Skip to main content

Advertisement

SpringerLink
Log in

Predictive factors of renal toxicities related to anti-VEGFR multikinase inhibitors in phase 1 trials

  • PHASE I STUDIES
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Summary

Purpose Renal toxicities are common with angiogenesis multikinase inhibitors (AMKI), and can be limiting in phase I trials. Factors associated with such toxicities are poorly known. The aims of this exploratory study were to describe renovascular toxicities associated with AMKI, impact on drug development and to identify baseline parameters associated with the occurrence of renal toxicities in phase I trials. Methods Consecutive patients treated with AMKI in Gustave Roussy phase I unit between October 2005 and August 2013 were included. We retrospectively collected baseline characteristics and renovascular side effects. Associations were assessed in univariate and multivariate analyses. Results Overall, 168 patients were included: male 53.0 %, mean age 55.5 years old, history of hypertension 26.8 %, diabetes 6.0 %, atherosclerosis 13.6 %, stage 3 Chronic Kidney Disease (CKD, NKF-KDOQI) 17.2 %. Incidences of reno-vascular side effects were: hypertension 47.6 %, proteinuria 19.0 %, renal failure 11.9 % and thrombotic microangiopathy 10.1 %. Eighty percent of dose limiting toxicities (DLTs) were related to a renal toxicity. Multivariate analysis showed that onset of renal failure was associated with history of hypertension (p = 0.0003) and stage 3 CKD (p = 0.032). Conclusions A majority of the DLTs associated with AMKI in phase 1 trials are renal toxicities. Baseline hypertension and stage 3 CKD (NKF-KDOQI) might help to better identify patients at risk of AMKI-related renal toxicities.

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

Similar content being viewed by others

References

  1. Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285(21):1182–1186

    Article  CAS  PubMed  Google Scholar 

  2. Folkman J (2002) Role of angiogenesis in tumor growth and metastasis. Semin Oncol 29(6 Suppl 16):15–18

    Article  CAS  PubMed  Google Scholar 

  3. Hicklin DJ, Ellis LM (2005) Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol Off J Am Soc Clin Oncol 23(5):1011–1027

    Article  CAS  Google Scholar 

  4. Ikeda N et al (1999) Prognostic significance of angiogenesis in human pancreatic cancer. Br J Cancer 79(9–10):1553–1563

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Manders P et al (2002) The prognostic value of vascular endothelial growth factor in 574 node-negative breast cancer patients who did not receive adjuvant systemic therapy. Br J Cancer 87(7):772–778

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. George DJ et al (2001) Prognostic significance of plasma vascular endothelial growth factor levels in patients with hormone-refractory prostate cancer treated on Cancer and Leukemia Group B 9480. Clin Cancer Res Off J Am Assoc Cancer Res 7(7):1932–1936

    CAS  Google Scholar 

  7. Fontanini G et al (1997) Angiogenesis as a prognostic indicator of survival in non-small-cell lung carcinoma: a prospective study. J Natl Cancer Inst 89(12):881–886

    Article  CAS  PubMed  Google Scholar 

  8. Gorski DH, Leal AD, Goydos JS (2003) Differential expression of vascular endothelial growth factor-A isoforms at different stages of melanoma progression. J Am Coll Surg 197(3):408–418

    Article  PubMed  Google Scholar 

  9. Jayson GC, Kerbel R, Ellis LM, Harris AL (2016) Antiangiogenic therapy in oncology: current status and future directions. Lancet Lond. Engl

  10. Bair SM, Choueiri TK, Moslehi J (2013) Cardiovascular complications associated with novel angiogenesis inhibitors: emerging evidence and evolving perspectives. Trends Cardiovasc Med 23(4):104–113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Launay-Vacher V et al (2015) Renal effects of molecular targeted therapies in oncology: a review by the Cancer and the Kidney International Network (C-KIN). Ann Oncol Off J Eur Soc Med Oncol ESMO 26(8):1677–1684

    Article  CAS  Google Scholar 

  12. Zhu X, Wu S, Dahut WL, Parikh CR (2007) Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: systematic review and meta-analysis. Am J Kidney Dis Off J Natl Kidney Found 49(2):186–193

    Article  CAS  Google Scholar 

  13. Levy A et al (2012) Reappraisal of treatment-induced renal dysfunction in patients receiving antiangiogenic agents in phase I trials. Invest New Drugs 30(3):1116–1120

    Article  CAS  PubMed  Google Scholar 

  14. Inker LA et al (2014) KDOQI US commentary on the 2012 KDIGO clinical practice guideline for the evaluation and management of CKD. Am J Kidney Dis 63(5):713–735

    Article  PubMed  Google Scholar 

  15. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D (1999) A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 130(6):461–470

    Article  CAS  PubMed  Google Scholar 

  16. Barbour T, Johnson S, Cohney S, Hughes P (2012) Thrombotic microangiopathy and associated renal disorders. Nephrol Dial Transpl Off Publ Eur Dial Transpl Assoc - Eur Ren Assoc 27(7):2673–2685

    CAS  Google Scholar 

  17. Schrijvers BF, Flyvbjerg A, De Vriese AS (2004) The role of vascular endothelial growth factor (VEGF) in renal pathophysiology. Kidney Int 65(6):2003–2017

    Article  CAS  PubMed  Google Scholar 

  18. Eremina V et al (2003) Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J Clin Invest 111(5):707–716

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Eremina V et al (2008) VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med 358(11):1129–1136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Halimi J-M et al (2008) Vascular and renal effects of anti-angiogenic therapy. Néphrol Thér 4(7):602–615

    Article  PubMed  Google Scholar 

Download references

Author contributions

BR, EB, OM designed the study.

BR, EB, OM performed the data collection.

BR performed the statistical analysis.

BR, EB, OM, AH wrote the manuscript.

All authors performed data interpretation and final review of the article.

Author information

Authors and Affiliations

  1. Department of Drug Development (DITEP), Gustave Roussy Institute, 114 Rue Edouard Vaillant, 94805, Villejuif, France

    Emilie Boissier, Olivier Mir, Antoine Hollebecque, Anas Gazzah, Rastislav Bahleda, Christophe Massard & Jean-Charles Soria

  2. Department of Nephrology, Park Monceau International Clinic, 21 Rue de Chazelles, 75017, Paris, France

    Hassan Izzedine

  3. Department of Cardiology, Saint Antoine Teaching Hospital, 184 Rue du Faubourg Saint-Antoine, Assistance Publique – Hôpitaux de Paris, 75012, Paris, France

    Stéphane Ederhy

  4. Clinical Pharmacology, Henri Mondor Teaching Hospital, 51 avenue du Maréchal de Lattre de Tassigny, Assistance Publique – Hôpitaux de Paris, 94000, Créteil, France

    Isabelle Macquin-Mavier & Benoît Rousseau

  5. Faculty of Medicine, University of Paris-Est, 61 Avenue du Général de Gaulle, 94000, Créteil, France

    Christophe Tournigand & Benoît Rousseau

  6. Department of Medical Oncology, Henri Mondor Teaching Hospital, Assistance Publique – Hôpitaux de Paris, 51 avenue du Maréchal de Lattre de Tassigny, 94000, Créteil, France

    Christophe Tournigand & Benoît Rousseau

  7. Department of Medical Oncology, Pitié Salpêtrière Teaching Hospital, 47-83 Boulevard de l’Hôpital, Assistance Publique-Hôpitaux de Paris, 75013, Paris, France

    Jean-Philippe Spano

  8. Faculty of Medicine, Université Pierre et Marie Curie, 91-105 Boulevard de l’Hôpital, 75013, Paris, France

    Jean-Philippe Spano

  9. Faculty of Medicine, Paris Sud University, 63 Rue Gabriel Péri, 94270, Le Kremlin-Bicêtre, France

    Jean-Charles Soria

  10. INSERM U955 Team 18, 8 rue du Général Sarrail, 94010, Créteil Cedex, France

    Benoît Rousseau

  11. Oncologie médicale, CHU Henri Mondor, 51 avenue du Maréchal de Lattre de Tassigny, 94000, Créteil, France

    Benoît Rousseau

Authors
  1. Emilie Boissier
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Olivier Mir
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Antoine Hollebecque
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hassan Izzedine
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Stéphane Ederhy
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Anas Gazzah
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Rastislav Bahleda
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Christophe Massard
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Isabelle Macquin-Mavier
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Christophe Tournigand
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jean-Philippe Spano
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jean-Charles Soria
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Benoît Rousseau
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Benoît Rousseau.

Ethics declarations

Conflict of interest

Emilie Boissier declares that she has no conflict of interest with respect to this manuscript.

Dr. Mir has acted as a consultant for Astra-Zeneca, Amgen, Bayer, BMS, GSK, Roche, Servier, Pfizer, PharmaMar, Novartis.

Antoine Hollebecque declares that he has no conflict of interest with respect to this manuscript.

Hassan Izzedine declares that he has no conflict of interest with respect to this manuscript.

Stéphane Ederhy declares that he has no conflict of interest with respect to this manuscript.

Anas Gazzah declares that he has no conflict of interest with respect to this manuscript.

Rastislav Bahleda declares that he has no conflict of interest with respect to this manuscript.

Christophe Massard has acted as consultant and advisory board for Astellas, Astra Zeneca, Bayer, Celgene, Genentech, Ipsen, Jansen, Lilly, Novartis, Pfizer, Roche, Sanofi, Orion, MedImmune, New Oncology, DebioPharm.

Isabelle Macquin-Mavier declares that he has no conflict of interest with respect to this manuscript.

Christophe Tournigand declares that he has no conflict of interest with respect to this manuscript.

Jean-Philippe Spano declares that he has no conflict of interest with respect to this manuscript.

Jean-Charles Soria declares that he has no conflict of interest with respect to this manuscript.

Benoît Rousseau received travel accommodation from Amgen, Novartis.

Funding

This work did not receive any financial support.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the national research committee and with the 1964 Helsinki declaration and its later amendments.

Human and animals rights and informed consent

This article does not contain any studies with animals performed by any of the authors.

Informed consent

For this type of study, formal consent is not required.

Additional information

Emilie Boissier and Olivier Mir participated equally to the work

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOCX 21 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Boissier, E., Mir, O., Hollebecque, A. et al. Predictive factors of renal toxicities related to anti-VEGFR multikinase inhibitors in phase 1 trials. Invest New Drugs 35, 79–86 (2017). https://doi.org/10.1007/s10637-016-0402-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-016-0402-3

Keywords

Search

Navigation