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A double-blind, randomized, multiple-dose, parallel-group study to characterize the occurrence of diarrhea following two different dosing regimens of neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor

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Abstract

Purpose

Neratinib, a potent, low-molecular-weight, orally administered, irreversible, pan-ErbB receptor tyrosine kinase inhibitor has antitumor activity in ErbB2 + breast cancer. The objective of this study was to characterize the onset, severity, and duration of diarrhea after administration of neratinib 240 mg once daily (QD) and 120 mg twice daily (BID) for ≤14 days in healthy subjects.

Methods

A randomized, double-blind, parallel-group, inpatient study was conducted in 50 subjects given oral neratinib either 240 mg QD or 120 mg BID with food for ≤14 days. The primary endpoint was the proportion of subjects with diarrhea of at least moderate severity (grade 2; 5–7 loose stools/day). In subjects with grade 2 diarrhea, fecal analytes were determined. Pharmacokinetic profiles were characterized for neratinib on Days 1 and 7.

Results

No severe (grade 3) diarrhea was reported. By Day 4, all subjects had grade 1 diarrhea. Grade 2 diarrhea occurred in 11/22 evaluable subjects (50 % [90 % confidence interval (CI): 28–72 %]) in the QD group and 17/23 evaluable subjects (74 % [90 % CI: 52–90 %]) in the BID group (P = 0.130). In fecal analyses, 18 % tested positive for hemoglobin and 46 % revealed fecal lactoferrin. Specimen pH was neutral to slightly alkaline. In pharmacokinetic analyses, Day 1 peak plasma concentration and Day 7 steady-state exposure were higher with the QD regimen than the BID regimen. In an exploratory analysis, ABCG2 genotype showed no correlation with severity or onset of diarrhea.

Conclusions

Incidences and onsets of at least grade 1 and at least grade 2 diarrhea were not improved on BID dosing compared with QD dosing.

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References

  1. Gutierrez C, Schiff R (2011) HER2: biology, detection, and clinical implications. Arch Pathol Lab Med 135:55–62

    PubMed  Google Scholar 

  2. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, Utriainen T, Kokko R, Hemminki A, Tarkkanen M, Turpeenniemi-Hujanen T, Jyrkkio S, Flander M, Helle L, Ingalsuo S, Johansson K, Jaaskelainen AS, Pajunen M, Rauhala M, Kaleva-Kerola J, Salminen T, Leinonen M, Elomaa I, Isola J (2006) Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 354:809–820

    Article  PubMed  CAS  Google Scholar 

  3. Smith I, Procter M, Gelber RD, Guillaume S, Feyereislova A, Dowsett M, Goldhirsch A, Untch M, Mariani G, Baselga J, Kaufmann M, Cameron D, Bell R, Bergh J, Coleman R, Wardley A, Harbeck N, Lopez RI, Mallmann P, Gelmon K, Wilcken N, Wist E, Sanchez RP, Piccart-Gebhart MJ (2007) 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 369:29–36

    Article  PubMed  CAS  Google Scholar 

  4. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that over expresses HER2. N Engl J Med 344:783–792

    Article  PubMed  CAS  Google Scholar 

  5. HERCEPTIN® (2009) (Trastuzumab) Intravenous infusion [package insert]. Genentech Inc, South San Francisco, CA

  6. Tripathy D, Slamon DJ, Cobleigh M, Arnold A, Saleh M, Mortimer JE, Murphy M, Stewart SJ (2004) Safety of treatment of metastatic breast cancer with trastuzumab beyond disease progression. J Clin Oncol 22:1063–1070

    Article  PubMed  CAS  Google Scholar 

  7. Montemurro F, Donadio M, Clavarezza M, Redana S, Jacomuzzi ME, Valabrega G, Danese S, Vietti-Ramus G, Durando A, Venturini M, Aglietta M (2006) Outcome of patients with HER2-positive advanced breast cancer progressing during trastuzumab-based therapy. Oncologist 11:318–324

    Article  PubMed  CAS  Google Scholar 

  8. Rabindran SK (2005) Antitumor activity of HER-2 inhibitors. Cancer Lett 227:9–23

    Article  PubMed  CAS  Google Scholar 

  9. Rabindran SK, Discafani CM, Rosfjord EC, Baxter M, Floyd MB, Golas J, Hallett WA, Johnson BD, Nilakantan R, Overbeek E, Reich MF, Shen R, Shi X, Tsou HR, Wang YF, Wissner A (2004) Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Res 64:3958–3965

    Article  PubMed  CAS  Google Scholar 

  10. Tsou HR, Overbeek-Klumpers EG, Hallett WA, Reich MF, Floyd MB, Johnson BD, Michalak RS, Nilakantan R, Discafani C, Golas J, Rabindran SK, Shen R, Shi X, Wang YF, Upeslacis J, Wissner A (2005) Optimization of 6,7-disubstituted-4-(arylamino)quinoline-3-carbonitriles as orally active, irreversible inhibitors of human epidermal growth factor receptor-2 kinase activity. J Med Chem 48:1107–1131

    Article  PubMed  CAS  Google Scholar 

  11. Paridaens R, Badwe R, Sun Y, Dirix L, Cardoso F, Powell C, Zacharchuk C, Burstein HJ (2009) Neratinib (HKI-272), an irreversible pan erbB2 + receptor tyrosine kinase inhibitor: phase 2 results in patients with erbB2 + advanced breast cancer. Ann Oncol 20:ii61, Abstract 186P

  12. Wong KK, Fracasso PM, Bukowski RM, Lynch TJ, Munster PN, Shapiro GI, Janne PA, Eder JP, Naughton MJ, Ellis MJ, Jones SF, Mekhail T, Zacharchuk C, Vermette J, Abbas R, Quinn S, Powell C, Burris HA (2009) A phase I study with neratinib (HKI-272), an irreversible pan ErbB receptor tyrosine kinase inhibitor, in patients with solid tumors. Clin Cancer Res 15:2552–2558

    Article  PubMed  CAS  Google Scholar 

  13. Chow L, Jiang Z, Epstein R, Bondarenko I, Awada A, Coughlin C, Gauthier E, Zhao Y, Abbas R, Hershman D (2009) Safety and efficacy of neratinib (HKI-272) in combination with paclitaxel in patients with solid tumors. J Clin Oncol 27:160s, Abstract 3557

  14. Swaby R, Blackwell K, Jiang Z, Sun Y, Dieras V, Zaman K, Zacharchuk C, Powell C, Abbas R, Thakuria M (2009) Neratinib in combination with trastuzumab for the treatment of advanced breast cancer: a phase I/II study. J Clin Oncol 27:1004

    Google Scholar 

  15. Burstein HJ, Sun Y, Dirix LY, Jiang Z, Paridaens R, Tan AR, Awada A, Ranade A, Jiao S, Schwartz G, Abbas R, Powell C, Turnbull K, Vermette J, Zacharchuk C, Badwe R (2010) Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer. J Clin Oncol 28:1301–1307

    Article  PubMed  CAS  Google Scholar 

  16. 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 353:123–132

    Article  PubMed  CAS  Google Scholar 

  17. Thatcher N, Chang A, Parikh P, Rodrigues PJ, Ciuleanu T, von Pawel J, Thongprasert S, Tan EH, Pemberton K, Archer V, Carroll K (2005) Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (iressa survival evaluation in lung cancer). Lancet 366:1527–1537

    Article  PubMed  CAS  Google Scholar 

  18. Blackwell KL, Burstein HJ, Storniolo AM, Rugo H, Sledge G, Koehler M, Ellis C, Casey M, Vukelja S, Bischoff J, Baselga J, O’Shaughnessy J (2010) Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol 28:1124–1130

    Article  PubMed  CAS  Google Scholar 

  19. Abbas R, Hug B, Leister C, Burns J, Sonnichsen D (2009) Single-ascending-dose study of safety, tolerability, and pharmacokinetics of neratinib (HKI-272) in healthy subjects. AAPS J 11(S2)

  20. Abbas R, Hug BA, Leister C, Burns J, Sonnichsen D (2011) Pharmacokinetics of oral neratinib during co-administration of ketoconazole in healthy subjects. Br J Clin Pharmacol 71:522–527

    Article  PubMed  CAS  Google Scholar 

  21. Lewis SJ, Heaton KW (1997) Stool form scale as a useful guide to intestinal transit time. Scand J Gastroenterol 32:920–924

    Article  PubMed  CAS  Google Scholar 

  22. Jusko WJ (1992) Guidelines for collection and analysis of pharmacokinetic data. In: Evans WE, Schentag JJ, Jusko WJ (eds) Applied pharmacokinetics: principles of therapeutic drug monitoring. Applied Therapeutics, Spokane, pp 2–43

    Google Scholar 

  23. Honjo Y, Morisaki K, Huff LM, Robey RW, Hung J, Dean M, Bates SE (2002) Single-nucleotide polymorphism (SNP) analysis in the ABC half-transporter ABCG2 (MXR/BCRP/ABCP1). Cancer Biol Ther 1:696–702

    PubMed  CAS  Google Scholar 

  24. Cha PC, Mushiroda T, Zembutsu H, Harada H, Shinoda N, Kawamoto S, Shimoyama R, Nishidate T, Furuhata T, Sasaki K, Hirata K, Nakamura Y (2009) Single nucleotide polymorphism in ABCG2 is associated with irinotecan-induced severe myelosuppression. J Hum Genet 54:572–580

    Article  PubMed  CAS  Google Scholar 

  25. Cusatis G, Gregorc V, Li J, Spreafico A, Ingersoll RG, Verweij J, Ludovini V, Villa E, Hidalgo M, Sparreboom A, Baker SD (2006) Pharmacogenetics of ABCG2 and adverse reactions to gefitinib. J Natl Cancer Inst 98:1739–1742

    Article  PubMed  CAS  Google Scholar 

  26. de Jong FA, Scott-Horton TJ, Kroetz DL, McLeod HL, Friberg LE, Mathijssen RH, Verweij J, Marsh S, Sparreboom A (2007) Irinotecan-induced diarrhea: functional significance of the polymorphic ABCC2 transporter protein. Clin Pharmacol Ther 81:42–49

    Article  PubMed  Google Scholar 

  27. (2007) TYKERB® (lapatinib) tablets [package insert]. GlaxoSmithKline, Research triangle park

  28. (2005) Iressa® (gefitinib tablets) [package insert]. AstraZeneca Pharmaceuticals LP, Wilmington

  29. (2004) Tarceva® (erlotinib tablets) [package insert]. Genentech, Inc, South San Franscisco

  30. Sequist LV, Besse B, Lynch TJ, Miller VA, Wong KK, Gitlitz B, Eaton K, Zacharchuk C, Freyman A, Powell C, Ananthakrishnan R, Quinn S, Soria JC (2010) Neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor: results of a phase II trial in patients with advanced non-small-cell lung cancer. J Clin Oncol 28:3076–3083

    Article  PubMed  CAS  Google Scholar 

  31. Ross HJ, Blumenschein GR Jr, Aisner J, Damjanov N, Dowlati A, Garst J, Rigas JR, Smylie M, Hassani H, Allen KE, Leopold L, Zaks TZ, Shepherd FA (2010) Randomized phase II multicenter trial of two schedules of lapatinib as first- or second-line monotherapy in patients with advanced or metastatic non-small cell lung cancer. Clin Cancer Res 16:1938–1949

    Article  PubMed  CAS  Google Scholar 

  32. Uribe JM, Gelbmann CM, Traynor-Kaplan AE, Barrett KE (1996) Epidermal growth factor inhibits Ca(2 +)-dependent Cl- transport in T84 human colonic epithelial cells. Am J Physiol 271:C914–C922

    PubMed  CAS  Google Scholar 

  33. Rudin CM, Liu W, Desai A, Karrison T, Jiang X, Janisch L, Das S, Ramirez J, Poonkuzhali B, Schuetz E, Fackenthal DL, Chen P, Armstrong DK, Brahmer JR, Fleming GF, Vokes EE, Carducci MA, Ratain MJ (2008) Pharmacogenomic and pharmacokinetic determinants of erlotinib toxicity. J Clin Oncol 26:1119–1127

    Article  PubMed  CAS  Google Scholar 

  34. de Jong FA, Marsh S, Mathijssen RH, King C, Verweij J, Sparreboom A, McLeod HL (2004) ABCG2 pharmacogenetics: ethnic differences in allele frequency and assessment of influence on irinotecan disposition. Clin Cancer Res 10:5889–5894

    Article  PubMed  Google Scholar 

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Acknowledgments

This study was sponsored by Wyeth Research, which was acquired by Pfizer Inc in October 2009. The authors thank the investigator Patricia A. Chandler, MD, of Charles River Clinical Services Northwest (Tacoma, WA). Editorial/medical writing support was provided by Tuli Ahmed, MS, at On Assignment and Kimberly Brooks, PhD, at a MedErgy HealthGroup company, and was funded by Pfizer Inc.

Conflict of interest

All authors were employees of Wyeth Research (now Pfizer Inc) at the time of the study; Richat Abbas, Cathie Leister, and Daryl Sonnichsen additionally own stock in Pfizer.

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Authors and Affiliations

  1. Pfizer Inc, 500 Arcola Road, Collegeville, PA, 19426, USA

    Richat Abbas, Bruce A. Hug, Cathie Leister & Daryl Sonnichsen

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  1. Richat Abbas
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  2. Bruce A. Hug
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Correspondence to Richat Abbas.

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Abbas, R., Hug, B.A., Leister, C. et al. A double-blind, randomized, multiple-dose, parallel-group study to characterize the occurrence of diarrhea following two different dosing regimens of neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor. Cancer Chemother Pharmacol 70, 191–199 (2012). https://doi.org/10.1007/s00280-012-1857-3

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  • DOI: https://doi.org/10.1007/s00280-012-1857-3

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