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A phase I study of bortezomib and temozolomide in patients with advanced solid tumors

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Abstract

Purpose

The primary objective was to determine the maximum tolerated doses (MTDs) of the combination of bortezomib and temozolomide in patients with solid tumors. The secondary objective was to evaluate the pharmacokinetics (PK) of bortezomib with and without concurrent hepatic enzyme-inducing anticonvulsants (HEIAs).

Methods

Bortezomib was administered on days 2, 5, 9, and 12; temozolomide on days 1–5 of a 28-day cycle. Dose escalation proceeded using a standard 3+3 design. Patients with primary or metastatic brain tumors were eligible and were stratified based on whether they were taking HEIAs or not.

Results

Of the 25 patients enrolled, 22 were not taking HEIAs. MTDs were only given to patients not receiving HEIAs. Dose-limiting toxicities (DLTs) consisted of grade-3 constipation, hyponatremia, fatigue, elevated hepatic enzymes, and grade-4 neutropenia, thrombocytopenia, constipation, and abdominal pain. Stable disease (>8 weeks) was observed in 5 patients. Bortezomib systemic clearance (CLsys) on day 9 was 51% of the CLsys on day 2 (P < 0.01) Similarly, the normalized area under the concentration–time curve (norm AUC) on day 9 was 1.9 times the norm AUC on day 2 (P < 0.01). The median bortezomib CLsys on days 2 and 9 was significantly higher (P < 0.04) in patients taking HEIAs, and the median norm AUC was correspondingly lower (P < 0.04).

Conclusions

The MTDs for the combination of bortezomib and temozolomide in patients not taking HEIAs are 1.3 and 200 mg/m2, respectively. The rate of bortezomib elimination in patients taking HEIAs was increased twofold. Additional trials are needed to better define the optimal dosing in such patients.

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References

  1. Adams J (2003) The proteasome: structure, function, and role in the cell. Cancer Treat Rev 29(Suppl. 1):3–9

    Article  PubMed  CAS  Google Scholar 

  2. Cusack JC (2003) Rationale for the treatment of solid tumors with the proteasome inhibitor bortezomib. Cancer Treat Rev 29(Suppl. 1):21–31

    Article  PubMed  CAS  Google Scholar 

  3. Adams J, Palombella VJ, Sausville EA et al (1999) Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res 59:2615–2622

    PubMed  CAS  Google Scholar 

  4. Frankel A, Man S, Elliott P et al (2000) Lack of multicellular drug resistance observed in human ovarian and prostate carcinoma treated with the proteasome inhibitor PS-341. Clin Cancer Res 6:3719–3728

    PubMed  CAS  Google Scholar 

  5. Williams SA, Papandreou C, McConkey D (2001) Preclinical effects of proteasome inhibitor PS-341 in combination chemotherapy for prostate cancer. Proc Am Soc Clin Oncol 20:169b

    Google Scholar 

  6. Shah SA, Potter MW, McDade TP et al (2001) 26S proteasome inhibition induces apoptosis and limits growth of human pancreatic cancer. J Cell Biochem 82:110–122

    Article  PubMed  CAS  Google Scholar 

  7. Bold RJ, Virudachalam S, McConkey DJ (2001) Chemosensitization of pancreatic cancer by inhibition of the 26S proteasome. J Surg Res 100:11–17

    Article  PubMed  CAS  Google Scholar 

  8. Nawrocki ST, McConkey DJ (2002) The proteasome inhibitor, PS-341, inhibits the growth of pancreatic cancer cells in vitro and in vivo. Proc Am Assoc Cancer Res 43:159

    Google Scholar 

  9. Sclabas GM, Dong Qg, Fujioka S et al (2002) Drug-elicited apoptosis in pancreatic tumor cells: the role of different complexes between IkB and NF-kB. Proc Am Assoc Cancer Res 43:882

    Google Scholar 

  10. Ling YH, Jiang JD, Liebes L et al (2002) Molecular mechanisms of proteasome inhibitor PS-341-induced G2/M phase arrest and apoptosis in human non-small cell lung cancer H460 cells. Proc Am Assoc Cancer Res 43:665

    Google Scholar 

  11. Gumerlock PH, Moisan LP, Lau AH et al (2001) Docetaxel followed by PS-341 results in phosphorylation and stabilization of p27 and increases response in non-small cell lung carcinoma (NSCLC). Clin Cancer Res 7:157

    Google Scholar 

  12. Sunwoo JB, Chen Z, Dong G et al (2001) Novel proteasome inhibitor PS-341 inhibits activation of nuclear factor kB, cell survival, tumor growth, and angiogenesis in squamous cell carcinoma. Clin Cancer Res 7:1419–1428

    PubMed  CAS  Google Scholar 

  13. Chen Z, Malhotra PS, Gill R et al (2002) Identification of sensitive and resistant head and neck squamous cell carcimoma lines to PS-341, a novel anti-cancer agent inhibiting proteasome dependent activation of NF-kB. Proc Am Assoc Cancer Res 43:158

    Google Scholar 

  14. Cusack JC, Liu R, Houston M et al (2001) Enhanced chemosensitivity to CPT-11 with proteasome inhibitor PS-341: implications for systemic nuclear factor-kB inhibition. Cancer Res 61:3535–3540

    PubMed  CAS  Google Scholar 

  15. Teicher BA, Ara G, Herbst R et al (1999) The proteasome inhibitor PS-341 in cancer therapy. Clin Cancer Res 5:2638–2645

    PubMed  CAS  Google Scholar 

  16. Thornton JD, Liu R, Orlowski RZ et al (2001) Doxorubicin-induced NF-kappaB activation in breast cancer is overcome by proteasome inhibition, resulting in enhanced tumoricidal response to treatment. Presented at the 87th annual clinical congress of the American college of surgeons, New Orleans, October 7–12

  17. Kamat AM, Karashima T, Dinney CP et al (2002) The proteasome inhibitor PS-341 sensitizes drug-refractory human transitional cell tumors to gemcitabine. Proc Am Assoc Cancer Res 43:157

    Google Scholar 

  18. Pink M, Pien CS, Worland P et al (2002) PS-341 enhances chemotherapeutic effect in human xenograft models. Proc Am Assoc Cancer Res 43:158

    Google Scholar 

  19. Ryan DP, Appleman LJ, Lynch T et al (2006) Phase I clinical trial of bortezomib in combination with gemcitabine in patients with advanced solid tumors. Cancer 15:2482–2489

    Article  Google Scholar 

  20. Ryan DP, O’Neill BH, Supko JG et al (2006) A phase I study of bortezomib plus irinotecan in patients with advanced solid tumors. Cancer 107:2688–2697

    Article  PubMed  CAS  Google Scholar 

  21. Messersmith WA, Baker SD, Lassiter L et al (2006) Phase I trial of bortezomib in combination with Docetaxel in patients with advanced solid tumors. Clin Cancer Res 12:1270–1275

    Article  PubMed  CAS  Google Scholar 

  22. Cohen SJ, Engstrom PF, Lewis NL et al (2008) Phase I study of capecitabine and oxaliplatin in combination with the proteasome inhibitor bortezomib in patients with advanced solid tumors. Am J Clin Oncol 31:1–5

    Article  PubMed  CAS  Google Scholar 

  23. Ma C, Mandrekar SJ, Alberts SR et al (2007) A phase I and pharmacologic study of sequences of the proteasome inhibitor, bortezomib (PS-341, Velcade), in combination with paclitaxel and carboplatin in patients with advanced malignancies. Cancer Chemother Pharmacol 59:207–215

    Article  PubMed  CAS  Google Scholar 

  24. Dees EC, O’Neil BH, Lindley CM et al (2008) A phase I and pharmacologic study of the combination of bortezomib and pegylated liposomal doxorubicin in patients with refractory solid tumors. Cancer Chemother Pharmacol 63:99–107

    Article  PubMed  CAS  Google Scholar 

  25. Stupp R, Mason WP, van den Bent MJ et al (2005) Radiotherapy plus comcomitant and adjuvant temozolomide for glioblastoma. New Eng J Med 352:987–996

    Article  PubMed  CAS  Google Scholar 

  26. Quirt I, Verma S, Petrella T et al (2007) Temozolomide for the treatment of metastatic melanoma: a systemic review. Oncologist 12:1114–1123

    Article  PubMed  CAS  Google Scholar 

  27. Gunther W, Pawlak E, Damasceno R et al (2003) Temozolomide induces apoptosis and senescence in glioma cells cultured as multicellular spheroids. Br J Cancer 88:463–469

    Article  PubMed  CAS  Google Scholar 

  28. Amiri KI, Horton LW, LaFleur BJ et al (2004) Augmenting chemosensitivity of malignant melanoma tumors via proteasome inhibition: implications for bortezomib (VELCADE, PS-341) as a therapeutic agent for malignant melanoma. Cancer Res 64:4912–4918

    Article  PubMed  CAS  Google Scholar 

  29. Abrey LE, Olson JD, Raizer JJ et al (2001) A phase II trial of temozolomide for patients with recurrent or progressive brain metastases. J Neurooncol 53:259–265

    Article  PubMed  CAS  Google Scholar 

  30. Christodoulou C, Bafaloukos D, Kosmidis P et al (2001) Phase II study of temozolomide in heavily pretreated cancer patients with brain metastases. Ann Oncol 12:249–254

    Article  PubMed  CAS  Google Scholar 

  31. Antonadou D, Paraskevaidis M, Sarris G et al (2002) Phase II randomized trial of temozolomide and concurrent radiotherapy in patients with brain metastases. J Clin Oncol 20:3644–3650

    Article  PubMed  CAS  Google Scholar 

  32. Aghajanian C, Soignet S, Dizon DS et al (2002) A phase I trial of the novel proteasome inhibitor PS-341 in advanced solid tumor malignancies. Clin Cancer Res 8:2505–2511

    PubMed  CAS  Google Scholar 

  33. 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 Oncology 22:2108–2121

    Article  CAS  Google Scholar 

  34. Newlands ES, Blackledge GR, Slack JA et al (1992) Phase I trial of temozolomide (CCRG 81045: M&B 39831: NSC 3628560. Br J Cancer 65:287–291

    Article  PubMed  CAS  Google Scholar 

  35. Brada M, Judson I, Beale P et al (1999) Phase I dose-escalation and pharmacokinetic study of temzolomide (SCH 52365) for refractory or relapsing malignancies. Br J Cancer 81:1022–1030

    Article  PubMed  CAS  Google Scholar 

  36. Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205–216

    Article  PubMed  CAS  Google Scholar 

  37. Macdonald DR, Cascino TL, Schold SC Jr, Cairncross JG (1990) Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 8:1277–1280

    PubMed  CAS  Google Scholar 

  38. Venkatakrishnan K, Rader M, Ramanathan RK et al (2009) Effect of the CYP3A inhibitor ketoconazole on the pharmacokinetics and pharmacodynamics of bortezomib in patients with advanced solid tumors: a prospective, multicenter, open-label, randomized, two-way crossover drug–drug interaction study. Clin Ther 31:2444–2458

    Article  PubMed  CAS  Google Scholar 

  39. Kubicek GJ, Werner-Wasik M, Machtay M et al (2009) Phase I trial using proteasome inhibitor bortezomib and concurrent temozolomide and radiotherapy for central nervous system malignancies. Int J Radia Oncol Biol Phys 74:433–439

    Article  CAS  Google Scholar 

  40. Su Y, Amiri KI, Horton LW et al (2010) A phase I trial of bortezomib with temozolomide in patients with advanced melanoma: toxicities, antitumor effects, and modulation of therapeutic targets. Clin Cancer Res 16:348–357

    Article  PubMed  CAS  Google Scholar 

  41. 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 33:1723–1728

    Article  PubMed  CAS  Google Scholar 

  42. Reece DE, Sullivan D, Lonial S et al (2011) Pharmacokinetic and pharmacodynamic study of two doses of bortezomib in patients with relapsed multiple myeloma. Cancer Chemother Pharmacol 67:57–67

    Article  PubMed  CAS  Google Scholar 

  43. Vecht CJ, Wagner GL, Wilms EB (2003) Interactions between antiepileptic and chemotherapeutic drugs. Lancet Neurol 2:404–409

    Article  PubMed  CAS  Google Scholar 

  44. Rowinsky EK (1997) Paclitaxel pharmacology and other tumor types. Semin Oncol 24:S19-1–S19-12

    Google Scholar 

  45. 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 9:2940–2949

    PubMed  CAS  Google Scholar 

  46. Nix D, Press RJ, Wehrman TG (2003) Tissue distribution, mass balance, and biliary excretion of bortezomib (VELCADE™) in male rats. Drug Metab Rev 35(2):224

    Google Scholar 

  47. Nix, D, Wherman, TG, Press RJ (2003) Tissue distribution and mass balance of bortezomib (VELCADE™) in non-human primates. AAPS PharmSci 5:4 (Abstract M1336)

    Google Scholar 

  48. Investigator Brochure for PS-341 (2010) Millennium pharmaceuticals, Inc. Edition 13

  49. Phuphanich S, Supko JG, Carson KA et al (2010) Phase 1 clinical trial of bortezomib in adults with recurrent malignant glioma. J Neurooncol 100:95–103

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We would like to thank Ms. Brenda Williams, the Phase I research nurse for this study. Grant Support: NIH training grant (K12 CA01727; J. Portnow), and a Cancer Center Support Grant (P30 CA33572).

Conflicts of interest

No financial conflict of interest exists for any of the authors.

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Authors and Affiliations

  1. Department of Medical Oncology, City of Hope, 1500 East Duarte Road, Duarte, CA, 91030, USA

    J. Portnow, P. Frankel, S. Koehler, P. Twardowski, S. Shibata, C. Martel, R. Morgan, M. Cristea, W. Chow, D. Lim, V. Chung, K. Reckamp, L. Leong & T. W. Synold

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  1. J. Portnow
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  2. P. Frankel
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  3. S. Koehler
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  10. D. Lim
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Correspondence to J. Portnow.

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Portnow, J., Frankel, P., Koehler, S. et al. A phase I study of bortezomib and temozolomide in patients with advanced solid tumors. Cancer Chemother Pharmacol 69, 505–514 (2012). https://doi.org/10.1007/s00280-011-1721-x

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  • DOI: https://doi.org/10.1007/s00280-011-1721-x

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