Advertisement

International Journal of Hematology

, Volume 106, Issue 6, pp 765–776 | Cite as

Eltrombopag for thrombocytopenia in patients with advanced solid tumors receiving gemcitabine-based chemotherapy: a randomized, placebo-controlled phase 2 study

  • Eric S. Winer
  • Howard Safran
  • Boguslawa Karaszewska
  • Sebastian Bauer
  • Dilawar Khan
  • Steffen Doerfel
  • Paul Burgess
  • Stacey Kalambakas
  • Yasser Mostafa Kamel
  • Frederic Forget
Original Article

Abstract

In this phase 2 study, patients with solid tumors receiving gemcitabine monotherapy or gemcitabine plus cisplatin/carboplatin were randomized 2:1 to eltrombopag 100 mg (n = 52) or placebo (n = 23) for 5 days before and after chemotherapy was started. The primary endpoint was prechemotherapy (Day 1) platelet count across ≤6 cycles. Prechemotherapy platelet counts were numerically higher with eltrombopag than placebo. Frequencies of grades 3/4 thrombocytopenia were lower with eltrombopag in both the combination therapy (77 vs. 100%) and monotherapy (36 vs. 42%) groups. Proportionately fewer eltrombopag-treated patients had platelet counts <100 × 109/L at nadir. Among patients receiving combination chemotherapy, mean time to recovery from platelet nadir was 8 days with eltrombopag vs. 15 days with placebo. Eltrombopag-treated patients had fewer dose delays/reductions or missed doses due to thrombocytopenia in both the combination therapy (77 vs. 91%) and monotherapy (62 vs. 83%) groups. Adverse events and serious adverse events were less frequent with eltrombopag in both chemotherapy groups, with reduced rates of anemia, neutropenia, and thrombocytopenia in patients receiving combination chemotherapy. In conclusion, eltrombopag treatment shortened the time to recovery from platelet nadir in patients treated with gemcitabine-based chemotherapy and reduced dose delays/reductions due to thrombocytopenia.

Keywords

Blood platelets Cancer chemotherapy drugs Eltrombopag Thrombocytopenia Gemcitabine 

Notes

Acknowledgements

Funding for this study (NCT01147809 available from https://clinicaltrials.gov/ct2/show/NCT01147809) was provided by GlaxoSmithKline; however, as of March 2, 2015, eltrombopag is an asset of Novartis AG. We thank Vassilios Aslanis, PharmD, of Novartis Pharmaceuticals Corporation, for his critical review of the manuscript and the pharmacology data. We also thank the patients and principal investigators and their institutions for their contributions to the study. All listed authors meet the criteria for authorship set forth by the International Committee for Medical Journal Editors. Editorial support (assembling tables and figures, collating author comments, copyediting, fact checking, and referencing) and graphic services were provided by Elizabeth Rosenberg, PhD, and Nancy E. Price, PhD, of AOI Communications, L.P., and were funded by Novartis Pharmaceuticals Corporation.

Compliance with ethical standards

Conflict of interest

EW, HS, BK, and SD have nothing to disclose. SB has provided consultancy for Blueprint Medicine, Novartis, and Pfizer. DK received honoraria from and provided consultancy for Incyte, Pfizer, and Pharmacyclics. PB held stock in and was an employee of GSK during the time of the study conduct and is now an employee of Novartis Pharma AG. SK was an employee of Novartis Pharmaceuticals Corporation and holds stock in Novartis. YMK was an employee of GlaxoSmithKline (GSK) during the time of study conduct and Novartis Pharmaceuticals Corporation, held GSK stock, and received travel accommodations and expenses from GSK. FF has received research funding from GSK.

References

  1. 1.
    Kuter DJ. Managing thrombocytopenia associated with cancer chemotherapy. Oncology. 2015;29:282–94.PubMedGoogle Scholar
  2. 2.
    Wu Y, Aravind S, Ranganathan G, Martin A, Nalysnyk L. Anemia and thrombocytopenia in patients undergoing chemotherapy for solid tumors: a descriptive study of a large outpatient oncology practice database, 2000–2007. Clin Ther. 2009;31:2416–32.CrossRefPubMedGoogle Scholar
  3. 3.
    Cairo MS. Dose reductions and delays: limitations of myelosuppressive chemotherapy. Oncology. 2000;14:21–31.PubMedGoogle Scholar
  4. 4.
    Choi JH, Oh SY, Kwon HC, Kim JH, Lee JH, Lee S, et al. Gemcitabine versus gemcitabine combined with cisplatin treatment locally advanced or metastatic pancreatic cancer: a retrospective analysis. Cancer Res Treat. 2008;40:22–6.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Poplin E, Feng Y, Berlin J, Rothenberg ML, Hochster H, Mitchell E, et al. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009;27:3778–85.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Gemzar [package insert]. Indianapolis: Eli Lilly & Co; 2014.Google Scholar
  7. 7.
    Sederholm C, Hillerdal G, Lamberg K, Kölbeck K, Dufmats M, Westberg R, et al. Phase III trial of gemcitabine plus carboplatin versus single-agent gemcitabine in the treatment of locally advanced or metastatic non-small-cell lung cancer: the Swedish Lung Cancer Study Group. J Clin Oncol. 2005;23:8380–8.CrossRefPubMedGoogle Scholar
  8. 8.
    Steward WP. Combination studies with gemcitabine in the treatment of non-small-cell lung cancer. Br J Cancer. 1998;78:15–9.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Tay SK, Ilanchadran A, Tan TY. First-line gemcitabine and carboplatin in advanced ovarian carcinoma: a phase II study. BJOG. 2006;113:1388–92.CrossRefPubMedGoogle Scholar
  10. 10.
    Zatloukal P, Petruzelka L, Zemanova M, Kolek V, Skricková J, Pesek M, et al. Gemcitabine plus cisplatin vs. gemcitabine plus carboplatin in stage IIIb and IV non-small cell lung cancer: a phase III randomized trial. Lung Cancer. 2003;41:321–31.CrossRefPubMedGoogle Scholar
  11. 11.
    Paraplatin [package insert]. Princeton: Bristol-Myers Squibb; 2004.Google Scholar
  12. 12.
    Cheng G, Saleh MN, Marcher C, Vasey S, Mayer B, Aivado M, et al. Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study. Lancet. 2011;377:393–402.CrossRefPubMedGoogle Scholar
  13. 13.
    Bussel JB, de Miguel PG, Despotovic JM, Grainger JD, Sevilla J, Blanchette VS, et al. Eltrombopag for the treatment of children with persistent and chronic immune thrombocytopenia (PETIT): a randomised, multicentre, placebo-controlled study. Lancet Haematol. 2015;2:e315–25.CrossRefPubMedGoogle Scholar
  14. 14.
    Grainger JD, Locatelli F, Chotsampancharoen T, Donyush E, Pongtanakul B, Komvilaisak P, et al. Eltrombopag for children with chronic immune thrombocytopenia (PETIT2): a randomised, multicentre, placebo-controlled trial. Lancet. 2015;386:1649–58.CrossRefPubMedGoogle Scholar
  15. 15.
    Afdhal NH, Giannini EG, Tayyab G, Mohsin A, Lee JW, Andriulli A, et al. Eltrombopag before procedures in patients with cirrhosis and thrombocytopenia. N Engl J Med. 2012;367:716–24.CrossRefPubMedGoogle Scholar
  16. 16.
    Afdhal NH, Dusheiko GM, Giannini EG, Chen PJ, Han KH, Mohsin A, et al. Eltrombopag increases platelet numbers in thrombocytopenic patients with HCV infection and cirrhosis, allowing for effective antiviral therapy. Gastroenterol. 2014;146:442–52.e1.CrossRefGoogle Scholar
  17. 17.
    Olnes MJ, Scheinberg P, Calvo KR, Desmond R, Tang Y, Dumitriu B, et al. Eltrombopag and improved hematopoiesis in refractory aplastic anemia. N Engl J Med. 2012;367:11–9.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Desmond R, Townsley DM, Dumitriu B, Olnes MJ, Scheinberg P, Bevans M, et al. Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug. Blood. 2014;123:1818–25.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    PROMACTA (eltrombopag) tablets for oral use [package insert]. East Hanover: Novartis; 2015.Google Scholar
  20. 20.
    Winer ES, Safran H, Karaszewska B, Richards DA, Hartner L, Forget F, et al. Eltrombopag with gemcitabine-based chemotherapy in patients with advanced solid tumors: a randomized phase I study. Cancer Med. 2015;4:16–26.CrossRefPubMedGoogle Scholar
  21. 21.
    Kellum A, Jagiello-Gruszfeld A, Bondarenko IN, Patwardhan R, Messam C, Mostafa Kamel Y, et al. A randomized, double-blind, placebo-controlled, dose ranging study to assess the efficacy and safety of eltrombopag in patients receiving carboplatin/paclitaxel for advanced solid tumors. Curr Med Res Opin. 2010;26:2339–46.CrossRefPubMedGoogle Scholar
  22. 22.
    Elting LS, Rubenstein EB, Martin CG, Kurtin D, Rodriguez S, Laiho E, et al. Incidence, cost, and outcomes of bleeding and chemotherapy dose modification among solid tumor patients with chemotherapy-induced thrombocytopenia. J Clin Oncol. 2001;19:1137–46.CrossRefPubMedGoogle Scholar
  23. 23.
    Natale R, Charu V, Schütte W, Albert I, Tehenes S, McCoy J, et al. Safety of romiplostim for treatment of chemotherapy-induced thrombocytopenia (CIT) in patients with advanced non-small cell lung cancer (NSCLC). EJC Suppl. 2009;7:574 (Abstract P9248).CrossRefGoogle Scholar
  24. 24.
    Platzbecker U, Wong RS, Verma A, Abboud C, Araujo S, Chiou T, et al. Safety and tolerability of eltrombopag versus placebo for treatment of thrombocytopenia in patients with advanced myelodysplastic syndromes or acute myeloid leukaemia: a multicentre, randomised, placebo-controlled, double-blind, phase 1/2 trial. Lancet Haematol. 2015;2:e417–26.CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2017

Authors and Affiliations

  • Eric S. Winer
    • 1
  • Howard Safran
    • 2
  • Boguslawa Karaszewska
    • 3
  • Sebastian Bauer
    • 4
  • Dilawar Khan
    • 5
  • Steffen Doerfel
    • 6
  • Paul Burgess
    • 7
  • Stacey Kalambakas
    • 8
  • Yasser Mostafa Kamel
    • 8
  • Frederic Forget
    • 9
  1. 1.Dana Farber Cancer InstituteBostonUSA
  2. 2.Brown University Oncology Research GroupProvidenceUSA
  3. 3.Komed Branch Medical CenterKoninPoland
  4. 4.Department of Medical OncologyUniversity Hospital Essen, University of Duisburg-EssenEssenGermany
  5. 5.Harbin ClinicRomeUSA
  6. 6.Onkozentrum DresdenDresdenGermany
  7. 7.Novartis Pharma AGBaselSwitzerland
  8. 8.Novartis Pharmaceuticals CorporationEast HanoverUSA
  9. 9.Center Hospital of the ArdenneLibramontBelgium

Personalised recommendations