Skip to main content
SpringerLink
Log in

Phase II study of bi-weekly temozolomide plus bevacizumab for adult patients with recurrent glioblastoma

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

A Correction to this article was published on 16 October 2017

This article has been updated

Abstract

Purpose

Bevacizumab is an active anti-angiogenic agent in the treatment of recurrent glioblastoma. Temozolomide can prolong survival in patients with newly diagnosed glioblastoma. At recurrence, alternate dosing of temozolomide has shown to further deplete methyl-guanine-methyltransferase (MGMT) conferring added activity for patients who have progressed on the standard dosing regimen. In this study, bevacizumab plus biweekly temozolomide was evaluated for efficacy in adult patients with recurrent glioblastoma.

Methods

Thirty patients with recurrent glioblastoma were treated with bevacizumab on (10 mg/kg i.v.) days 1 and 15 of a 28-day cycle combined with temozolomide (100 mg/m2) on days 1–5 and 15–19 on a 28-day cycle. Responses were assessed at week 4 and then every 8 weeks. MGMT status and quality of life measures were also assessed.

Results

Overall response rate from diagnosis was 51 weeks, the 6-month progression-free survival was 52%, and median time to tumor progression was 5.5 months.

Conclusion

Bevacizumab plus bi-weekly temozolomide was well tolerated and may be a salvage regimen to be considered in a subset of patients with recurrent glioblastoma.

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
Fig. 2

Similar content being viewed by others

Change history

  • 16 October 2017

    A correction to this article has been published.

References

  1. CBTRUS (Central Brain Tumor Registry of the United States) (2015) http://www.cbtrus.org. Accessed 1 April 2015

  2. Johnson DR, O’Neill BP (2012) Glioblastoma survival in the United States before and during the temozolomide era. J Neurooncol 107:359–364

    Article  CAS  PubMed  Google Scholar 

  3. Stupp R, Dietrich PY, Kraljevic SO, Pica A, Maillard I, Maeder P et al (2002) Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide. J Clin Oncol 20:1375–1382

    Article  CAS  PubMed  Google Scholar 

  4. Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE et al (2009) Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 27:4733–4740

    Article  CAS  PubMed  Google Scholar 

  5. Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I 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

    Article  CAS  PubMed  Google Scholar 

  6. Wen PY. Phase II study of prolonged daily temozolomide for low-grade glioma. In Schering-Plough oncology North America Temodar investigator advisory board. 2007. St. Petersburg, FL

  7. Perry JR, Bélanger K, Mason WP, Fulton D, Kavan P, Easaw J et al (2010) Phase II trial of continuous dose-intense temozolomide in recurrent malignant glioma: RESCUE Study. J Clin Oncol 28:2051–2057

    Article  CAS  PubMed  Google Scholar 

  8. Gilbert MR, Wang M, Aldape KD, Stupp R, Hegi ME, Jaeckle KA et al (2013) Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol 31:4085–4091

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Verhoeff JJC, Lavini C, van Linde ME, Stalpers LJA, Majoie CBLM, Reijneveld JC et al (2010) Bevacizumab and dose-intense temozolomide in recurrent high-grade glioma. Ann Oncol 21:1723–1727

    Article  CAS  PubMed  Google Scholar 

  10. Desjardins A, Reardon DA, Coan A, Marcello J, Herndon JE, Bailey L et al (2012) Bevacizumab and daily temozolomide for recurrent glioblastoma. Cancer 118:1302–1312

    Article  CAS  PubMed  Google Scholar 

  11. Onco Methylome Sciences, Durham, NC

  12. Castle Biosciences, Friendswood, TX

  13. Vlassenbroeck I, Califice S, Diserens AC, Migliavacca E, Straub J, di Stefano I et al (2008) Validation of real-time methylation-specific PCR to determine O6-methylguanine-DNA methyltransferase gene promoter methylation in glioma. J Med Diagn 10:332–337

    CAS  Google Scholar 

  14. Colman H, Zhang L, Sulman EP, McDonald JM, Shooshtari NL, Rivera A et al (2010) A multigene predictor of outcome in glioblastoma. Neuro Oncol 12(1):49–57

    Article  CAS  PubMed  Google Scholar 

  15. Vredenburgh JJ, Desjardins A, Herndon JE 2nd, 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(30):4722–4729

    Article  CAS  PubMed  Google Scholar 

  16. Stupp R, Hegi ME, Mason WP, Vandenbent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff RO, European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups, National Cancer Institute of Canada Clinical Trials Group (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(5):459–466

    Article  CAS  PubMed  Google Scholar 

  17. Tolcher AW, Gerson SL, Denis L, Geyer C, Hammond LA, Patnaik A et al (2003) Marked inactivation of O6-alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedules. Br J Cancer 88:1004–1011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kesari S, Schiff D, Drappatz J, LaFrankie D, Doherty L, Macklin EA et al (2009) Phase II study of protracted daily temozolomide for low-grade gliomas in adults. Clin Cancer Res 15:330–337

    Article  CAS  PubMed  Google Scholar 

  19. Balmaceda C, Peereboom D, Pannullo S, Cheung YKK, Fisher PG, Alavi J et al (2008) Multi-institutional phase II study of temozolomide administered twice daily in the treatment of recurrent high-grade gliomas. Cancer 112:1139–1146

    Article  CAS  PubMed  Google Scholar 

  20. Brandes AA, Tosoni A, Cavallo G, Bertorelle R, Gioia V, Franceschi E et al (2006) Temozolomide 3 weeks on and 1 week off as first-line therapy for recurrent glioblastoma: phase II study from gruppo italiano cooperativo di neuro-oncologia (GICNO). Br J Cancer 95:1155–1160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Jauch T, Hau P, Bogdahn U (2007) Re-challenge with temozolomide (TMZ) at recurrence in high-grade gliomas (HGG) [abstract 2034]. J Clin Oncol 25(suppl):83s

    Google Scholar 

  22. Wick A, Felsberg J, Steinbach JP, Herrlinger U, Platten M, Blaschke B et al (2007) Efficacy and tolerability of temozolomide in an alternating weekly regimen in patients with recurrent glioma. J Clin Oncol 25:3357–3361

    Article  CAS  PubMed  Google Scholar 

  23. Wick W, Steinbach JP, Küker WM, Dichgans J, Bamberg M, Weller M (2004) One week on/one week off: a novel active regimen of temozolomide for recurrent glioblastoma. Neurology 62:2113–2115

    Article  CAS  PubMed  Google Scholar 

  24. 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. doi:10.1158/1078-0432.CCR-13-0708 (Epub 2013 Jul)

    Article  CAS  PubMed  Google Scholar 

  25. Sathornsumetee S, Desjardins A, Vredenburgh JJ, McLendon RE, Marcello J, Herndon JE, Mathe A, Hamilton M, Rich JN, Norfleet JA, Gururangan S, Friedman HS, Reardon DA (2010) Phase II trial of bevacizumab and erlotinib in patients with recurrent malignant glioma. Neuro Oncol 12(12):1300–1310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Soffietti R, Trevisan E, Bertero L, Cassoni P, Morra I, Fabrini MG, Pasqualetti F, Lolli I, Castiglione A, Ciccone G, Rudà R (2014) Bevacizumab and fotemustine for recurrent glioblastoma: a phase II study of AINO (Italian Association of Neuro-Oncology). J Neurooncol 116(3):533–541

    Article  CAS  PubMed  Google Scholar 

  27. Reardon DA, Desjardin 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 naïve, recurrent glioblastoma. J Neuro Oncol 107(1):155–164

    Article  CAS  Google Scholar 

  28. Lassen U, Sorensen M, Gaziel TB, Hasselbalch B, Poulsen HS (2013) Phase II study of bevacizumab and temsirolimus combination therapy for recurrent glioblastoma multiforme. Anticancer Res 33(4):1657–1660

    CAS  PubMed  Google Scholar 

  29. Reardon DA, Desjardins A, Vredenburgh JJ, Gururangan S, Sampson JH, Sathornsumetee S, McLendon RE, Herndon JE 2nd, Marcello JE, Norfleet J, Friedman AH, Bigner DD, Friedman HS (2009) Metronomic chemotherapy with daily, oral etoposide plus bevacizumab for recurrent malignant glioma: a phase II study. Br J Cancer 101(12):1986–1994

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Reardon DA, Desjardins A, Peters KB, Vredenburgh JJ, Gururangan S, Sampson JH, McLendon RE, Herndon JE, Coan A, Threatt S, Friedman AH, Friedman HS (2011) Phase II study of carboplatin, irinotecan and bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy. Cancer 117(23):5351–5358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Iwamoto FM et al (2009) Pattterns of relapse and prognosis after bevacizumab failure in recurrent gliobmastoma. Neurology 73:1200–1206

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Norden AD et al (2008) Bevacizumab for recurrent malignant gliomas: efficacy, toxicity and patters of recurrence. Neurology 70:779–787

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors wish to thank patients and their caregivers for participating in this study. Support for the study was provided by Genentech, Inc.

Author information

Authors and Affiliations

  1. Center for Neurosciences, 2450 E River Rd, Tucson, AZ, 85718, USA

    Michael A. Badruddoja, Marjorie Pazzi, Abhay Sanan, Kurt Schroeder, Thomas Norton, Thomas Scully & Michael Malek Ahmadi

  2. Department of Radiation Oncology, Banner University Medical Center, 1501 N. Campbell Avenue, Tucson, AZ, 85724, USA

    Michael A. Badruddoja

  3. Genentech, Inc., DNA Way, South San Francisco, CA, 94080, USA

    Kevin Kuzma & Michael Malek Ahmadi

  4. Northwest Neurospecialists, 5860 N. La Cholla Blvd. Suite 100, Tucson, AZ, 85741, USA

    Thomas Scully

  5. University of Arizona Cancer Center, 1515 N. Campbell Avenue, Tucson, AZ, 85724, USA

    Daruka Mahadevan

Authors
  1. Michael A. Badruddoja
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marjorie Pazzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Abhay Sanan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kurt Schroeder
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kevin Kuzma
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Thomas Norton
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Thomas Scully
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Daruka Mahadevan
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Michael Malek Ahmadi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Michael A. Badruddoja or Daruka Mahadevan.

Ethics declarations

This study was funded by Genentech. MP, AS, KS, TN, TS, DM and MMA have no potential conflict of interest. Informed consent was obtained prior to patient enrollment and was approved by an Institutional Review Board (PROTOCOL #: AVF4514s). All procedures performed in this study were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration.

Conflict of interest

M.A. Badruddoja, MD, has received research support from Genentech, Lilly, Stem-line, Kadmon, Nativis, NanoHelix LLC. BeiGene USA Inc., Boston Bio Inc. and Biogen. No other conflicts of interest are reported by any other authors sited.

Additional information

A correction to this article is available online at https://doi.org/10.1007/s00280-017-3448-9.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Badruddoja, M.A., Pazzi, M., Sanan, A. et al. Phase II study of bi-weekly temozolomide plus bevacizumab for adult patients with recurrent glioblastoma. Cancer Chemother Pharmacol 80, 715–721 (2017). https://doi.org/10.1007/s00280-017-3405-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-017-3405-7

Keywords

Search

Navigation