Skip to main content

Advertisement

SpringerLink
Log in

Phase I trial of aflibercept (VEGF trap) with radiation therapy and concomitant and adjuvant temozolomide in patients with high-grade gliomas

  • Clinical Study
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Anti-vascular endothelial growth factor (VEGF) therapy has shown promise in the treatment of high-grade gliomas (HGG). Aflibercept is a recombinant human fusion protein that acts as a soluble decoy receptor for VEGF-A, VEGF-B and placental growth factor, depleting circulating levels of these growth factors. The Adult Brain Tumor Consortium conducted a phase I trial of aflibercept and temozolomide (TMZ) in patients with newly diagnosed HGG with 2 dose levels and a 3+3 design. Three arms using aflibercept were examined; with radiation and concomitant temozolomide; with adjuvant temozolomide using the 5/28 regimen; and with adjuvant temozolomide using the 21/28 day regimen. Fifty-nine patients were enrolled, 21 in arm 1, 20 in arm 2 and 18 in arm 3. Median age was 56 years (24–69); median KPS 90 (60–100). The maximum tolerated dose (MTD) of aflibercept for all 3 arms was 4 mg/kg every 2 weeks. Dose limiting toxicities at the MTD were: Arm 1: 0/21 patients; Arm 2: 2/20 patients (G3 deep vein thrombosis, G4 neutropenia; Arm 3: 3/18 patients) (G4 biopsy-confirmed thrombotic microangiopathy, G3 rash, G4 thrombocytopenia). The median number of cycles of aflibercept was 5 (range, 1–16). All patients stopped treatment; 28 (47%) for disease progression, 21 (36%) for toxicities, 8 (14%) for other reasons, and 2 (3%) patients completed the full treatment course. This study met its primary endpoint and the MTD of aflibercept with radiation and concomitant and adjuvant temozolomide is 4 mg/kg every 2 weeks.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Chi AS, Sorensen AG, Jain RK, Batchelor TT (2009) Angiogenesis as a therapeutic target in malignant gliomas. Oncologist 14:621–636. doi:10.1634/theoncologist.2008-0272

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. 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 27:4733–4740. doi:10.1200/JCO.2008.19.8721

    Article  CAS  PubMed  Google Scholar 

  3. 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 27:740–745. doi:10.1200/JCO.2008.16.3055

    Article  CAS  PubMed  Google Scholar 

  4. Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, Colman H, Chakravarti A, Pugh S, Won M, Jeraj R, Brown PD, Jaeckle KA, Schiff D, Stieber VW, Brachman DG, Werner-Wasik M, Tremont-Lukats IW, Sulman EP, Aldape KD, Curran WJ Jr, Mehta MP (2014) A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med 370:699–708. doi:10.1056/NEJMoa1308573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, Carpentier AF, Hoang-Xuan K, Kavan P, Cernea D, Brandes AA, Hilton M, Abrey L, Cloughesy T (2014) Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med 370:709–722. doi:10.1056/NEJMoa1308345

    Article  CAS  PubMed  Google Scholar 

  6. Arrillaga-Romany I, Reardon DA, Wen PY (2014) Current status of antiangiogenic therapies for glioblastomas. Expert Opin Investig Drugs 23:199–210. doi:10.1517/13543784.2014.856880

    Article  CAS  PubMed  Google Scholar 

  7. de Groot JF, Lamborn KR, Chang SM, Gilbert MR, Cloughesy TF, Aldape K, Yao J, Jackson EF, Lieberman F, Robins HI, Mehta MP, Lassman AB, Deangelis LM, Yung WK, Chen A, Prados MD, Wen PY (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

    Article  PubMed  PubMed Central  Google Scholar 

  8. Winkler F, Kozin SV, Tong RT, Chae SS, Booth MF, Garkavtsev I, Xu L, Hicklin DJ, Fukumura D, di Tomaso E, Munn LL, Jain RK (2004) Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6:553–563. doi:10.1016/j.ccr.2004.10.011

    CAS  PubMed  Google Scholar 

  9. Wachsberger PR, Burd R, Cardi C, Thakur M, Daskalakis C, Holash J, Yancopoulos GD, Dicker AP (2007) VEGF trap in combination with radiotherapy improves tumor control in u87 glioblastoma. Int J Radiat Oncol Biol Phys 67:1526–1537. doi:10.1016/j.ijrobp.2006.11.011

    Article  CAS  PubMed  Google Scholar 

  10. Gilbert MR, Wang M, Aldape KD, Stupp R, Hegi ME, Jaeckle KA, Armstrong TS, Wefel JS, Won M, Blumenthal DT, Mahajan A, Schultz CJ, Erridge S, Baumert B, Hopkins KI, Tzuk-Shina T, Brown PD, Chakravarti A, Curran WJ Jr, Mehta MP (2013) Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol 31:4085–4091. doi:10.1200/JCO.2013.49.6968

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Brada M, Stenning S, Gabe R, Thompson LC, Levy D, Rampling R, Erridge S, Saran F, Gattamaneni R, Hopkins K, Beall S, Collins VP, Lee SM (2010) Temozolomide versus procarbazine, lomustine, and vincristine in recurrent high-grade glioma. J Clin Oncol 28:4601–4608. doi:10.1200/JCO.2009.27.1932

    Article  CAS  PubMed  Google Scholar 

  12. Tombaugh TN (2004) Trail Making Test A and B: normative data stratified by age and education. Arch Clin Neuropsychol 19:203–214. doi:10.1016/S0887-6177(03)00039-8

    Article  PubMed  Google Scholar 

  13. Benedict RHB, Schretien D, Groninger L, Brandt J (1998) Hopkins Verbal Learning Test-Revised: normative data and analysis of inter-form and test-retest reliability. Clin Neuropsychol 12:43–55

    Article  Google Scholar 

  14. Ruff RM, Light RH, Parker SB, Levin HS (1996) Benton Controlled Oral Word Association Test: reliability and updated norms. Arch Clin Neuropsychol 11:329–338

    Article  CAS  PubMed  Google Scholar 

  15. Levine AJ, Miller EN, Becker JT, Selnes OA, Cohen BA (2004) Normative data for determining significance of test-retest differences on eight common neuropsychological instruments. Clin Neuropsychol 18:373–384. doi:10.1080/1385404049052420

    Article  PubMed  Google Scholar 

  16. Armstrong TS, Wefel JS, Wang M, Gilbert MR, Won M, Bottomley A, Mendoza TR, Coens C, Werner-Wasik M, Brachman DG, Choucair AK, Mehta M (2013) Net clinical benefit analysis of radiation therapy oncology group 0525: a phase III trial comparing conventional adjuvant temozolomide with dose-intensive temozolomide in patients with newly diagnosed glioblastoma. J Clin Oncol 31:4076–4084. doi:10.1200/JCO.2013.49.6067

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lin NU, Wefel JS, Lee EQ, Schiff D, van den Bent MJ, Soffietti R, Suh JH, Vogelbaum MA, Mehta MP, Dancey J, Linskey ME, Camidge DR, Aoyama H, Brown PD, Chang SM, Kalkanis SN, Barani IJ, Baumert BG, Gaspar LE, Hodi FS, Macdonald DR, Wen PY, Response Assessment in Neuro-Oncology g (2013) Challenges relating to solid tumour brain metastases in clinical trials, part 2: neurocognitive, neurological, and quality-of-life outcomes. A report from the RANO group. Lancet Oncol 14: e407–416 doi:10.1016/S1470-2045(13)70308-5

    Article  PubMed  Google Scholar 

  18. van den Bent MJ, Wefel JS, Schiff D, Taphoorn MJ, Jaeckle K, Junck L, Armstrong T, Choucair A, Waldman AD, Gorlia T, Chamberlain M, Baumert BG, Vogelbaum MA, Macdonald DR, Reardon DA, Wen PY, Chang SM, Jacobs AH (2011) Response assessment in neuro-oncology (a report of the RANO group): assessment of outcome in trials of diffuse low-grade gliomas. Lancet Oncol 12:583–593. doi:10.1016/S1470-2045(11)70057-2

    Article  PubMed  Google Scholar 

  19. de Groot JF, Piao Y, Tran H, Gilbert M, Wu HK, Liu J, Bekele BN, Cloughesy T, Mehta M, Robins HI, Lassman A, DeAngelis L, Camphausen K, Chen A, Yung WK, Prados M, Wen PY, Heymach JV (2011) Myeloid biomarkers associated with glioblastoma response to anti-VEGF therapy with aflibercept. Clin Cancer Res 17:4872–4881. doi:10.1158/1078-0432.CCR-11-0271

    Article  PubMed  PubMed Central  Google Scholar 

  20. Lassen U, Chinot OL, McBain C, Mau-Sorensen M, Larsen VA, Barrie M, Roth P, Krieter O, Wang K, Habben K, Tessier J, Lahr A, Weller M (2015) Phase 1 dose-escalation study of the antiplacental growth factor monoclonal antibody RO5323441 combined with bevacizumab in patients with recurrent glioblastoma. Neuro-oncology 17:1007–1015. doi:10.1093/neuonc/nov019

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by Grant No. UM1 CA137443 from the Adult Brain Tumor Consortium.

Author information

Author notes

  1. Mark R. Gilbert

    Present address: Neuro-oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

  2. Kenneth D. Aldape

    Present address: Department of Pathology, Toronto General Hospital/Princess Margaret Cancer Center, Toronto, ON, Canada

Authors and Affiliations

  1. Center for Neuro-Oncology, Dana-Farber/Brigham and Women’s Cancer Center, 450 Brookline Avenue, Boston, MA, 02215, USA

    Lakshmi Nayak & Patrick Y. Wen

  2. Department of Neuro-Oncology, M.D. Anderson Cancer Center, Houston, TX, USA

    John de Groot, Jeffrey S. Wefel, Mark R. Gilbert, Kenneth D. Aldape & Alfred W. K. Yung

  3. Neuro-Oncology Program, The Ronald Reagan UCLA Medical Center, University of California, Los Angeles, Los Angeles, CA, USA

    Timothy F. Cloughesy

  4. University of Pittsburgh Medical Center, Pittsburgh, PA, USA

    Frank Lieberman & Jan Drappatz

  5. Division of Neuro-Oncology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA

    Susan M. Chang & Michael Prados

  6. Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Antonio Omuro & Lisa M. DeAngelis

  7. Pappas Center For Neuro-Oncology, Massachusetts General Hospital, Boston, MA, USA

    Tracy T. Batchelor

  8. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA

    Joy Fisher, Xiaobu Ye & Stuart Grossman

  9. Investigational Drug Branch, Cancer Therapeutics Evaluation Program, National Cancer Institute, Bethesda, MD, USA

    Alice Chen

Authors
  1. Lakshmi Nayak
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John de Groot
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jeffrey S. Wefel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Timothy F. Cloughesy
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Frank Lieberman
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Susan M. Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Antonio Omuro
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jan Drappatz
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Tracy T. Batchelor
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Lisa M. DeAngelis
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Mark R. Gilbert
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Kenneth D. Aldape
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Alfred W. K. Yung
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Joy Fisher
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Xiaobu Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Alice Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Stuart Grossman
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Michael Prados
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Patrick Y. Wen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Patrick Y. Wen.

Ethics declarations

Conflict of interest

LN, JdG, FL, JD, MG, KA, JF, XY, AC, MP: None related to the current study. JW: Advisory board for AbbVie, Angiochem, Bayer, Genetech, Juno, Novocure, Roche. TC: Advisory board for Roche/Genentech, Novartis, Pfizer, Novocure, Celldex, Agios, VBL, Tocagen, Notable labs, Upshire Smith, Cytrx, Cortice, Pronia, Medqia, Oxigene, Nektar, Newgen, AbbVie. SC: Research support from Agios, Quest, Roche and Novartis; Advisory Board for Agios, Tocagen, NeOnc, Egde Therapeutics, Blaze. AO: Advisory board for Bristol Meyer Squibb, Oxigene, Stemline. TTB: Advisory board for Merck, Proximagen/Upsher, Roche, Oxigene, Cavion, Foundation Medicine, Accerta, Champions Biotechnology. CME Lectures for Up to Date, Oakstone Medical Publishing, Imedex. Research support from Pfizer. LMD: Advisory board for Sapience, Juno Therapeutics. AWKY: Advisory board for DNAtrix. SG: Research support from Erimos, Advisory board for Midatech, Stock/other in Axxia, Honararia from Roche/Genentech, Medimmune. PW: Research Support from Agios, Angiochem, Astra Zeneca, Exelixis, Genentech/Roche, GlaxoSmith Kline, Karyopharm, Novartis, Sanofi-Aventis, Regeneron Pharmaceuticals Inc., Vascular Biogenics; Advisory Board for AbbVie, Cavion, Celldex, Genentech/Roche, Midatech, Momenta, Novartis, Novocure, SigmaTau, Vascular Biogenics; Speakers Bureau for Merck.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nayak, L., de Groot, J., Wefel, J.S. et al. Phase I trial of aflibercept (VEGF trap) with radiation therapy and concomitant and adjuvant temozolomide in patients with high-grade gliomas. J Neurooncol 132, 181–188 (2017). https://doi.org/10.1007/s11060-016-2357-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-016-2357-9

Keywords

Search

Navigation