Skip to main content

Advertisement

SpringerLink
Log in

Phase I dosage finding and pharmacokinetic study of intravenous topotecan and oral erlotinib in adults with refractory solid tumors

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

Abstract

Purpose

Topotecan is widely used for refractory solid tumors but multi-drug resistance may occur due to tumor expression of ATP-binding cassette (ABC) transporters. Since erlotinib, an inhibitor of the epidermal growth factor receptor, also inhibits several ABC transporters, we performed a phase I study to evaluate the safety, efficacy, and pharmacokinetics of intravenous topotecan given in combination with erlotinib.

Methods

Patients received 150 mg of oral erlotinib daily and a 30 min intravenous infusion of topotecan on days 1–5 of a 21-day cycle. Dosage escalation of topotecan occurred with a starting dosage of 0.75 mg/m2. The pharmacokinetics of topotecan was evaluated on day 1 of cycle 1 without erlotinib and on day 1 of cycle 2 or 3 with erlotinib.

Results

Twenty-nine patients were enrolled. The maximum tolerated dosage was determined to be 1.0 mg/m2. Dose-limiting toxicities included neutropenia and thrombocytopenia. The average duration of treatment was 97 days. Two partial responses were observed. Topotecan clearance and exposure were similar with and without erlotinib.

Conclusions

The combination of topotecan and erlotinib is tolerable at clinically effective doses. Erlotinib does not affect the disposition of topotecan to a clinically significant extent.

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. Pizzolato JF, Saltz LB (2003) The camptothecins. Lancet 361(9376):2235–2242. doi:10.1016/S0140-6736(03)13780-4

    Article  CAS  PubMed  Google Scholar 

  2. Simon GR, Wagner H (2003) Small cell lung cancer. Chest 123(1 Suppl):259S–271S

    Article  PubMed  Google Scholar 

  3. Kruijtzer CM, Beijnen JH, Rosing H, ten Bokkel Huinink WW, Schot M, Jewell RC, Paul EM, Schellens JH (2002) Increased oral bioavailability of topotecan in combination with the breast cancer resistance protein and P-glycoprotein inhibitor GF120918. J Clin Oncol 20(13):2943–2950

    Article  CAS  PubMed  Google Scholar 

  4. Diestra JE, Scheffer GL, Catala I, Maliepaard M, Schellens JH, Scheper RJ, Germa-Lluch JR, Izquierdo MA (2002) Frequent expression of the multi-drug resistance-associated protein BCRP/MXR/ABCP/ABCG2 in human tumours detected by the BXP-21 monoclonal antibody in paraffin-embedded material. J Pathol 198(2):213–219. doi:10.1002/path.1203

    Article  CAS  PubMed  Google Scholar 

  5. Tian Q, Zhang J, Chan SY, Tan TM, Duan W, Huang M, Zhu YZ, Chan E, Yu Q, Nie YQ, Ho PC, Li Q, Ng KY, Yang HY, Wei H, Bian JS, Zhou SF (2006) Topotecan is a substrate for multidrug resistance associated protein 4. Curr Drug Metab 7(1):105–118

    Article  CAS  PubMed  Google Scholar 

  6. Gottesman MM, Fojo T, Bates SE (2002) Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer 2(1):48–58. doi:10.1038/nrc706

    Article  CAS  PubMed  Google Scholar 

  7. Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W (2007) Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25(15):1960–1966. doi:10.1200/JCO.2006.07.9525

    Article  CAS  PubMed  Google Scholar 

  8. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, Maoleekoonpiroj S, Smylie M, Martins R, van Kooten M, Dediu M, Findlay B, Tu D, Johnston D, Bezjak A, Clark G, Santabarbara P, Seymour L (2005) Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353(2):123–132. doi:10.1056/NEJMoa050753

    Article  CAS  PubMed  Google Scholar 

  9. Rosell R, Moran T, Carcereny E, Quiroga V, Molina MA, Costa C, Benlloch S, Taron M (2010) Non-small-cell lung cancer harbouring mutations in the EGFR kinase domain. Clin Transl Oncol 12(2):75–80

    Google Scholar 

  10. Saif MW Colorectal cancer in review: the role of the EGFR pathway. Expert Opin Investig Drugs 19(3):357–369. doi:10.1517/13543781003593962

  11. Milanezi F, Carvalho S, Schmitt FC (2008) EGFR/HER2 in breast cancer: a biological approach for molecular diagnosis and therapy. Expert Rev Mol Diagn 8(4):417–434. doi:10.1586/14737159.8.4.417

    Article  CAS  PubMed  Google Scholar 

  12. Papageorgio C, Perry MC (2007) Epidermal growth factor receptor-targeted therapy for pancreatic cancer. Cancer Invest 25(7):647–657. doi:10.1080/07357900701522653

    Article  CAS  PubMed  Google Scholar 

  13. Lafky JM, Wilken JA, Baron AT, Maihle NJ (2008) Clinical implications of the ErbB/epidermal growth factor (EGF) receptor family and its ligands in ovarian cancer. Biochim Biophys Acta 1785(2):232–265. doi:10.1016/j.bbcan.2008.01.001

    CAS  PubMed  Google Scholar 

  14. Molinolo AA, Amornphimoltham P, Squarize CH, Castilho RM, Patel V, Gutkind JS (2009) Dysregulated molecular networks in head and neck carcinogenesis. Oral Oncol 45(4–5):324–334. doi:10.1016/j.oraloncology.2008.07.011

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Pande AU, Iyer RV, Rani A, Maddipatla S, Yang GY, Nwogu CE, Black JD, Levea CM, Javle MM (2007) Epidermal growth factor receptor-directed therapy in esophageal cancer. Oncology 73(5–6):281–289. doi:10.1159/000132393

    Article  CAS  PubMed  Google Scholar 

  16. El-Jawahri A, Patel D, Zhang M, Mladkova N, Chakravarti A (2008) Biomarkers of clinical responsiveness in brain tumor patients: progress and potential. Mol Diagn Ther 12(4):199–208

    Article  CAS  PubMed  Google Scholar 

  17. Soulieres D, Senzer NN, Vokes EE, Hidalgo M, Agarwala SS, Siu LL (2004) Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck. J Clin Oncol 22(1):77–85. doi:10.1200/JCO.2004.06.075

    Article  CAS  PubMed  Google Scholar 

  18. Gordon AN, Finkler N, Edwards RP, Garcia AA, Crozier M, Irwin DH, Barrett E (2005) Efficacy and safety of erlotinib HCl, an epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor, in patients with advanced ovarian carcinoma: results from a phase II multicenter study. Int J Gynecol Cancer 15(5):785–792. doi:10.1111/j.1525-1438.2005.00137.x

    Article  CAS  PubMed  Google Scholar 

  19. Dickler MN, Cobleigh MA, Miller KD, Klein PM, Winer EP (2009) Efficacy and safety of erlotinib in patients with locally advanced or metastatic breast cancer. Breast Cancer Res Treat 115(1):115–121. doi:10.1007/s10549-008-0055-9

    Article  CAS  PubMed  Google Scholar 

  20. Townsley CA, Major P, Siu LL, Dancey J, Chen E, Pond GR, Nicklee T, Ho J, Hedley D, Tsao M, Moore MJ, Oza AM (2006) Phase II study of erlotinib (OSI-774) in patients with metastatic colorectal cancer. Br J Cancer 94(8):1136–1143. doi:10.1038/sj.bjc.6603055

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Shi Z, Peng XX, Kim IW, Shukla S, Si QS, Robey RW, Bates SE, Shen T, Ashby CR Jr, Fu LW, Ambudkar SV, Chen ZS (2007) Erlotinib (Tarceva, OSI-774) antagonizes ATP-binding cassette subfamily B member 1 and ATP-binding cassette subfamily G member 2-mediated drug resistance. Cancer Res 67(22):11012–11020

    Article  CAS  PubMed  Google Scholar 

  22. Carcaboso AM, Elmeliegy MA, Shen J, Juel SJ, Zhang ZM, Calabrese C, Tracey L, Waters CM, Stewart CF (2010) Tyrosine kinase inhibitor gefitinib enhances topotecan penetration of gliomas. Cancer Res 70(11):4499–4508. doi:10.1158/0008-5472.CAN-09-4264

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Shen J, Carcaboso AM, Hubbard KE, Tagen M, Wynn HG, Panetta JC, Waters CM, Elmeliegy MA, Stewart CF (2009) Compartment-specific roles of ATP-binding cassette transporters define differential topotecan distribution in brain parenchyma and cerebrospinal fluid. Cancer Res 69(14):5885–5892. doi:10.1158/0008-5472.CAN-09-0700

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Rowinsky EK, Grochow LB, Hendricks CB, Ettinger DS, Forastiere AA, Hurowitz LA, McGuire WP, Sartorius SE, Lubejko BG, Kaufmann SH et al (1992) Phase I and pharmacologic study of topotecan: a novel topoisomerase I inhibitor. J Clin Oncol 10:647–656

    CAS  PubMed  Google Scholar 

  25. Kadlubar FF, Berkowitz GS, Delongchamp RR, Wang C, Green BL, Tang G, Lamba J, Schuetz E, Wolff MS (2003) The CYP3A4*1B variant is related to the onset of puberty, a known risk factor for the development of breast cancer. Cancer Epidemiol Biomark Prev 12(4):327–331

    CAS  Google Scholar 

  26. Lee SJ, Goldstein JA (2005) Functionally defective or altered CYP3A4 and CYP3A5 single nucleotide polymorphisms and their detection with genotyping tests. Pharmacogenomics 6(4):357–371

    Article  CAS  PubMed  Google Scholar 

  27. Zheng H, Webber S, Zeevi A, Schuetz E, Zhang J, Lamba J, Bowman P, Burckart GJ (2002) The MDR1 polymorphisms at exons 21 and 26 predict steroid weaning in pediatric heart transplant patients. Hum Immunol 63(9):765–770

    Article  CAS  PubMed  Google Scholar 

  28. Zamber CP, Lamba JK, Yasuda K, Farnum J, Thummel K, Schuetz JD, Schuetz EG (2003) Natural allelic variants of breast cancer resistance protein (BCRP) and their relationship to BCRP expression in human intestine. Pharmacogenetics 13(1):19–28

    Article  CAS  PubMed  Google Scholar 

  29. Poonkuzhali B, Lamba J, Strom S, Sparreboom A, Thummel K, Watkins P, Schuetz E (2008) Association of breast cancer resistance protein/ABCG2 phenotypes and novel promoter and intron 1 single nucleotide polymorphisms. Drug Metab Dispos 36(4):780–795. doi:10.1124/dmd.107.018366

    Article  CAS  PubMed  Google Scholar 

  30. Turner PK, Iacono LC, Panetta JC, Santana VM, Daw NC, Gajjar A, Stewart CF (2006) Development and validation of limited sampling models for topotecan lactone pharmacokinetic studies in children. Cancer Chemother Pharmacol 57(4):475–482

    Article  CAS  PubMed  Google Scholar 

  31. Stewart CF, Baker SD, Heideman RL, Jones D, Crom WR, Pratt CB (1994) Clinical pharmacodynamics of continuous infusion topotecan in children: systemic exposure predicts hematologic toxicity. J Clin Oncol 12(9):1946–1954

    CAS  PubMed  Google Scholar 

  32. D’argenio DZ, Schumitzky A (2009) ADAPT 5 user’s guide: pharmacokinetic/pharmacodynamic systems analysis software. Biomedical Simulations Resource, Los Angeles

    Google Scholar 

  33. Mould DR, Holford NH, Schellens JH, Beijnen JH, Hutson PR, Rosing H, ten Bokkel Huinink WW, Rowinsky EK, Schiller JH, Russo M, Ross G (2002) Population pharmacokinetic and adverse event analysis of topotecan in patients with solid tumors. Clin Pharmacol Ther 71(5):334–348

    Article  CAS  PubMed  Google Scholar 

  34. Dennis MJ, Beijnen JH, Grochow LB, van Warmerdam LJ (1997) An overview of the clinical pharmacology of topotecan. Semin Oncol 24(1 Suppl 5):S5

    CAS  PubMed  Google Scholar 

  35. Matsumoto S, Yoshida K, Ishiguro N, Maeda T, Tamai I (2007) Involvement of rat and human organic anion transporter 3 in the renal tubular secretion of topotecan [(S)-9-dimethylaminomethyl-10-hydroxy-camptothecin hydrochloride]. J Pharmacol Exp Ther 322(3):1246–1252. doi:10.1124/jpet.107.123323

    Article  CAS  PubMed  Google Scholar 

  36. Continuous infusion topotecan with erlotinib for topotecan pretreated ovarian cancer: tumor features and phase II/pharmacokinetic evaluation (2009) OSI Pharm. http://clinicaltrials.gov/show/NCT01003938. Accessed 27 Nov 2013

  37. Weroha SJ, Oberg AL, Ziegler KL, Dakhilm SR, Rowland KM, Hartmann LC, Moore DF Jr, Keeney GL, Peethambaram PP, Haluska P (2011) Phase II trial of lapatinib and topotecan (LapTop) in patients with platinum-refractory/resistant ovarian and primary peritoneal carcinoma. Gynecol Oncol 122(1):116–120. doi:10.1016/j.ygyno.2011.03.030

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Lheureux S, Krieger S, Weber B, Pautier P, Fabbro M, Selle F, Bourgeois H, Petit T, Lortholary A, Plantade A, Briand M, Leconte A, Richard N, Vilquin P, Clarisse B, Blanc-Fournier C, Joly F (2012) Expected benefits of topotecan combined with lapatinib in recurrent ovarian cancer according to biological profile: a phase 2 trial. Int J Gynecol Cancer 22(9):1483–1488. doi:10.1097/IGC.0b013e31826d1438

    PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the National Institutes of Health, Cancer Center Support CA 21765, GlaxoSmithKline, and the American Lebanese Syrian Associated Charities (ALSAC). Dr. Stewart and Dr. Schwartzberg received study funding from GlaxoSmithKline. Dr. Tauer had served in a consultant/advisory role to GlaxoSmithKline. All other authors report that they have no disclosures.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, MS 313, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105-2794, USA

    Clinton F. Stewart & Michael Tagen

  2. The West Clinic, 100 N. Humphreys Blvd., Memphis, TN, 38120, USA

    Lee S. Schwartzberg, L. Johnetta Blakely, Kurt W. Tauer & Linda M. Smiley

Authors
  1. Clinton F. Stewart
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael Tagen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lee S. Schwartzberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L. Johnetta Blakely
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kurt W. Tauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Linda M. Smiley
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Clinton F. Stewart.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stewart, C.F., Tagen, M., Schwartzberg, L.S. et al. Phase I dosage finding and pharmacokinetic study of intravenous topotecan and oral erlotinib in adults with refractory solid tumors. Cancer Chemother Pharmacol 73, 561–568 (2014). https://doi.org/10.1007/s00280-014-2385-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-014-2385-0

Keywords

Search

Navigation