Advertisement

Investigational New Drugs

, Volume 29, Issue 5, pp 978–983 | Cite as

A phase I evaluation of the combination of vinflunine and erlotinib in patients with refractory solid tumors

  • Hanna K. Sanoff
  • Janine M. Davies
  • Christine Walko
  • William Irvin
  • Larry Buie
  • Kimberly Keller
  • Anastasia Ivanova
  • Wing-Keung Chiu
  • Bert H. O’Neil
  • Thomas E. Stinchcombe
  • E. Claire Dees
PHASE I STUDIES

Summary

Purpose. Epidermal growth factor receptor (EGFR) inhibition may overcome chemotherapy resistance by inhibiting important anti-apoptotic signals that are constitutively activated by an overstimulated EGFR pathway. Methods. This phase I dose escalation trial assessed the safety and efficacy of vinflunine, a novel vinca alkaloid microtubule inhibitor, with erlotinib, an EGFR tyrosine kinase inhibitor, in patients with refractory solid tumors. Results. Seventeen patients were treated, 10 with continuous erlotinib, and 7 with intermittent erlotinib. At dose level 1, vinflunine 280 mg/m2 IV day 1 and erlotinib 75 mg PO days 2–21 (“continuous erlotinib”) in 21 day cycles, two of four patients experienced DLTs. At dose level −1 (vinflunine 250 mg/m2 every 21 days and erlotinib 75 mg/day), two of six patients experienced DLTs. The study was amended to enroll to “intermittent erlotinib” dosing: vinflunine day 1 and erlotinib days 2–15 of a 21 day cycle. Two of seven experienced DLTs and the study was terminated. One patient with breast cancer had a partial response; three had stable disease ≥6 cycles. All were treated in the continuous erlotinib group. Conclusions. Given the marked toxicity in our patient population, the combination of vinflunine and erlotinib cannot be recommended for further study with these dosing schemas.

Keywords

Influnine Erlotinib Phase I Safety and toxicity 

Notes

Funding

This work was supported by Bristol-Myers Squibb; Genentech; General Clinical Research Centers Program of Division of Research Resources, National Institutes of Health (RR00046); and K12 (RR025746 to H.K.S.); Alberta Heritage Foundation for Medical Research Clinical Fellowship (JMD); and Canadian Association of Medical Oncology Fellowship (JMD).

References

  1. 1.
    Kruczynski A et al (1998) Preclinical in vivo antitumor activity of vinflunine, a novel fluorinated Vinca alkaloid. Cancer Chemother Pharmacol 41(6):437–447PubMedCrossRefGoogle Scholar
  2. 2.
    Bennouna J et al (2008) Vinflunine: a new microtubule inhibitor agent. Clin Cancer Res 14(6):1625–1632PubMedCrossRefGoogle Scholar
  3. 3.
    Bennouna J et al (2003) Phase I and pharmacokinetic study of the new vinca alkaloid vinflunine administered as a 10-min infusion every 3 weeks in patients with advanced solid tumours. Ann Oncol 14(4):630–637PubMedCrossRefGoogle Scholar
  4. 4.
    Yun-San Yip A, Yuen-Yuen Ong E, Chow LW (2008) Vinflunine: clinical perspectives of an emerging anticancer agent. Expert Opin Investig Drugs 17(4):583–591PubMedCrossRefGoogle Scholar
  5. 5.
    Culine S et al (2006) A phase II study of vinflunine in bladder cancer patients progressing after first-line platinum-containing regimen. Br J Cancer 94(10):1395–1401PubMedCrossRefGoogle Scholar
  6. 6.
    Campone M et al (2006) Vinflunine: a new active drug for second-line treatment of advanced breast cancer. Results of a phase II and pharmacokinetic study in patients progressing after first-line anthracycline/taxane-based chemotherapy. Br J Cancer 95(9):1161–1166PubMedCrossRefGoogle Scholar
  7. 7.
    Krzakowski M et al (2007) Phase III study of vinflunine versus docetaxel in patients (pts) with advanced non-small cell lung cancer (NSCLC) previously treated with a platinum-containing regimen. J Clin Oncol 25(18S): (abstr 7511)Google Scholar
  8. 8.
    Talbot DC et al (2007) Phase II study of vinflunine in malignant pleural mesothelioma. J Clin Oncol 25(30):4751–4756PubMedCrossRefGoogle Scholar
  9. 9.
    Hanauske AR et al (1994) Effects of the microtubule-disturbing agents docetaxel (Taxotere), vinblastine and vincristine on epidermal growth factor-receptor binding of human breast cancer cell lines in vitro. Eur J Cancer 30A(11):1688–1694PubMedCrossRefGoogle Scholar
  10. 10.
    Depenbrock H et al (1995) Effects of vinorelbine on epidermal growth factor-receptor binding of human breast cancer cell lines in vitro. Invest New Drugs 13(3):187–193PubMedCrossRefGoogle Scholar
  11. 11.
    Cunningham D et al (2004) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351(4):337–345PubMedCrossRefGoogle Scholar
  12. 12.
    Huang SM, Harari PM (1999) Epidermal growth factor receptor inhibition in cancer therapy: biology, rationale and preliminary clinical results. Invest New Drugs 17(3):259–269PubMedCrossRefGoogle Scholar
  13. 13.
    Genentech (OSI) Oncology (2004) FDA package insert Tarceva (erlotinib). November 18Google Scholar
  14. 14.
    Burstein HJ et al (2003) Trastuzumab and vinorelbine as first-line therapy for HER2-overexpressing metastatic breast cancer: multicenter phase II trial with clinical outcomes, analysis of serum tumor markers as predictive factors, and cardiac surveillance algorithm. J Clin Oncol 21(15):2889–2895PubMedCrossRefGoogle Scholar
  15. 15.
    Mahaffey C et al (2007) Schedule-dependent apoptosis in K-ras mutant non-small-cell lung cancer cell lines treated with docetaxel and erlotinib: rationale for pharmacodynamic separation. Clin Lung Cancer 8(9):548–553PubMedCrossRefGoogle Scholar
  16. 16.
    Solit DB et al (2005) Pulsatile administration of the epidermal growth factor receptor inhibitor gefitinib is significantly more effective than continuous dosing for sensitizing tumors to paclitaxel. Clin Cancer Res 11(5):1983–1989PubMedCrossRefGoogle Scholar
  17. 17.
    Davies AM et al (2006) Pharmacodynamic separation of epidermal growth factor receptor tyrosine kinase inhibitors and chemotherapy in non-small-cell lung cancer. Clin Lung Cancer 7(6):385–388PubMedCrossRefGoogle Scholar
  18. 18.
    Cancer Therapy Evaluation Program (2006) Common terminology criteria for adverse events, version 3.0, DCTD, NCI, NIH, DHHS. 2003 March 13 (http://ctep.cancer.gov), Publish Date: August 9
  19. 19.
    Therasse P et al (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):205–216PubMedCrossRefGoogle Scholar
  20. 20.
    Hirth J et al (2000) The effect of an individual's cytochrome CYP3A4 activity on docetaxel clearance. Clin Cancer Res 6(4):1255–1258PubMedGoogle Scholar
  21. 21.
    Kanazawa H et al (2004) Determination of midazolam and its metabolite as a probe for cytochrome P450 3A4 phenotype by liquid chromatography-mass spectrometry. J Chromatogr A 1031:213–218PubMedCrossRefGoogle Scholar
  22. 22.
    Pujol JL et al (2006) Gefitinib (IRESSA) with vinorelbine or vinorelbine/cisplatin for chemotherapy-naive non-small cell lung cancer patients. J Thorac Oncol 1(5):417–424PubMedCrossRefGoogle Scholar
  23. 23.
    Chen YM et al (2007) Phase II randomized study of daily gefitinib treatment alone or with vinorelbine every 2 weeks in patients with adenocarcinoma of the lung who failed at least 2 regimens of chemotherapy. Cancer 109(9):1821–1828PubMedCrossRefGoogle Scholar
  24. 24.
    Bellmunt J et al (2009) Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J Clin OncolGoogle Scholar
  25. 25.
    Shah U et al (2008) A phase I trial of pemetrexed and vinflunine (VFL). J Clin Oncol 26(May 20 suppl; abstr 13508)Google Scholar
  26. 26.
    Stinchcombe TE et al (2008) Preliminary safety and efficacy data of a phase II trial of vinflunine and cetuximab in the second-line treatment of patients with advanced non-small cell lung cancer. J Clin Oncol 26(May 20 suppl; abstr 19100)Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Hanna K. Sanoff
    • 1
    • 2
  • Janine M. Davies
    • 1
    • 2
  • Christine Walko
    • 2
    • 3
  • William Irvin
    • 1
    • 2
  • Larry Buie
    • 4
  • Kimberly Keller
    • 2
  • Anastasia Ivanova
    • 2
  • Wing-Keung Chiu
    • 2
  • Bert H. O’Neil
    • 1
    • 2
  • Thomas E. Stinchcombe
    • 1
    • 2
  • E. Claire Dees
    • 1
    • 2
  1. 1.Department of Medicine, Division of Hematology-Oncology, School of MedicineUniversity of North Carolina at Chapel HillChapel HillUSA
  2. 2.Lineberger Comprehensive Cancer CenterChapel HillUSA
  3. 3.School of PharmacyUniversity of North Carolina at Chapel HillChapel HillUSA
  4. 4.Department of PharmacyUniversity of North Carolina HospitalsChapel HillUSA

Personalised recommendations