Skip to main content

Advertisement

SpringerLink
Log in

Phase I study of sorafenib and tipifarnib for recurrent glioblastoma: NABTC 05-02

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

Abstract

Recurrent glioblastoma (GBM) has a very low 6-month progression free survival (PFS) with currently available treatments. Combination chemotherapy to target multiple cell signaling pathways is currently being investigated in order to improve prognosis for recurrent disease. The purpose of this phase I study was to determine the maximum tolerated dose (MTD) for the combination of tipifarnib and sorafenib for the treatment of recurrent GBM. Patients with pathologically proven WHO grade IV GBM and radiographically proven tumor recurrence were eligible for this study. Treatments included sorafenib at twice daily and escalating dosages of tipifarnib. Dose-limiting toxicity (DLT) was determined over the first 28-days of treatments, and the MTD was determined in a 3 + 3 study design. We enrolled 24 patients, and 21 patients completed the MTD period. The study was stopped early with no MTD determination for excessive toxicities. The last dose level reached was sorafenib at 200 mg twice a day and tipifarnib 100 mg twice a day on an alternating week schedule. The DLTs included diarrhea, lipase elevation, hypophosphatemia, and arthralgia. The combination of sorafenib and tipifarnib has excessive toxicities and full single agent dosages could not be achieved in combination.

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. American Cancer Society (2010) Cancer Facts and Figs. 2010. American Cancer Society, Atlanta

    Google Scholar 

  2. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJB, 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, The European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups and the National Cancer Institute of Canada Clinical Trials Group (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352 (10):987–996. doi:10.1056/NEJMoa043330

    Article  CAS  PubMed  Google Scholar 

  3. Wong E, Hess K, Gleason M, Jaeckle K, AP K, MD P, VA L, WK Y (1999) Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol 17(8):2572

    Article  CAS  PubMed  Google Scholar 

  4. Lamborn KR, Yung WKA, Chang SM, Wen PY, Cloughesy TF, DeAngelis LM, Robins HI, Lieberman FS, Fine HA, Fink KL, Junck L, Abrey L, Gilbert MR, Mehta M, Kuhn JG, Aldape KD, Hibberts J, Peterson PM, Prados MD, North American Brain Tumor Consortium Study (2008) Progression-free survival: an important end point in evaluating therapy for recurrent high-grade gliomas. Neuro Oncol 10 (2):162–170. doi:10.1215/15228517-2007-062

    Article  PubMed  PubMed Central  Google Scholar 

  5. Friedman HS, Prados M, 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

    Article  CAS  PubMed  Google Scholar 

  6. Kreisl TN, Zhang W, Odia Y, Shih JH, Butman JA, Hammoud D, Iwamoto FM, Sul J, Fine HA (2011) A phase II trial of single-agent bevacizumab in patients with recurrent anaplastic glioma. Neuro Oncol 13(10):1143–1150. doi:10.1093/neuonc/nor091

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Maher EA, Furnari FB, Bachoo RM, Rowitch DH, Louis DN, Cavenee WK, DePinho RA (2001) Malignant glioma: genetics and biology of a grave matter. Genes Dev 15(11):1311–1333

    Article  CAS  PubMed  Google Scholar 

  8. Feldkamp MM, Lala P, Lau N, Roncari L, Guha A (1999) Expression of activated epidermal growth factor receptors, Ras-guanosine triphosphate, and mitogen-activated protein kinase in human glioblastoma multiforme specimens. Neurosurgery 45(6):1442–1453

    Article  CAS  PubMed  Google Scholar 

  9. Dancey J, Sausville EA (2003) Issues and progress with protein kinase inhibitors for cancer treatment. Nat Rev Drug Discov 2(4):296–313. doi:10.1038/nrd1066

    Article  CAS  PubMed  Google Scholar 

  10. Guha A (1998) Ras activation in astrocytomas and neurofibromas. Can J Neurol Sci 25(4):267–281

    Article  CAS  PubMed  Google Scholar 

  11. Delmas C, Heliez C, Cohen-Jonathan E, End D, Bonnet J, Favre G, Toulas C (2002) Farnesyltransferase inhibitor, R115777, reverses the resistance of human glioma cell lines to ionizing radiation. Int J Cancer 100(1):43–48. doi:10.1002/ijc.10439

    Article  CAS  PubMed  Google Scholar 

  12. End DW, Smets G, Todd AV, Applegate TL, Fuery CJ, Angibaud P, Venet M, Sanz G, Poignet H, Skrzat S, Devine A, Wouters W, Bowden C (2001) Characterization of the antitumor effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro. Cancer Res 61(1):131–137

    CAS  PubMed  Google Scholar 

  13. Feldkamp MM, Lau N, Roncari L, Guha A (2001) Isotype-specific Ras. GTP-levels predict the efficacy of farnesyl transferase inhibitors against human astrocytomas regardless of Ras mutational status. Cancer Res 61(11):4425–4431

    CAS  PubMed  Google Scholar 

  14. Delmas C, End D, Rochaix P, Favre G, Toulas C, Cohen-Jonathan E (2003) The farnesyltransferase inhibitor R115777 reduces hypoxia and matrix metalloproteinase 2 expression in human glioma xenograft. Clin Cancer Res 9(16 Pt 1):6062–6068

    CAS  PubMed  Google Scholar 

  15. Wick W, Weller M, Weiler M, Batchelor T, Yung AW, Platten M (2011) Pathway inhibition: emerging molecular targets for treating glioblastoma. Neuro Oncol 13(6):566–579. doi:10.1093/neuonc/nor039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gilbert MR (2011) Recurrent glioblastoma: a fresh look at current therapies and emerging novel approaches. Semin Oncol 38(Suppl 4):S21–S33. doi:10.1053/j.seminoncol.2011.09.008

    Article  PubMed  Google Scholar 

  17. Hudes G, Schol J, Baab J (1999) Phase I clinical and pharmacokinetic trial of the farnesyltransferase inhibitor R115777 in a 21-day dosing schedule. Paper presented at the proceedings of the annual meeting of the Amercian Society of Clinical Oncology, May 1999

  18. Zujewski J, Horak ID, Bol CJ, Woestenborghs R, Bowden C, End DW, Piotrovsky VK, Chiao J, Belly RT, Todd A, Kopp WC, Kohler DR, Chow C, Noone M, Hakim FT, Larkin G, Gress RE, Nussenblatt RB, Kremer AB, Cowan KH (2000) Phase I and pharmacokinetic study of farnesyl protein transferase inhibitor R115777 in advanced cancer. J Clin Oncol 18(4):927–941

    Article  CAS  PubMed  Google Scholar 

  19. Cloughesy TF, Kuhn J, Robins HI, Abrey L, Wen P, Fink K, Lieberman FS, Mehta M, Chang S, Yung A, DeAngelis L, Schiff D, Junck L, Groves M, Paquette S, Wright J, Lamborn K, Sebti SM, Prados M (2005) Phase I trial of tipifarnib in patients with recurrent malignant glioma taking enzyme-inducing antiepileptic drugs: a North American Brain Tumor Consortium Study. J Clin Oncol 23(27):6647–6656. doi:10.1200/JCO.2005.10.068

    Article  CAS  PubMed  Google Scholar 

  20. Cloughesy TF, Wen PY, Robins HI, Chang SM, Groves MD, Fink KL, Junck L, Schiff D, Abrey L, Gilbert MR, Lieberman F, Kuhn J, DeAngelis LM, Mehta M, Raizer JJ, Yung WK, Aldape K, Wright J, Lamborn KR, Prados MD (2006) Phase II trial of tipifarnib in patients with recurrent malignant glioma either receiving or not receiving enzyme-inducing antiepileptic drugs: a North American Brain Tumor Consortium Study. J Clin Oncol 24(22):3651–3656. doi:10.1200/JCO.2006.06.2323

    Article  CAS  PubMed  Google Scholar 

  21. Kuhn J, Prados M, Robins H (2000) Phase I trial of R115777 (Zarnestra) in patients with recurrent malignant glioma taking enzyme inducting antiepileptic drugs (EIAED): a North American Brain Tumor Consortium (NABTC) report. In: Proceedings of the American Society of Clinical Oncology, pp 86a, Abstract no. 342

  22. Wilhelm S, Chien DS (2002) BAY 43-9006: preclinical data. Curr Pharm Des 8(25):2255–2257

    Article  CAS  PubMed  Google Scholar 

  23. Dy GK, Adjei AA (2002) Novel targets for lung cancer therapy: part II. J Clin Oncol 20(13):3016–3028. doi:10.1200/JCO.2002.02.112

    Article  CAS  PubMed  Google Scholar 

  24. Dy GK, Adjei AA (2002) Novel targets for lung cancer therapy: part I. J Clin Oncol 20(12):2881–2894. doi:10.1200/JCO.2002.11.145

    Article  CAS  PubMed  Google Scholar 

  25. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, Cao Y, Shujath J, Gawlak S, Eveleigh D, Rowley B, Liu L, Adnane L, Lynch M, Auclair D, Taylor I, Gedrich R, Voznesensky A, Riedl B, Post LE, Bollag G, Trail PA (2004) BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64(19):7099–7109. doi:10.1158/0008-5472.CAN-04-1443

    Article  CAS  PubMed  Google Scholar 

  26. Heim M, Scharifi M, Zisowsky J, Jaehde U, Voliotis D, Seeber S, Strumberg D (2005) The Raf kinase inhibitor BAY 43-9006 reduces cellular uptake of platinum compounds and cytotoxicity in human colorectal carcinoma cell lines. Anticancer Drugs 16(2):129–136

    Article  CAS  PubMed  Google Scholar 

  27. Lee EQ, Kuhn J, Lamborn KR, Abrey L, DeAngelis LM, Lieberman F, Robins HI, Chang SM, Yung WK, Drappatz J, Mehta MP, Levin VA, Aldape K, Dancey JE, Wright JJ, Prados MD, Cloughesy TF, Gilbert MR, Wen PY (2012) Phase I/II study of sorafenib in combination with temsirolimus for recurrent glioblastoma or gliosarcoma: North American Brain Tumor Consortium study 05-02. Neuro Oncol 14(12):1511–1518. doi:10.1093/neuonc/nos264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Prados M, Gilbert M, Kuhn J, Lamborn K, Cloughesy T, Lieberman F, Puduvalli V, Robins HI, Lassman A, Wen PY (2009) Phase I/II study of sorefenib and erlotinib for patients with recurrent glioblastoma (GBM) (NABTC 05-02). J Clin Oncol 27:15 (suppl; abstr 2005)

    Article  Google Scholar 

  29. Kirschbaum M, Synold T, Stein AS, Tuscano J, Zain JM, Popplewell L, Karanes C, O’Donnell MR, Pulone B, Rincon A, Wright J, Frankel P, Forman SJ, Newman EM (2011) A phase 1 trial dose escalation study of tipifarnib on a week-on, week-off schedule in relapsed, refractory or high-risk myeloid leukemia. Leukemia 25(10):1543–1547. doi:10.1038/leu.2011.124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wen PY, Chang SM, Van den Bent MJ, Vogelbaum MA, Macdonald DR, Lee EQ (2017) Response assessment in neuro-oncology clinical trials. J Clin Oncol 35(21):2439–2449. doi:10.1200/JCO.2017.72.7511

    Article  PubMed  Google Scholar 

  31. Strumberg D, Richly H, Hilger RA, Schleucher N, Korfee S, Tewes M, Faghih M, Brendel E, Voliotis D, Haase CG, Schwartz B, Awada A, Voigtmann R, Scheulen ME, Seeber S (2005) Phase I clinical and pharmacokinetic study of the Novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors. J Clin Oncol 23(5):965–972. doi:10.1200/JCO.2005.06.124

    Article  CAS  PubMed  Google Scholar 

  32. 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(5848):287–290. doi:10.1126/science.1142946

    Article  CAS  PubMed  Google Scholar 

  33. Reardon DA, Cloughesy T, Rich J, Alfred Yung WK, Yung L, DiLea C, Huang J, Dugan M, Mietlowski W, Maes A, Conrad C (2012) Pharmacokinetic drug interaction between AEE788 and RAD001 causing thrombocytopenia in patients with glioblastoma. Cancer Chemother Pharmacol 69(1):281–287. doi:10.1007/s00280-011-1754-1

    Article  CAS  PubMed  Google Scholar 

  34. 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

    Article  CAS  PubMed  Google Scholar 

  35. Peereboom DM, Ahluwalia MS, Ye X, Supko JG, Hilderbrand SL, Phuphanich S, Nabors LB, Rosenfeld MR, Mikkelsen T, Grossman SA, New Approaches to Brain Tumor Therapy Consortium (2013) NABTT 05-02: a phase II and pharmacokinetic study of erlotinib and sorafenib for patients with progressive or recurrent glioblastoma multiforme. Neuro Oncol 15 (4):490–496. doi:10.1093/neuonc/nos322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Clarke JL, Pao W, Wu N, Miller VA, Lassman AB (2010) High dose weekly erlotinib achieves therapeutic concentrations in CSF and is effective in leptomeningeal metastases from epidermal growth factor receptor mutant lung cancer. J Neurooncol 99(2):283–286. doi:10.1007/s11060-010-0128-6

    Article  PubMed  PubMed Central  Google Scholar 

  37. Vivanco I, Robins HI, Rohle D, Campos C, Grommes C, Nghiemphu PL, Kubek S, Oldrini B, Chheda MG, Yannuzzi N, Tao H, Zhu S, Iwanami A, Kuga D, Dang J, Pedraza A, Brennan CW, Heguy A, Liau LM, Lieberman F, Yung WKA, Gilbert MR, Reardon DA, Drappatz J, Wen PY, Lamborn KR, Chang SM, Prados MD, Fine HA, Horvath S, Wu N, Lassman AB, DeAngelis LM, Yong WH, Kuhn JG, Mischel PS, Mehta MP, Cloughesy TF, Mellinghoff IK (2012) Differential sensitivity of glioma-versus lung cancer–specific EGFR mutations to EGFR kinase inhibitors. Cancer Discov. doi:10.1158/2159-8290.cd-11-0284

    PubMed  PubMed Central  Google Scholar 

  38. EGFR Inhibition Using High Dose Administration of Erlotinib Weekly for Recurrent malignant Gliomas with EGFR Variant III Mutation (2011) ClinicalTrials.gov. http://clinicaltrials.gov/ct2/show/NCT01257594?term=erlotinib+AND+new+York+AND+glioblastoma&rank=5. Accessed Feb 2012

  39. Yu A, Faiq N, Green S, Lai A, Green R, Hu J, Cloughesy TF, Mellinghoff I, Nghiemphu PL (2017) Report of safety of pulse dosing of lapatinib with temozolomide and radiation therapy for newly-diagnosed glioblastoma in a pilot phase II study. J Neurooncol. doi:10.1007/s11060-017-2533-6

    PubMed Central  Google Scholar 

Download references

Funding

This study was sponsored by NIH Grant U01 CA-062412. Tipifarnib and sorafenib were provided by the National Cancer Institute, NIH.

Author information

Author notes

  1. Victoria Asuquo Ebiana

    Present address: Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

Authors and Affiliations

  1. Department of Neurology, University of California, Los Angeles, 710 Westwood Plaza, Reed 1-230, Los Angeles, CA, 90230, USA

    Phioanh Leia Nghiemphu, Victoria Asuquo Ebiana & Timothy F. Cloughesy

  2. Dana Farber Cancer Institute, Boston, MA, USA

    Patrick Wen

  3. Neuro-Oncology Branch National Cancer Institute, Bethesda, MD, USA

    Mark Gilbert & J. J. Wright

  4. Department of Neurosurgery, University of California San Francisco, San Francisco, CA, USA

    Susan Chang & Michael Prados

  5. Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Lauren E. Abrey & Lisa M. DeAngelis

  6. University of Wisconsin, Madison, WI, USA

    H. Ian Robins

  7. Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    W. K. Alfred Yung & Victor A. Levin

  8. University of Pittsburgh, Pittsburgh, PA, USA

    F. Lieberman & Jan Drappatz

  9. University Health Ontario, Toronto, ON, Canada

    Kenneth Aldape

  10. National Cancer Institute Cancer Therapy Evaluation Program, Investigational Branch, Toronto, ON, Canada

    Janet E. Dancey

  11. Baptist Health South Florida, Coral Gables, FL, USA

    Minesh P. Mehta

  12. The University of Texas College of Pharmacy, Austin, TX, USA

    John Kuhn

Authors
  1. Phioanh Leia Nghiemphu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Victoria Asuquo Ebiana
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Patrick Wen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mark Gilbert
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lauren E. Abrey
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. F. Lieberman
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lisa M. DeAngelis
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. H. Ian Robins
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. W. K. Alfred Yung
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Susan Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jan Drappatz
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Minesh P. Mehta
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Victor A. Levin
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Kenneth Aldape
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Janet E. Dancey
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. J. J. Wright
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Michael Prados
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. John Kuhn
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Timothy F. Cloughesy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Phioanh Leia Nghiemphu.

Ethics declarations

Conflict of interest

Dr. Chang is a consultant to Edge and Blaze and serves as research support to Route and Novartis. Dr. Dancey receives funding from AstraZeneca, Pfizer, and Merck for her institution. Dr. Wen provides research support to Agios, Angiochem, AstraZeneca, Genentech, Roche, Glaxosmith Kline, Immunocellular Therapeutics, Karyopharm, Merck, Novartis, Oncoceotics, Sanofi-Aventis. Dr. Wen serves on the advisory board for AstraZeneca, Cavion, Genentech/Roche, Insys, Monteris, Novogen, Novartis, Regeneron Vascular Biogenics, VBI Vaccines. Dr. Wen is a speaker for Merck and serves on the Data Monitoring Safety Board for Tocagen and Monteris. Dr. DeAngelis serves on the scientific advisory boards of Sapience, Roche, and Tocagen.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 17 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nghiemphu, P.L., Ebiana, V.A., Wen, P. et al. Phase I study of sorafenib and tipifarnib for recurrent glioblastoma: NABTC 05-02. J Neurooncol 136, 79–86 (2018). https://doi.org/10.1007/s11060-017-2624-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-017-2624-4

Keywords

Search

Navigation