Skip to main content

Advertisement

Log in

Phase I study of nintedanib in combination with pemetrexed as second-line treatment of Japanese patients with advanced non-small cell lung cancer

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

Abstract

Purpose

This open-label, phase I, dose-escalation part of a phase I/II study evaluated the safety, pharmacokinetics, and preliminary efficacy of nintedanib, a triple angiokinase inhibitor, combined with pemetrexed in Japanese patients with advanced non-small cell lung cancer (NSCLC) after first-line chemotherapy.

Methods

A fixed dose of pemetrexed (500 mg/m2 iv) was administered on Day 1 of each 21-day cycle followed by oral nintedanib twice daily (bid) on days 2–21, starting at 100 mg bid and escalating to 200 mg bid in 50-mg intervals, using a standard 3 + 3 design. After ≥4 cycles of combination therapy, patients could continue nintedanib monotherapy until disease progression or undue adverse events (AEs). Primary endpoints were maximum tolerated dose (MTD), defined as the highest dose at which the incidence of dose-limiting toxicities (DLTs) was <33.3 % during the first treatment course, and AEs (CTCAE v3.0). DLTs were primarily defined as grade ≥3 non-hematologic or grade 4 hematologic AEs.

Results

Eighteen patients were included in the analysis. DLTs were experienced by 2/9 patients receiving 200 mg bid, 1/6 receiving 150 mg bid, and 0/3 receiving the lowest dose. The MTD of nintedanib plus pemetrexed was 200 mg bid. The most common drug-related AEs were elevated liver enzymes and gastrointestinal AEs. Two patients achieved partial response, and 10 had stable disease.

Conclusions

Nintedanib plus pemetrexed had a manageable safety profile and showed promising signs of efficacy in previously treated Japanese patients with advanced NSCLC. As in Caucasian patients, the MTD of nintedanib was 200 mg bid.

Clinical trial information NCT00979576.

This is a preview of subscription content, log in via an institution to check access.

Access this article

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. Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin D, Forman D, Bray F (2013) GLOBOCAN 2012 v1.0, cancer incidence and mortality worldwide: IARC CancerBase No. 11 [Internet]. International Agency for Research on Cancer. http://globocan.iarc.fr. Accessed 4 Dec 2014

  2. Peters S, Adjei AA, Gridelli C, Reck M, Kerr K, Felip E (2012) Metastatic non-small-cell lung cancer (NSCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 23(Suppl 7):vii56–vii64. doi:10.1093/annonc/mds226

    Article  PubMed  Google Scholar 

  3. Kuribayashi K, Tabata C (2014) Cutting-edge medical treatment for advanced non-small cell lung cancer. J Cancer Biol Res 2(1):1026

    Google Scholar 

  4. National Comprehensive Cancer Network (2015) NCCN clinical practice guidelines in oncology. Non-Small Cell Lung Cancer Version 7.2015. http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed 25 June 2015

  5. Reck M, Kaiser R, Mellemgaard A, Douillard JY, Orlov S, Krzakowski M, von Pawel J, Gottfried M, Bondarenko I, Liao M, Gann CN, Barrueco J, Gaschler-Markefski B, Novello S, for the LUME-Lung 1 Study Group (2014) Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol 15(2):143–155. doi:10.1016/S1470-2045(13)70586-2

    Article  CAS  PubMed  Google Scholar 

  6. Qi WX, Wang Q, Jiang YL, Sun YJ, Tang LN, He AN, Min DL, Lin F, Shen Z, Yao Y (2013) Overall survival benefits for combining targeted therapy as second-line treatment for advanced non-small-cell-lung cancer: a meta-analysis of published data. PLoS One 8(2):e55637. doi:10.1371/journal.pone.0055637

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Makrilia N, Lappa T, Xyla V, Nikolaidis I, Syrigos K (2009) The role of angiogenesis in solid tumours: an overview. Eur J Intern Med 20(7):663–671. doi:10.1016/j.ejim.2009.07.009

    Article  CAS  PubMed  Google Scholar 

  8. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355(24):2542–2550. doi:10.1056/NEJMoa061884

    Article  CAS  PubMed  Google Scholar 

  9. Hilberg F, Roth GJ, Krssak M, Kautschitsch S, Sommergruber W, Tontsch-Grunt U, Garin-Chesa P, Bader G, Zoephel A, Quant J, Heckel A, Rettig WJ (2008) BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res 68(12):4774–4782. doi:10.1158/0008-5472.CAN-07-6307

    Article  CAS  PubMed  Google Scholar 

  10. Hilberg F, Brandstetter I (2007) Efficacy of BIBF 1120, a potent triple angiokinase inhibitor, in models of human non- small cell lung cancer is augmented by chemotherapy. J Thorac Oncol 2(8):S320 (Abstract C327-303). http://journals.lww.com/jto/Fulltext/2007/08001/Efficacy_of_BIBF_1120,_a_potent_triple_angiokinase.317.aspx. Accessed 25 June 2015

  11. Mross K, Stefanic M, Gmehling D, Frost A, Baas F, Unger C, Strecker R, Henning J, Gaschler-Markefski B, Stopfer P, de Rossi L, Kaiser R (2010) Phase I study of the angiogenesis inhibitor BIBF 1120 in patients with advanced solid tumors. Clin Cancer Res 16(1):311–319. doi:10.1158/1078-0432.CCR-09-0694

    Article  CAS  PubMed  Google Scholar 

  12. Okamoto I, Kaneda H, Satoh T, Okamoto W, Miyazaki M, Morinaga R, Ueda S, Terashima M, Tsuya A, Sarashina A, Konishi K, Arao T, Nishio K, Kaiser R, Nakagawa K (2010) Phase I safety, pharmacokinetic, and biomarker study of BIBF 1120, an oral triple tyrosine kinase inhibitor in patients with advanced solid tumors. Mol Cancer Ther 9(10):2825–2833. doi:10.1158/1535-7163.MCT-10-0379

    Article  CAS  PubMed  Google Scholar 

  13. Hanna NH, Kaiser R, Sullivan RN, Aren OR, Ahn MJ, Tiangco B, Zvirbule Z, Barrios CH, Demirkazik A, Gaschler-Markefski B, Voccia I, Barrueco J, Kim JH (2013) LUME-Lung 2: A multicenter, randomized, double-blind, phase III study of nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with advanced nonsquamous non-small cell lung cancer (NSCLC) after failure of first-line chemotherapy. J Clin Oncol 31(15 Suppl):Abstract 8034. http://meetinglibrary.asco.org/content/112349-132. Accessed 25 June 2015

  14. Ellis PM, Kaiser R, Zhao Y, Stopfer P, Gyorffy S, Hanna N (2010) Phase I open-label study of continuous treatment with BIBF 1120, a triple angiokinase inhibitor, and pemetrexed in pretreated non-small cell lung cancer patients. Clin Cancer Res 16(10):2881–2889. doi:10.1158/1078-0432.CCR-09-2944

    Article  CAS  PubMed  Google Scholar 

  15. National Cancer Institute (2006) Common Terminology Criteria for Adverse Events v3.0 (CTCAE). http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf. Accessed 20 May 2015

  16. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92(3):205–216. doi:10.1093/jnci/92.3.205

    Article  CAS  PubMed  Google Scholar 

  17. Eli Lilly and Company (2013) Alimta (pemetrexed for injection), prescribing information. http://pi.lilly.com/us/alimta-pi.pdf. Accessed 1 June 2015

  18. Doebele RC, Conkling P, Traynor AM, Otterson GA, Zhao Y, Wind S, Stopfer P, Kaiser R, Camidge DR (2012) A phase I, open-label dose-escalation study of continuous treatment with BIBF 1120 in combination with paclitaxel and carboplatin as first-line treatment in patients with advanced non-small-cell lung cancer. Ann Oncol 23(8):2094–2102. doi:10.1093/annonc/mdr596

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Ledermann JA, Hackshaw A, Kaye S, Jayson G, Gabra H, McNeish I, Earl H, Perren T, Gore M, Persic M, Adams M, James L, Temple G, Merger M, Rustin G (2011) Randomized phase II placebo-controlled trial of maintenance therapy using the oral triple angiokinase inhibitor BIBF 1120 after chemotherapy for relapsed ovarian cancer. J Clin Oncol 29(28):3798–3804. doi:10.1200/jco.2010.33.5208

    Article  CAS  PubMed  Google Scholar 

  20. Reck M, Kaiser R, Eschbach C, Stefanic M, Love J, Gatzemeier U, Stopfer P, von Pawel J (2011) A phase II double-blind study to investigate efficacy and safety of two doses of the triple angiokinase inhibitor BIBF 1120 in patients with relapsed advanced non-small-cell lung cancer. Ann Oncol 22(6):1374–1381. doi:10.1093/annonc/mdq618

    Article  CAS  PubMed  Google Scholar 

  21. Stopfer P, Rathgen K, Bischoff D, Lüdtke S, Marzin K, Kaiser R, Wagner K, Ebner T (2011) Pharmacokinetics and metabolism of BIBF 1120 after oral dosing to healthy male volunteers. Xenobiotica 41(4):297–311. doi:10.3109/00498254.2010.545452

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Aurora O’Brate of inVentiv Medical Communications during the preparation of this manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Haruko Daga.

Ethics declarations

Conflict of interest

K. Yoh has received personal fees from Chugai Pharmaceutical, AstraZeneca, Taiho Pharmaceutical, Eli Lilly and Company, Sanofi, and Boehringer Ingelheim. K. Goto has received grants and personal fees from Boehringer Ingelheim, and Eli Lilly and Company. K. Konishi, A. Sarashina, and R. Kaiser are employees of Boehringer Ingelheim. H. Daga, K. Takeda, H. Okada, M. Miyazaki, S. Ueda, H. Kaneda, I. Okamoto, T. Tanaka, and K. Nakagawa declare no conflict of interest.

Ethical approval

The trial was conducted in compliance with the protocol, the principles laid down in the Declaration of Helsinki, and Good Clinical Practice guidelines. The protocol and all amendments were approved by the local institutional review board. All patients provided written informed consent.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Daga, H., Takeda, K., Okada, H. et al. Phase I study of nintedanib in combination with pemetrexed as second-line treatment of Japanese patients with advanced non-small cell lung cancer. Cancer Chemother Pharmacol 76, 1225–1233 (2015). https://doi.org/10.1007/s00280-015-2896-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-015-2896-3

Keywords

Navigation