Advertisement

Phase 1b trial of nintedanib in combination with bevacizumab in patients with advanced solid tumors

  • Ravi Paluri
  • Ankit Madan
  • Peng Li
  • Benjamin Jones
  • Mansoor Saleh
  • Mary Jerome
  • Deborah Miley
  • Jennifer Keef
  • Francisco Robert
Original Article

Abstract

Purpose

Vascular endothelial growth factor (VEGF) inhibitors have produced demonstrable but limited benefit for various cancers. One mechanism of resistance includes revascularization, secondary to upregulation of alternative pro-angiogenic platelet-derived growth factor receptor and fibroblast growth factor receptor pathways. Nintedanib is an oral, triple kinase inhibitor that blocks these pathways and may improve anti-tumor activity by overcoming resistance to anti-VEGF therapies. The primary objective of this first in-human study was to evaluate the safety and tolerability of nintedanib in combination with bevacizumab.

Methods

Patients were treated with escalating doses of nintedanib (150 mg or 200 mg oral twice daily) and bevacizumab (15 mg/kg once intravenously every 3 weeks) until disease progression or unacceptable toxicity using standard 3 + 3 phase 1 design. Plasma levels of angiogenic biomarkers were correlated with clinical outcomes.

Results

Eighteen patients with advanced tumors [lung (n = 9), colon (n = 8), and cervical (n = 1)] previously treated with at least two lines of chemotherapy including bevacizumab (n = 9, 50%) were enrolled. The highest dose of nintedanib was 200 mg twice a day with no observed dose-limiting toxicities (DLT). Common adverse events (AE) were fatigue (grade 1–3) and diarrhea (grade 1–2). Durable clinical response was observed in 55% patients pretreated with bevacizumab (1 complete and 4 stable response). Better disease control was correlated with higher than median baseline values for VEFGR2 and E-selectin, and lower levels for SDF-1α.

Conclusion

Nintedanib was well-tolerated with bevacizumab with no DLT. Significant clinical activity was observed, including in bevacizumab-pretreated patients, suggesting nintedanib can overcome bevacizumab resistance.

Keywords

Nintedanib Bevacizumab Metastasis Solid tumors Vascular endothelial growth factors 

Notes

Acknowledgements

The authors thank the patients and their caregivers, in addition to the research nurses, study coordinators, and operations staff who contributed to this study.

Author contributions

Conception, design and methodology: FR, AM, BJ, RP. Acquisition of data: MJ, JK, DM, RP. Writing, review, and/or revision of the manuscript: RP, FR, MS. Study enrollment and supervision: FR, RP. Analysis and interpretation of data: PL, RP.

Funding

The study was supported by Cancer Center core grant (CA 13148) and partially by Boehringer Ingelheim. This study was registered at ClinicalTrials.gov (NCT02835833).The funding sources provided financial resources only with no involvement in the study design, data collection, analysis and interpretation of data, and in the decision to submit the article for publication.

Compliance with ethical standards

Conflict of interest

Dr. Francisco Robert: He is a member of speaker bureau for Boehringer Ingelheim. He is not involved with any of the drugs in this clinical study. No affiliations with or involvement in any organization or entity with any financial interest. All the authors declare that they have no potential conflicts of interest.

References

  1. 1.
    Ferrara N (2004) Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 25(4):581–611.  https://doi.org/10.1210/er.2003-0027 CrossRefPubMedGoogle Scholar
  2. 2.
    Erber R, Thurnher A, Katsen AD, Groth G, Kerger H, Hammes H-P et al (2004) Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J 18(2):338–340.  https://doi.org/10.1096/fj.03-0271fje CrossRefPubMedGoogle Scholar
  3. 3.
    Presta M, Dell’Era P, Mitola S, Moroni E, Ronca R, Rusnati M (2005) Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis. Cytokine Growth Factor Rev 16(2):159–178.  https://doi.org/10.1016/j.cytogfr.2005.01.004 CrossRefPubMedGoogle Scholar
  4. 4.
    Bergers G, Hanahan D (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8(8):592–603.  https://doi.org/10.1038/nrc2442 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Bottsford-Miller JN, Coleman RL, Sood AK (2012) Resistance and escape from antiangiogenesis therapy: clinical implications and future strategies. J Clin Oncol 30(32):4026–4034.  https://doi.org/10.1200/jco.2012.41.9242 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Kutluk Cenik B, Ostapoff KT, Gerber DE, Brekken RA (2013) BIBF 1120 (nintedanib), a triple angiokinase inhibitor, induces hypoxia but not EMT and blocks progression of preclinical models of lung and pancreatic cancer. Mol Cancer Ther 12(6):992–1001.  https://doi.org/10.1158/1535-7163.mct-12-0995 CrossRefPubMedGoogle Scholar
  7. 7.
    Hilberg F, Roth GJ, Krssak M, Kautschitsch S, Sommergruber W, Tontsch-Grunt U et al (2008) BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res 68(12):4774–4782.  https://doi.org/10.1158/0008-5472.can-07-6307 CrossRefPubMedGoogle Scholar
  8. 8.
    Stopfer P, Rathgen K, Bischoff D, Lüdtke S, Marzin K, Kaiser R et al (2011) Pharmacokinetics and metabolism of BIBF 1120 after oral dosing to healthy male volunteers. Xenobiotica 41(4):297–311.  https://doi.org/10.3109/00498254.2010.545452 CrossRefPubMedGoogle Scholar
  9. 9.
    Mross K, Stefanic M, Gmehling D, Frost A, Baas F, Unger C et al (2009) Phase I study of the angiogenesis inhibitor BIBF 1120 in patients with advanced solid tumors. Clin Cancer Res 16(1):311–319.  https://doi.org/10.1158/1078-0432.ccr-09-0694 CrossRefPubMedGoogle Scholar
  10. 10.
    Reck M, Kaiser R, Mellemgaard A, Douillard J-Y, Orlov S, Krzakowski M et al (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.  https://doi.org/10.1016/s1470-2045(13)70586-2 CrossRefPubMedGoogle Scholar
  11. 11.
    Lenz H-J, Yoshino T, Argiles G, Iveson T, Sastre J, Harrison M et al (2017) Nintedanib (N) plus best supportive care (BSC) versus placebo (P) plus BSC for the treatment of patients (pts) with colorectal cancer (CRC) refractory to standard therapies: subanalysis of the phase III LUME-colon 1 study in pts by prior regorafenib (R) treatment. J Clin Oncol 35(4_suppl):660–660.  https://doi.org/10.1200/jco.2017.35.4_suppl.660 CrossRefGoogle Scholar
  12. 12.
    Cheng A-L, Yen C-J, Kim T-Y, Feng Y-H, Chao Y, Lin D-Y et al (2015) Efficacy and safety of nintedanib versus sorafenib in Asian patients with advanced hepatocellular carcinoma (HCC): a randomized phase II trial. J Clin Oncol 33(3_suppl):339–339.  https://doi.org/10.1200/jco.2015.33.3_suppl.339 CrossRefGoogle Scholar
  13. 13.
    Van Cutsem E, Prenen H, Guillen-Ponce C, Bennouna J, Di Benedetto M, Bouche O et al (2011) A phase l/lI, open-label, randomised study of BIBF 1120 plus mFOLFOX6 compared to bevacizumab plus mFOLFOX6 in patients with metastatic colorectal cancer. Eur J Cancer 47:8–9.  https://doi.org/10.1016/s0959-8049(11)70113-7 CrossRefGoogle Scholar
  14. 14.
    Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350(23):2335–2342.  https://doi.org/10.1056/nejmoa032691 CrossRefPubMedGoogle Scholar
  15. 15.
    Saltz LB, Clarke S, Diaz-Rubio E et al (2008) Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 26(12):2013–2019.  https://doi.org/10.1200/jco.2007.14.9930 CrossRefPubMedGoogle Scholar
  16. 16.
    Giantonio BJ, Catalano PJ, Meropol NJ, O’Dwyer PJ, Mitchell EP, Alberts SR et al (2007) Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the eastern cooperative oncology group study E3200. J Clin Oncol 25(12):1539–1544.  https://doi.org/10.1200/jco.2006.09.6305 CrossRefPubMedGoogle Scholar
  17. 17.
    Mross K, Stefanic M, Gmehling D, Frost A, Baas F, Unger C et al (2010) Phase I study of the angiogenesis inhibitor BIBF 1120 in patients with advanced solid tumors. Clin Cancer Res Off J Am Assoc Cancer Res 16(1):311–319.  https://doi.org/10.1158/1078-0432.ccr-09-0694 (e-pub ahead of print 2009/12/24) CrossRefGoogle Scholar
  18. 18.
    Hanna NH, Kaiser R, Sullivan RN, Aren OR, Ahn M-J, Tiangco B et al (2016) Nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with relapsed or refractory, advanced non-small cell lung cancer (LUME-Lung 2): a randomized, double-blind, phase III trial. Lung Cancer 102:65–73.  https://doi.org/10.1016/j.lungcan.2016.10.011 CrossRefPubMedGoogle Scholar
  19. 19.
    Ledermann JA, Hackshaw A, Kaye S, Jayson G, Gabra H, McNeish I et al (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.  https://doi.org/10.1200/jco.2010.33.5208 CrossRefPubMedGoogle Scholar
  20. 20.
    Fernando NT, Koch M, Rothrock C, Gollogly LK, D’Amore PA, Ryeom S et al (2008) Tumor escape from endogenous, extracellular matrix-associated angiogenesis inhibitors by up-regulation of multiple proangiogenic factors. Clin Cancer Res 14(5):1529–1539.  https://doi.org/10.1158/1078-0432.ccr-07-4126 CrossRefPubMedGoogle Scholar
  21. 21.
    Kopetz S, Hoff PM, Morris JS, Wolff RA, Eng C, Glover KY et al (2010) Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistance. J Clin Oncol 28(3):453–459.  https://doi.org/10.1200/jco.2009.24.8252 CrossRefPubMedGoogle Scholar
  22. 22.
    Okamoto I, Kaneda H, Satoh T, Okamoto W, Miyazaki M, Morinaga R et al (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.  https://doi.org/10.1158/1535-7163.mct-10-0379 CrossRefPubMedGoogle Scholar
  23. 23.
    Jones BS, Jerome MS, Miley D, Jackson BE, DeShazo MR, Reddy VVB et al (2017) Pilot phase II study of metronomic chemotherapy in combination with bevacizumab in patients with advanced non-squamous non-small cell lung cancer. Lung Cancer 106:125–130.  https://doi.org/10.1016/j.lungcan.2017.02.004 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Tran HT, Liu Y, Zurita AJ, Lin Y, Baker-Neblett KL, Martin A-M et al (2012) Prognostic or predictive plasma cytokines and angiogenic factors for patients treated with pazopanib for metastatic renal-cell cancer: a retrospective analysis of phase 2 and phase 3 trials. Lancet Oncol 13(8):827–837.  https://doi.org/10.1016/s1470-2045(12)70241-3 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Ravi Paluri
    • 1
  • Ankit Madan
    • 1
  • Peng Li
    • 1
  • Benjamin Jones
    • 1
  • Mansoor Saleh
    • 1
  • Mary Jerome
    • 1
  • Deborah Miley
    • 1
  • Jennifer Keef
    • 1
  • Francisco Robert
    • 1
  1. 1.University of Alabama at Birmingham, Comprehensive Cancer CenterBirminghamUSA

Personalised recommendations