 29:2689–2695. doi: 10.1200/JCO.2010.34.1636 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Du Four S, Maenhout SK, De Pierre K et al (2015) Axitinib increases the infiltration of immune cells and reduces the suppressive capacity of monocytic MDSCs in an intracranial mouse melanoma model. Oncoimmunology 4:e998107. doi: 10.1080/2162402X.2014.998107 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Du Four S, Maenhout SK, Benteyn D et al (2016) Disease progression in recurrent glioblastoma patients treated with the VEGFR inhibitor axitinib is associated with increased regulatory T cell numbers and T cell exhaustion. Cancer Immunol Immunother 65:727–740. doi: 10.1007/s00262-016-1836-3 CrossRefPubMedGoogle Scholar
  32. 32.
    Zhang X, Fang X, Gao Z et al (2014) Axitinib, a selective inhibitor of vascular endothelial growth factor receptor, exerts an anticancer effect in melanoma through promoting antitumor immunity. Anticancer Drugs 25:204–211. doi: 10.1097/CAD.0000000000000033 CrossRefPubMedGoogle Scholar
  33. 33.
    Stehle F, Schulz K, Fahldieck C et al (2013) Reduced immunosuppressive properties of axitinib in comparison with other tyrosine kinase inhibitors. J Biol Chem 288:16334–16347. doi: 10.1074/jbc.M112.437962 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Bose A, Lowe DB, Rao A, Storkus WJ (2012) Combined vaccine + axitinib therapy yields superior antitumor efficacy in a murine melanoma model. Melanoma Res 22:236–243. doi: 10.1097/CMR.0b013e3283538293 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Du Four S, Maenhout SK, Niclou SP et al (2016) Combined VEGFR and CTLA-4 blockade increases the antigen-presenting function of intratumoral DCs and reduces the suppressive capacity of intratumoral MDSCs. Am J Cancer Res 6:2514–2531PubMedPubMedCentralGoogle Scholar
  36. 36.
    Larkin J, Rini BI, Nathan P et al (2016) Phase 1b dose-finding study of avelumab (anti-PD-L1)+ axitinib in treatment-naïve patients with advanced renal cell carcinoma. European Society for Medical Oncology Congress, Copenhagen, Denmark, 27 SupplementGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • J. Duerinck
    • 1
    Email author
  • S. Du Four
    • 1
  • F. Bouttens
    • 2
  • C. Andre
    • 3
  • V. Verschaeve
    • 4
  • F. Van Fraeyenhove
    • 5
  • C. Chaskis
    • 6
  • N. D’Haene
    • 7
  • M. Le Mercier
    • 7
  • A. Rogiers
    • 8
  • A. Michotte
    • 9
  • I. Salmon
    • 7
  • B. Neyns
    • 10
  1. 1.Department of NeurosurgeryUniversitair Ziekenhuis BrusselBrusselsBelgium
  2. 2.Department of Medical and Radiation OncologyAZ Sint-Lucas GentGhentBelgium
  3. 3.Department of Medical OncologyCHU LiègeLiègeBelgium
  4. 4.Department of Medical OncologyGHDCCharleroiBelgium
  5. 5.Department of Medical OncologyZNA MiddelheimAntwerpBelgium
  6. 6.Department of NeurosurgeryCHU CharleroiCharleroiBelgium
  7. 7.Department of PathologyHopital Erasme Université Libre de BruxellesBrusselsBelgium
  8. 8.Department of PsychiatryCHU BrugmannBrusselsBelgium
  9. 9.Departments of Pathology and NeurologyUniversitair Ziekenhuis BrusselBrusselsBelgium
  10. 10.Department of Medical OncologyUniversitair Ziekenhuis BrusselBrusselsBelgium

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