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Phase II study of Dovitinib in recurrent glioblastoma

Journal of Neuro-Oncology volume 144, pages 359–368 (2019)Cite this article

Abstract

Introduction

Dovitinib is an oral, potent inhibitor of FGFR and VEGFR, and can be a promising strategy in patients with recurrent or progressive glioblastoma (GBM).

Methods

This was an open label phase II study of two arms: Arm 1 included anti-angiogenic naïve patients with recurrent GBM and Arm 2 included patients with recurrent GBM that had progressed on prior anti-angiogenic therapy. Nineteen subjects were enrolled in Arm 1 and 14 subjects in Arm 2. The primary endpoint was 6-month progression-free survival (PFS-6) in Arm 1 and time to progression (TTP) in Arm 2. The secondary endpoints were toxicity, objective response rate (ORR) and overall survival.

Results

Patients in Arm 2 (compared to Arm 1) tended to have longer intervals from diagnosis to study entry (median 26.9 vs. 8.9 months, p = 0.002), experienced more recurrences (64%, had 3–4 prior recurrences compared to 0, p < 0.0001) and tended to be heavily pretreated (71% vs. 26–32% p = 0.04 or 0.02). 6-month PFS was 12% ± 6% for the Arm 1 and 0% for Arm 2. TTP was similar in both treatment arms (median 1.8 months Arm 1 and 0.7–1.8 months Arm 2, p = 0.36). Five patients (15%) had grade 4 toxicities and 22 patients (67%) had grade 3 toxicities. There were no significant differences between the two arms with respect to the amount of change in the levels of biomarkers from baseline.

Conclusion

Dovitinib was not efficacious in prolonging the PFS in patients with recurrent GBM irrespective of prior treatment with anti-angiogenic therapy (including bevacizumab).

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References

  1. 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

    Article  CAS  PubMed  Google Scholar 

  2. Takahashi Y, Kitadai Y, Bucana CD, Cleary KR, Ellis LM (1995) Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Can Res 55(18):3964–3968

    CAS  Google Scholar 

  3. Stefanik DF, Fellows WK, Rizkalla LR, Rizkalla WM, Stefanik PP, Deleo AB, Welch WC (2001) Monoclonal antibodies to vascular endothelial growth factor (VEGF) and the VEGF receptor, FLT-1, inhibit the growth of C6 glioma in a mouse xenograft. J Neurooncol 55(2):91–100

    Article  CAS  PubMed  Google Scholar 

  4. Hurwitz HI, Fehrenbacher L, Hainsworth JD, Heim W, Berlin J, Holmgren E, Hambleton J, Novotny WF, Kabbinavar F (2005) Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer. J Clin Oncol 23(15):3502–3508. https://doi.org/10.1200/jco.2005.10.017

    Article  CAS  PubMed  Google Scholar 

  5. Kerr C (2005) Bevacizumab and chemotherapy improves survival in NSCLC. Lancet Oncol 6(5):266

    Article  PubMed  Google Scholar 

  6. 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(28):4733–4740. https://doi.org/10.1200/jco.2008.19.8721

    Article  CAS  PubMed  Google Scholar 

  7. Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, Garren N, Mackey M, Butman JA, Camphausen K, Park J, Albert PS, Fine HA (2009) Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 27(5):740–745. https://doi.org/10.1200/jco.2008.16.3055

    Article  CAS  PubMed  Google Scholar 

  8. 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. Can Res 54(10):2794–2799

    CAS  Google Scholar 

  9. Pintucci G, Froum S, Pinnell J, Mignatti P, Rafii S, Green D (2002) Trophic effects of platelets on cultured endothelial cells are mediated by platelet-associated fibroblast growth factor-2 (FGF-2) and vascular endothelial growth factor (VEGF). Thromb Haemost 88(5):834–842

    Article  PubMed  Google Scholar 

  10. Batchelor TT, Sorensen AG, di Tomaso E, Zhang WT, Duda DG, Cohen KS, Kozak KR, Cahill DP, Chen PJ, Zhu M, Ancukiewicz M, Mrugala MM, Plotkin S, Drappatz J, Louis DN, Ivy P, Scadden DT, Benner T, Loeffler JS, Wen PY, Jain RK (2007) AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11(1):83–95. https://doi.org/10.1016/j.ccr.2006.11.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 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

    Article  PubMed  Google Scholar 

  12. Atkinson TM, Ryan SJ, Bennett AV, Stover AM, Saracino RM, Rogak LJ, Jewell ST, Matsoukas K, Li Y, Basch E (2016) The association between clinician-based common terminology criteria for adverse events (CTCAE) and patient-reported outcomes (PRO): a systematic review. Support Care Cancer 24(8):3669–3676. https://doi.org/10.1007/s00520-016-3297-9

    Article  PubMed  PubMed Central  Google Scholar 

  13. Hatch AJ, Sibley AB, Starr MD, Brady JC, Jiang C, Jia J, Bowers DL, Pang H, Owzar K, Niedzwiecki D, Innocenti F, Venook AP, Hurwitz HI, Nixon AB (2016) Blood-based markers of efficacy and resistance to cetuximab treatment in metastatic colorectal cancer: results from CALGB 80203 (Alliance). Cancer Med 5(9):2249–2260. https://doi.org/10.1002/cam4.806

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wu M, Barnard J, Kundu S, McCrae KR (2015) A novel pathway of cellular activation mediated by antiphospholipid antibody-induced extracellular vesicles. J Thromb Haemost JTH 13(10):1928–1940. https://doi.org/10.1111/jth.13072

    Article  CAS  PubMed  Google Scholar 

  15. Yamada SM, Yamada S, Hayashi Y, Takahashi H, Teramoto A, Matsumoto K (2002) Fibroblast growth factor receptor (FGFR) 4 correlated with the malignancy of human astrocytomas. Neurol Res 24(3):244–248. https://doi.org/10.1179/016164102101199864

    Article  CAS  PubMed  Google Scholar 

  16. Ueba T, Takahashi JA, Fukumoto M, Ohta M, Ito N, Oda Y, Kikuchi H, Hatanaka M (1994) Expression of fibroblast growth factor receptor-1 in human glioma and meningioma tissues. Neurosurgery 34(2):221–225. (discussion 225-226)

    Article  CAS  PubMed  Google Scholar 

  17. Tkachenko E, Lutgens E, Stan RV, Simons M (2004) Fibroblast growth factor 2 endocytosis in endothelial cells proceed via syndecan-4-dependent activation of Rac1 and a Cdc42-dependent macropinocytic pathway. J Cell Sci 117(Pt 15):3189–3199. https://doi.org/10.1242/jcs.01190

    Article  CAS  PubMed  Google Scholar 

  18. Arteaga CL (2001) The epidermal growth factor receptor: from mutant oncogene in nonhuman cancers to therapeutic target in human neoplasia. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 19(18 Suppl):32s–40s

    CAS  Google Scholar 

  19. Cohen P (2002) Protein kinases–the major drug targets of the twenty-first century? Nat Rev Drug Discovery 1(4):309–315. https://doi.org/10.1038/nrd773

    Article  CAS  PubMed  Google Scholar 

  20. Lemmon MA, Schlessinger J (2010) Cell signaling by receptor tyrosine kinases. Cell 141(7):1117–1134. https://doi.org/10.1016/j.cell.2010.06.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Dvorak HF (2003) Rous-Whipple Award Lecture. How tumors make bad blood vessels and stroma. Am J Pathol 162 (6):1747-1757

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Nagy JA, Vasile E, Feng D, Sundberg C, Brown LF, Manseau EJ, Dvorak AM, Dvorak HF (2002) VEGF-A induces angiogenesis, arteriogenesis, lymphangiogenesis, and vascular malformations. Cold Spring Harb Symp Quant Biol 67:227–237

    Article  CAS  PubMed  Google Scholar 

  23. Auguste P, Javerzat S, Bikfalvi A (2003) Regulation of vascular development by fibroblast growth factors. Cell Tissue Res 314(1):157–166. https://doi.org/10.1007/s00441-003-0750-0

    Article  CAS  PubMed  Google Scholar 

  24. Casanovas O, Hicklin DJ, Bergers G, Hanahan D (2005) Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 8(4):299–309. https://doi.org/10.1016/j.ccr.2005.09.005

    Article  CAS  PubMed  Google Scholar 

  25. Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D (2003) Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Investig 111(9):1287–1295. https://doi.org/10.1172/jci17929

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Escudier B, Grunwald V, Ravaud A, Ou YC, Castellano D, Lin CC, Gschwend JE, Harzstark A, Beall S, Pirotta N, Squires M, Shi M, Angevin E (2014) Phase II results of Dovitinib (TKI258) in patients with metastatic renal cell cancer. Clin Cancer Res 20(11):3012–3022. https://doi.org/10.1158/1078-0432.ccr-13-3006

    Article  CAS  PubMed  Google Scholar 

  27. Norden AD, Schiff D, Ahluwalia MS, Lesser GJ, Nayak L, Lee EQ, Rinne ML, Muzikansky A, Dietrich J, Purow B, Doherty LM, LaFrankie DC, Pulverenti JR, Rifenburg JA, Ruland SF, Smith KH, Gaffey SC, McCluskey C, Ligon KL, Reardon DA, Wen PY (2015) Phase II trial of triple tyrosine kinase receptor inhibitor nintedanib in recurrent high-grade gliomas. J Neurooncol 121(2):297–302. https://doi.org/10.1007/s11060-014-1631-y

    Article  CAS  PubMed  Google Scholar 

  28. Batchelor TT, Mulholland P, Neyns B, Nabors LB, Campone M, Wick A, Mason W, Mikkelsen T, Phuphanich S, Ashby LS, Degroot J, Gattamaneni R, Cher L, Rosenthal M, Payer F, Jurgensmeier JM, Jain RK, Sorensen AG, Xu J, Liu Q, van den Bent M (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(26):3212–3218. https://doi.org/10.1200/jco.2012.47.2464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Galanis E, Anderson SK, Lafky JM, Uhm JH, Giannini C, Kumar SK, Kimlinger TK, Northfelt DW, Flynn PJ, Jaeckle KA, Kaufmann TJ, Buckner JC (2013) Phase II study of bevacizumab in combination with sorafenib in recurrent glioblastoma (N0776): a north central cancer treatment group trial. Clin Cancer Res 19(17):4816–4823. https://doi.org/10.1158/1078-0432.ccr-13-0708

    Article  CAS  PubMed  Google Scholar 

  30. Hutterer M, Nowosielski M, Haybaeck J, Embacher S, Stockhammer F, Gotwald T, Holzner B, Capper D, Preusser M, Marosi C, Oberndorfer S, Moik M, Buchroithner J, Seiz M, Tuettenberg J, Herrlinger U, Wick A, Vajkoczy P, Stockhammer G (2014) A single-arm phase II Austrian/German multicenter trial on continuous daily sunitinib in primary glioblastoma at first recurrence (SURGE 01–07). Neuro-oncology 16(1):92–102. https://doi.org/10.1093/neuonc/not161

    Article  CAS  PubMed  Google Scholar 

  31. Yang C, Wang C, Chen X, Chen S, Zhang Y, Zhi F, Wang J, Li L, Zhou X, Li N, Pan H, Zhang J, Zen K, Zhang CY, Zhang C (2013) Identification of seven serum microRNAs from a genome-wide serum microRNA expression profile as potential noninvasive biomarkers for malignant astrocytomas. Int J Cancer 132(1):116–127. https://doi.org/10.1002/ijc.27657

    Article  CAS  PubMed  Google Scholar 

  32. Li R, Gao K, Luo H, Wang X, Shi Y, Dong Q, Luan W, You Y (2014) Identification of intrinsic subtype-specific prognostic microRNAs in primary glioblastoma. J Exp Clin Cancer Res CR 33:9. https://doi.org/10.1186/1756-9966-33-9

    Article  CAS  PubMed  Google Scholar 

  33. Dong L, Li Y, Han C, Wang X, She L, Zhang H (2014) miRNA microarray reveals specific expression in the peripheral blood of glioblastoma patients. Int J Oncol 45(2):746–756. https://doi.org/10.3892/ijo.2014.2459

    Article  CAS  PubMed  Google Scholar 

  34. Wang G, Wang J, Zhao H, Wang J, Tony To SS (2015) The role of Myc and let-7a in glioblastoma, glucose metabolism and response to therapy. Arch Biochem Biophys 580:84–92. https://doi.org/10.1016/j.abb.2015.07.005

    Article  CAS  PubMed  Google Scholar 

  35. Boyerinas B, Park SM, Hau A, Murmann AE, Peter ME (2010) The role of let-7 in cell differentiation and cancer. Endocr Relat Cancer 17(1):F19–F36. https://doi.org/10.1677/erc-09-0184

    Article  CAS  PubMed  Google Scholar 

  36. Roush S, Slack FJ (2008) The let-7 family of microRNAs. Trends Cell Biol 18(10):505–516. https://doi.org/10.1016/j.tcb.2008.07.007

    Article  CAS  PubMed  Google Scholar 

  37. Lee ST, Chu K, Oh HJ, Im WS, Lim JY, Kim SK, Park CK, Jung KH, Lee SK, Kim M, Roh JK (2011) Let-7 microRNA inhibits the proliferation of human glioblastoma cells. J Neurooncol 102(1):19–24. https://doi.org/10.1007/s11060-010-0286-6

    Article  CAS  PubMed  Google Scholar 

  38. Corbin R, Olsson-Carter K, Slack F (2009) The role of microRNAs in synaptic development and function. BMB Rep 42(3):131–135

    Article  CAS  PubMed  Google Scholar 

  39. Liu Y, Starr MD, Brady JC, Rushing C, Bulusu A, Pang H, Honeycutt W, Amara A, Altomare I, Uronis HE, Hurwitz HI, Nixon AB (2015) Biomarker signatures correlate with clinical outcome in refractory metastatic colorectal cancer patients receiving bevacizumab and everolimus. Mol Cancer Ther 14(4):1048–1056. https://doi.org/10.1158/1535-7163.mct-14-0923-t

    Article  CAS  PubMed  Google Scholar 

  40. Liu Y, Starr MD, Bulusu A, Pang H, Wong NS, Honeycutt W, Amara A, Hurwitz HI, Nixon AB (2013) Correlation of angiogenic biomarker signatures with clinical outcomes in metastatic colorectal cancer patients receiving capecitabine, oxaliplatin, and bevacizumab. Cancer Med 2(2):234–242. https://doi.org/10.1002/cam4.71

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Murukesh N, Dive C, Jayson GC (2010) Biomarkers of angiogenesis and their role in the development of VEGF inhibitors. Br J Cancer 102(1):8–18. https://doi.org/10.1038/sj.bjc.6605483

    Article  CAS  PubMed  Google Scholar 

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Funding

This study was supported by Novartis.

Author information

Authors and Affiliations

  1. Burkhardt Brain Tumor and Neuro-Oncology Center, Neurological Institute, Cleveland Clinic, 9500 Euclid Ave, S73, Cleveland, OH, 44195, USA

    Mayur Sharma, Cathy Schilero, David M. Peereboom, Glen H. J. Stevens & Manmeet S. Ahluwalia

  2. Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

    David M. Peereboom, Glen H. J. Stevens, Keith McCrae & Manmeet S. Ahluwalia

  3. Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA

    Brian P. Hobbs & Paul Elson

  4. Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA

    Andrew B. Nixon

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  1. Mayur Sharma
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Correspondence to Manmeet S. Ahluwalia.

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Conflicts of interest

Dr. Ahluwalia’s disclosures are: receipt of grants/research supports: Astrazeneca, Abbvie, BMS, Bayer, Incyte, Pharmacyclics, Novocure, Merck. Receipt of honoraria or consultation fees: Elsevier, Wiley, Astrazeneca, Abvvie, VBI Vaccines, Flatiron, Varian Medical Systems, Prime Education, Bayer; Stock shareholder: Doctible, Mimivax. There are no potential conflicts of interest for other authors.

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11060_2019_3236_MOESM3_ESM.jpg

Supplementary file3 (JPG 385 kb). Correlation between biomarkers and progression free survival (PFS) a) BMP 9 [<27.0 (blue) vs >27.0 (red)] b) Baseline Endoglin [<250.0 (blue) vs > 250.0 (red)] c) Baseline CD73 [<1.2 (blue) vs >1.2 (red)] d) Baseline TSP 2 [<1800 (blue) vs >1800 (red)] e) Overall Change in TGFβ 2 at Cycle 1 Day 28 f) Overall Change in VEGF R3 at Cycle 1 Day 28. (Blue (-1) =decrease compared to baseline; red (1) =increase)

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Sharma, M., Schilero, C., Peereboom, D.M. et al. Phase II study of Dovitinib in recurrent glioblastoma. J Neurooncol 144, 359–368 (2019). https://doi.org/10.1007/s11060-019-03236-6

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  • DOI: https://doi.org/10.1007/s11060-019-03236-6

Keywords

  • Dovitinib
  • Glioblastoma
  • Recurrent
  • Bevacizumab
  • Anti-angiogenic therapy