Journal of Neuro-Oncology

, Volume 100, Issue 1, pp 95–103 | Cite as

Phase 1 clinical trial of bortezomib in adults with recurrent malignant glioma

  • Surasak Phuphanich
  • Jeffrey G. Supko
  • Kathryn A. Carson
  • Stuart A. Grossman
  • L. Burt Nabors
  • Tom Mikkelsen
  • Glenn Lesser
  • Steve Rosenfeld
  • Serena Desideri
  • Jeffrey J. Olson
Clinical Study - Patient Study


Bortezomib selectively binds and inhibits the 20S proteasome enzyme’s active sites. This study was conducted to determine the side effects and maximum tolerated dose (MTD) of bortezomib in patients with recurrent malignant glioma. Separate dose escalations were conducted in patients taking or not taking enzyme-inducing anti-seizure drugs (+/−EIASD). The starting dose in both groups was 0.9 mg/m2 intravenously twice weekly for the first three of each 4 week cycle. Imaging assessment of response was carried out and Plasma 20S proteasome activity inhibition and imaging was conducted to monitor efficacy. The 66 patients enrolled had a median age of 51 years, median KPS of 90%, and 77% had glioblastoma multiforme. The MTD in the −EIASD group was 1.70 mg/m2 based on grade 3 thrombocytopenia, sensory neuropathy and fatigue. In the +EIASD group escalation was terminated at 2.5 mg/m2 without meeting meet the MTD criteria. However, proteasome inhibition in this group did not change at doses above 1.90 mg/m2 suggesting that further escalations would be unlikely to increase a biologic effect. Mean proteasome inhibition plateaued in +EIASD patients receiving 2.1 mg/m2 of bortezomib at 77 ± 12% and in −EIASD patients treated with a dose of 1.7 mg/m2 at 79 ± 6%. Two partial responses were observed. This study determined that EIASDs effect the MTD of bortezomib and the dose required for maximal inhibition of whole blood 20S proteasome. Some evidence of clinical activity was noted in this phase I study in patients with recurrent high grade gliomas.


Bortezomib Proteasome inhibitors Cancer Clinical trials Malignant gliomas Pharmacodynamics 


  1. 1.
    Adams J, Palombella VJ, Elliott PJ (2000) Proteasome inhibition: a new strategy in cancer treatment. Invest New Drugs 18:109–121CrossRefPubMedGoogle Scholar
  2. 2.
    King RW, Deshaies RJ, Peters JM, Kirschner MW (1996) How proteolysis drives the cell cycle. Science 274:1652–1659CrossRefPubMedGoogle Scholar
  3. 3.
    Sherr CJ (1996) Cancer cell cycles. Science 274:1672–1677CrossRefPubMedGoogle Scholar
  4. 4.
    Read MA, Neish AS, Luscinskas FW, Palombella VJ, Maniatis T, Collins T (1995) The proteasome pathway is required for cytokine-induced endothelial-leukocyte adhesion molecule expression. Immunity 2:493–506CrossRefPubMedGoogle Scholar
  5. 5.
    Tariman JD (2007) Current therapies for multiple myeloma. J Infus Nurs 30:113–118 quiz 121CrossRefPubMedGoogle Scholar
  6. 6.
    Sunwoo JB, Chen Z, Dong G et al (2001) Novel proteasome inhibitor PS-341 inhibits activation of nuclear factor-kappa B, cell survival, tumor growth, and angiogenesis in squamous cell carcinoma. Clin Cancer Res 7:1419–1428PubMedGoogle Scholar
  7. 7.
    Lun M, Zhang PL, Pellitteri PK, Law A, Kennedy TL, Brown RE (2005) Nuclear factor-kappaB pathway as a therapeutic target in head and neck squamous cell carcinoma: Pharmaceutical and molecular validation in human cell lines using velcade and siRNA/NF-kappaB. Ann Clin Lab Sci 35:251–258PubMedGoogle Scholar
  8. 8.
    Allen C, Saigal K, Nottingham L, Arun P, Chen Z, Van Waes C (2008) Bortezomib-induced apoptosis with limited clinical response is accompanied by inhibition of canonical but not alternative nuclear factor-{kappa}B subunits in head and neck cancer. Clin Cancer Res 14:4175–4185CrossRefPubMedGoogle Scholar
  9. 9.
    Frankel A, Man S, Elliott P, Adams J, Kerbel RS (2000) Lack of multicellular drug resistance observed in human ovarian and prostate carcinoma treated with the proteasome inhibitor PS-341. Clin Cancer Res 6:3719–3728PubMedGoogle Scholar
  10. 10.
    Bold RJ, Virudachalam S, McConkey DJ (2001) Chemosensitization of pancreatic cancer by inhibition of the 26S proteasome. J Surg Res 100:11–17CrossRefPubMedGoogle Scholar
  11. 11.
    Hideshima T, Richardson P, Chauhan D et al (2001) The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res 61:3071–3076PubMedGoogle Scholar
  12. 12.
    LeBlanc R, Catley LP, Hideshima T et al (2002) Proteasome inhibitor PS-341 inhibits human myeloma cell growth in vivo and prolongs survival in a murine model. Cancer Res 62:4996–5000PubMedGoogle Scholar
  13. 13.
    Mitsiades N, Mitsiades CS, Richardson PG et al (2003) The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications. Blood 101:2377–2380CrossRefPubMedGoogle Scholar
  14. 14.
    Schenkein D (2002) Proteasome inhibitors in the treatment of B-cell malignancies. Clin Lymphoma 3:49–55CrossRefPubMedGoogle Scholar
  15. 15.
    Orlowski RZ, Eswara JR, Lafond-Walker A, Grever MR, Orlowski M, Dang CV (1998) Tumor growth inhibition induced in a murine model of human burkitt’s lymphoma by a proteasome inhibitor. Cancer Res 58:4342–4348PubMedGoogle Scholar
  16. 16.
    Giles F (2002) New drugs in acute myeloid leukemia. Curr Oncol Rep 4:369–374CrossRefPubMedGoogle Scholar
  17. 17.
    Yu C, Rahmani M, Conrad D, Subler M, Dent P, Grant S (2003) The proteasome inhibitor bortezomib interacts synergistically with histone deacetylase inhibitors to induce apoptosis in Bcr/Abl+ cells sensitive and resistant to STI571. Blood 102:3765–3774CrossRefPubMedGoogle Scholar
  18. 18.
    Sayers TJ, Brooks AD, Koh CY et al (2003) The proteasome inhibitor PS-341 sensitizes neoplastic cells to TRAIL-mediated apoptosis by reducing levels of c-FLIP. Blood 102:303–310CrossRefPubMedGoogle Scholar
  19. 19.
    Tan C, Waldmann TA (2002) Proteasome inhibitor PS-341, a potential therapeutic agent for adult T-cell leukemia. Cancer Res 62:1083–1086PubMedGoogle Scholar
  20. 20.
    Richardson PG, Barlogie B, Berenson J et al (2003) A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348:2609–2617CrossRefPubMedGoogle Scholar
  21. 21.
    Richardson PG, Barlogie B, Berenson J et al (2005) Clinical factors predictive of outcome with bortezomib in patients with relapsed, refractory multiple myeloma. Blood 106:2977–2981CrossRefPubMedGoogle Scholar
  22. 22.
    Jagannath S, Barlogie B, Berenson J et al (2004) A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol 127:165–172CrossRefPubMedGoogle Scholar
  23. 23.
    Richardson PG, Sonneveld P, Schuster MW et al (2007) Safety and efficacy of bortezomib in high-risk and elderly patients with relapsed multiple myeloma. Br J Haematol 137:429–435CrossRefPubMedGoogle Scholar
  24. 24.
    Anderson K, Richardson P, Chanan-Khan A (2006) Single-agent bortezomib in previously untreated multiple myeloma (MM): results of a phase II multicenter study. J Clin Oncol 24(18S):7504Google Scholar
  25. 25.
    Raab MS, Breitkreutz I, Anderson KC (2007) Targeted treatments to improve stem cell outcome: Old and new drugs. Bone Marrow Transplant 40:1129–1137CrossRefPubMedGoogle Scholar
  26. 26.
    Strzelczyk J, Safadi R (2004) Radiation safety considerations in GliaSite 125I brain implant procedures. Health Phys 86:S120–S123CrossRefPubMedGoogle Scholar
  27. 27.
    Koschny R, Holland H, Sykora J et al (2007) Bortezomib sensitizes primary human astrocytoma cells of WHO grades I to IV for tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. Clin Cancer Res 13:3403–3412CrossRefPubMedGoogle Scholar
  28. 28.
    Olson JJ, Bowers G, Zhang Z (2004) Protease inhibitors in a brain tumor model. In: Adams J (ed) Cancer drug discovery and development: proteasome inhibitors in cancer therapy. Humana Press Inc, TotowaGoogle Scholar
  29. 29.
    Zunkeler B, Carson RE, Olson J et al (1996) Quantification and pharmacokinetics of blood-brain barrier disruption in humans. J Neurosurg 85:1056–1065CrossRefPubMedGoogle Scholar
  30. 30.
    Glantz MJ, Cole BF, Forsyth PA et al (2000) Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumors. Report of the quality standards subcommittee of the American academy of neurology. Neurology 54:1886–1893PubMedGoogle Scholar
  31. 31.
    Vecht CJ, Wagner GL, Wilms EB (2003) Interactions between antiepileptic and chemotherapeutic drugs. Lancet Neurol 2:404–409CrossRefPubMedGoogle Scholar
  32. 32.
    Pekol T, Daniels JS, Labutti J et al (2005) Human metabolism of the proteasome inhibitor bortezomib: identification of circulating metabolites. Drug Metab Dispos 33:771–777CrossRefPubMedGoogle Scholar
  33. 33.
    Watling CJ, Lee DH, Macdonald DR, Cairncross JG (1994) Corticosteroid-induced magnetic resonance imaging changes in patients with recurrent malignant glioma. J Clin Oncol 12:1886–1889PubMedGoogle Scholar
  34. 34.
    Gilbert MR, Supko JG, Batchelor T et al (2003) Phase I clinical and pharmacokinetic study of irinotecan in adults with recurrent malignant glioma. Clin Cancer Res 9:2940–2949PubMedGoogle Scholar
  35. 35.
    Lightcap ES, McCormack TA, Pien CS, Chau V, Adams J, Elliott PJ (2000) Proteasome inhibition measurements: clinical application. Clin Chem 46:673–683PubMedGoogle Scholar
  36. 36.
    Aghajanian C, Soignet S, Dizon DS et al (2002) A phase I trial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies. Clin Cancer Res 8:2505–2511PubMedGoogle Scholar
  37. 37.
    Orlowski RZ, Stinchcombe TE, Mitchell BS et al (2002) Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol 20:4420–4427CrossRefPubMedGoogle Scholar
  38. 38.
    Papandreou CN, Daliani DD, Nix D et al (2004) Phase I trial of the proteasome inhibitor bortezomib in patients with advanced solid tumors with observations in androgen-independent prostate cancer. J Clin Oncol 22:2108–2121CrossRefPubMedGoogle Scholar
  39. 39.
    Cortes J, Thomas D, Koller C et al (2004) Phase I study of bortezomib in refractory or relapsed acute leukemias. Clin Cancer Res 10:3371–3376CrossRefPubMedGoogle Scholar
  40. 40.
    Richardson PG, Sonneveld P, Schuster M et al (2007) Extended follow-up of a phase 3 trial in relapsed multiple myeloma: Final time-to-event results of the APEX trial. Blood 110:3557–3560CrossRefPubMedGoogle Scholar
  41. 41.
    Fetell MR, Grossman SA, Fisher JD et al (1997) Preirradiation paclitaxel in glioblastoma multiforme: efficacy, pharmacology, and drug interactions. New approaches to brain tumor therapy central nervous system consortium. J Clin Oncol 15:3121–3128PubMedGoogle Scholar
  42. 42.
    Faucette SR, Wang H, Hamilton GA et al (2004) Regulation of CYP2B6 in primary human hepatocytes by prototypical inducers. Drug Metab Dispos 32:348–358CrossRefPubMedGoogle Scholar
  43. 43.
    Raucy JL (2003) Regulation of CYP3A4 expression in human hepatocytes by pharmaceuticals and natural products. Drug Metab Dispos 31:533–539CrossRefPubMedGoogle Scholar
  44. 44.
    Uttamsingh V, Lu C, Miwa G, Gan LS (2005) Relative contributions of the five major human cytochromes P450, 1A2, 2C9, 2C19, 2D6, and 3A4, to the hepatic metabolism of the proteasome inhibitor bortezomib. Drug Metab Dispos 33:1723–1728CrossRefPubMedGoogle Scholar
  45. 45.
    Horton TM, Pati D, Plon SE et al (2007) A phase 1 study of the proteasome inhibitor bortezomib in pediatric patients with refractory leukemia: a children’s oncology group study. Clin Cancer Res 13:1516–1522CrossRefPubMedGoogle Scholar
  46. 46.
    Attar EC, De Angelo DJ, Supko JG et al (2008) Phase I and pharmacokinetic study of bortezomib in combination with idarubicin and cytarabine in patients with acute myelogenous leukemia. Clin Cancer Res 14:1446–1454CrossRefPubMedGoogle Scholar
  47. 47.
    Stanford BL, Zondor SD (2003) Bortezomib treatment for multiple myeloma. Ann Pharmacother 37:1825–1830CrossRefPubMedGoogle Scholar
  48. 48.
    Davis NB, Taber DA, Ansari RH et al (2004) Phase II trial of PS-341 in patients with renal cell cancer: a university of Chicago phase II consortium study. J Clin Oncol 22:115–119CrossRefPubMedGoogle Scholar
  49. 49.
    Richardson PG, Briemberg H, Jagannath S et al (2006) Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. J Clin Oncol 24:3113–3120CrossRefPubMedGoogle Scholar
  50. 50.
    Lonial S, Waller EK, Richardson PG et al (2005) Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma. Blood 106:3777–3784CrossRefPubMedGoogle Scholar
  51. 51.
    Balmaceda C, Peereboom D, Pannullo S, Cheung YK, Fisher PG, Alavi J, Sisti M, Chen J, Fine RL (2008) Multi-institutional phase II study of temozolomide administered twice daily in the treatment of recurrent high-grade gliomas. Cancer 112:1139–1146CrossRefPubMedGoogle Scholar
  52. 52.
    Carson KA, Grossman SA, Fisher JD, Shaw EG (2007) Prognostic factors for survival in adult patients with recurrent glioma enrolled onto the new approaches to brain tumor therapy CNS consortium phase I and II clinical trials. J Clin Oncol 25:2601–2606CrossRefPubMedGoogle Scholar
  53. 53.
    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 17:2572–2578PubMedGoogle Scholar
  54. 54.
    Grossman SA, Carson KA, Phuphanich S et al (2008) Phase I and pharmacokinetic study of karenitecin in patients with recurrent malignant gliomas. Neuro Oncol 10:608–616CrossRefPubMedGoogle Scholar
  55. 55.
    Shapiro WR, Shapiro JR (2006) A changing paradigm of glioma biology. Hematol Oncol Clin North Am 20:1171–1191CrossRefPubMedGoogle Scholar
  56. 56.
    Chi A, Norden AD, Wen PY (2007) Inhibition of angiogenesis and invasion in malignant gliomas. Expert Rev Anticancer Ther 7:1537–1560CrossRefPubMedGoogle Scholar
  57. 57.
    de Groot JF, Gilbert MR (2007) New molecular targets in malignant giomas. Curr Opin Neurol 20:712–718CrossRefPubMedGoogle Scholar
  58. 58.
    Anderson KC, Jagannath S, Jakubowiak SA, Lonial S, Raje N, Schlossman R, Munshi N, Knight Esseltine RD, Richardson PG (2008) Phase II study to evaluate the efficacy and safety of bortezomib (PS-341) in chemotherapy-naive patients with advanced stage non-small cell lung cancer. J Clin Oncol 26(15S):8545Google Scholar
  59. 59.
    Ho L, Li T, Piperdi B, Macapinlac M, Rigas JR, Camacho F, Perez-Soler R, Gucalp R (2008) Phase II study of lenalidomide, bortezomib, and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma. J Clinc Oncol 26(15S):19096Google Scholar

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Surasak Phuphanich
    • 1
    • 2
  • Jeffrey G. Supko
    • 1
  • Kathryn A. Carson
    • 1
  • Stuart A. Grossman
    • 1
  • L. Burt Nabors
    • 1
  • Tom Mikkelsen
    • 1
  • Glenn Lesser
    • 1
  • Steve Rosenfeld
    • 1
  • Serena Desideri
    • 1
  • Jeffrey J. Olson
    • 1
  1. 1.The New Approaches to Brain Tumor Therapy (NABTT) Consortium, NABTT Central OfficeBaltimoreUSA
  2. 2.Johnnie Cochran Brain Tumor Center, Department of Neurosurgery and NeurologyCedars-Sinai Medical CenterLos AngelesUSA

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