Advertisement

Investigational New Drugs

, Volume 30, Issue 3, pp 1065–1073 | Cite as

Phase 1 study of the novel vascular disrupting agent plinabulin (NPI-2358) and docetaxel

  • Michael Millward
  • Paul Mainwaring
  • Alain Mita
  • Kristine Federico
  • G. K. Lloyd
  • Natasha Reddinger
  • Steffan Nawrocki
  • Monica Mita
  • Matthew A. Spear
PHASE I STUDIES

Summary

Background Plinabulin (NPI-2358) is a vascular disrupting agent (VDA) that destabilizes tumor vascular endothelial cell architecture resulting in selective collapse of established tumor vasculature producing anti-tumor activity alone or in combination with cytotoxic agents. The objective of this study was to assess the recommended Phase 2 dose (RP2D) of plinabulin combined with docetaxel. Patients and Methods Patients received 75 mg/m2 docetaxel on day 1 and plinabulin on days 1 and 8 intravenously in 21 day cycles. Plinabulin was escalated from the biologically effective dose (BED) of 13.5 mg/m2 to the standard single agent dose of 30 mg/m2 using a “3+3” design. Results Thirteen patients were enrolled. Adverse events were consistent with those of both agents alone. Fatigue, pain, nausea, diarrhea and vomiting were the most common events. One dose limiting toxicity of nausea, vomiting, dehydration and neutropenia occurred. The RP2D was 30 mg/m2 of plinabulin with 75 mg/m2 docetaxel. Pharmacokinetics did not indicate drug-drug interactions. Of the 8 patients with NSCLC evaluable for response, 2 achieved a partial response and 4 demonstrated lesser decreases in tumor measurements. Conclusions The combination of full doses of plinabulin and docetaxel is tolerable. With encouraging antitumor activity, this supported further development of this combination.

Keywords

Angiogenesis Docetaxel Non-small cell lung cancer (NSCLC) Vascular disrupting agent (VDA) Vascular targeting 

Notes

Acknowledgements

We also acknowledge others instrumental in the preparation of this data and manuscript: Lada Keenan, Kathy McArthur, Zlatka Iamboliyska

Funding

This study was funded by Nereus Pharmaceuticals, Inc.

Disclosures

The following authors declare a conflict of interest on the basis that they are full-time employees of Nereus Pharmaceuticals: MAS, KCF, GKL, NR. The following authors have received meeting travel reimbursement: MM, PM, ACM, MMM. The following authors have received honoraria: MM, PM, MMM. The following authors are or have conducted research sponsored by Nereus Pharmaceuticals: MM (this and/or other clinical trials), PM (this and/or other clinical trials), ACM (this and/or other clinical trials), MMM (this and/or other clinical trials), SN (laboratory studies on plinabulin).

References

  1. 1.
    Denekamp J (1982) Endothelial cell proliferation as a novel approach to targeting tumour therapy. Br J Cancer 45:136–9PubMedCrossRefGoogle Scholar
  2. 2.
    Denekamp J (1991) The current status of targeting tumour vasculature as a means of cancer therapy: an overview. Int J Radiat Biol 60:401–8PubMedCrossRefGoogle Scholar
  3. 3.
    Kakolyris S, Fox SB, Koukourakis M et al (2000) Relationship of vascular maturation in breast cancer blood vessels to vascular density and metastasis, assessed by expression of a novel basement membrane component, LH39. Br J Cancer 85:844–51CrossRefGoogle Scholar
  4. 4.
    Escudier B, Eisen T, Stadler WM et al (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356:125–134PubMedCrossRefGoogle Scholar
  5. 5.
    Motzer RJ, Hutson TE, Tomczak P et al (2007) Sunitinib versus Interferon Alfa in metastatic renal cellcarcinoma. N Engl J Med 356:115–124PubMedCrossRefGoogle Scholar
  6. 6.
    Sandler A, Gray R, Perry MC et al (2006) Paclitaxel–Carboplatin alone or with bevacizumab for non-small cell lung cancer. N Engl J Med 355:2542–2550PubMedCrossRefGoogle Scholar
  7. 7.
    Hurwitz H, Fehrenbacher L, Novotny W et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–42PubMedCrossRefGoogle Scholar
  8. 8.
    Ramaswamy B, Elias AD, Kelbick NT et al (2006) Phase II trial of bevacizumab in combination with weekly docetaxel in metastatic breast cancer patients. Clin Cancer Res 10:3124–29CrossRefGoogle Scholar
  9. 9.
    Keating GM, Santoro A (2009) Sorafenib: a review of its use in advanced hepatocellular carcinoma. Drugs 69:223–240PubMedCrossRefGoogle Scholar
  10. 10.
    Nathan PD, Judson I, Padhani A et al (2008) A phase I study of combretastatin A4 phosphate (CA4P) and bevacizumab in subjects with advanced solid tumors. J Clin Oncol 26 Suppl. (Abstr 3550).Google Scholar
  11. 11.
    Siemann DW, Shi W (2008) Dual targeting of tumor vasculature: combining Avastin and vascular disrupting agents (CA4P or OXi4503). Anticancer Res 28:2027–31PubMedGoogle Scholar
  12. 12.
    Shi W, Siemann DW (2005) Targeting the tumor vasculature: enhancing antitumor efficacy through combination treatment with ZD6126 and ZD6474. In Vivo 19:1045–50PubMedGoogle Scholar
  13. 13.
    A Study to Assess the Effectiveness of the Combination of Carboplatin, Paclitaxel, Bevacizumab and Combretastatin (CA4P) in Patients With Chemotherapy Naïve Lung Cancer. http://www.clinicaltrials.gov/ct2/show/NCT00653939
  14. 14.
    McKeage MJ, Von Pawel J, Reck M et al (2008) Randomised phase II study of ASA404 combined with carboplatin and paclitaxel in previously untreated advanced non-small cell lung cancer. Br J Cancer 99:2006–12PubMedCrossRefGoogle Scholar
  15. 15.
    Rustin GJS, Galbraith SM, Anderson H et al (2003) Phase I clinical trial of weekly combretastatin a4 phosphate: clinical and pharmacokinetic results. J Clin Oncol 21:2815–22PubMedCrossRefGoogle Scholar
  16. 16.
    Beerepoot LV, Radema SA, Witteveen EO et al (2006) Phase I clinical evaluation of weekly administration of the novel vascular- targeting agent, ZD6126, in patients with solid tumors. J Clin Oncol 24:1491–98PubMedCrossRefGoogle Scholar
  17. 17.
    Vamsidhar V, Avinash V, Ramaswamy G (2006) The proportion of patients with metastatic non-small cell lung cancer potentially eligible for treatment with Bevacizumab: a single institutional survey. Journal of Thoracic Oncol 1(5):501CrossRefGoogle Scholar
  18. 18.
    Scagliotti GV, Park K, Patil S et al (2009) Survival without toxicity for cisplatin plus pemetrexed versus cisplatin plus gemcitabine in chemonaïve patients with advanced non-small cell lung cancer: a risk-benefit analysis of a large phase III study. Eur J Cancer 45(13):2298–2303PubMedCrossRefGoogle Scholar
  19. 19.
    Nicholson B, Lloyd GK, Miller BR et al (2006) NPI-2358 is a tubulin-depolymerizing agent: In-vitro evidence for activity as a tumor vascular-disrupting agent. Anticancer Drugs 17:25–31PubMedCrossRefGoogle Scholar
  20. 20.
    Mita M, Spear MA, Yee LK et al (2010) Phase 1 first-in-human trial of the vascular disrupting agent plinabulin (NPI-2358) in patients with solid tumors or lymphomas. Clin Cancer Res 16(23):5892–9PubMedCrossRefGoogle Scholar
  21. 21.
    Lloyd GK, Nicholson B, Neuteboom STC et al (2003) NPI-2358: A new vascular/tubulin modifying agent greatly potentiates standard chemotherapy in xenograft models. EORTC-NCI-AACR Molecular Targets and Therapeutics Meeting, Boston, MAGoogle Scholar
  22. 22.
    Neuteboom STC, Medina E, Palladino MA et al (2008) NPI-2358, A novel tumor vascular disrupting agent potentiates the anti-tumor activity of docetaxel in the non small cell lung cancer model MV522. Eur J Cancer 6 Suppl. (Abstr 141).Google Scholar
  23. 23.
    Taxotere (docetaxel) Prescribing Information (2007) Sanofi-AventisGoogle Scholar
  24. 24.
    LoRusso PM, Jones SF, Koch KM et al (2008) Phase I and pharmacokinetic study of lapatinib and docetaxel in patients with advanced cancer. J Clin Oncol 26:3051–6PubMedCrossRefGoogle Scholar
  25. 25.
    Heist R, Aren O, Millward M et al (2009) Phase 1/2 study of the vascular disrupting agent (VDA) plinabulin (NPI-2358) combined with docetaxel in patients with non-small cell lung cancer (NSCLC). Mol Cancer Ther 8 Suppl. (Abstr C30)Google Scholar
  26. 26.
    Shepherd FA, Dancey J, Ramlau R et al (2000) Prospective randomized trial of docetaxel versus best supportive care in patients with non–small cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 18:2095–2103PubMedGoogle Scholar
  27. 27.
    Hanna N, Shepherd FA, Fossella FV et al (2004) Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 22:1589–97PubMedCrossRefGoogle Scholar
  28. 28.
    Phase 1/2 Study of Vascular Disrupting Agent NPI-2358 + Docetaxel in Patients With Advanced Non-Small Cell Lung Cancer. http://www.clinicaltrials.gov/ct2/show/NCT00630110

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Michael Millward
    • 1
  • Paul Mainwaring
    • 2
    • 5
  • Alain Mita
    • 3
  • Kristine Federico
    • 4
  • G. K. Lloyd
    • 4
  • Natasha Reddinger
    • 4
  • Steffan Nawrocki
    • 3
  • Monica Mita
    • 3
  • Matthew A. Spear
    • 4
  1. 1.Department of Medical OncologySir Charles Gairdner Hospital & University of Western AustraliaPerthAustralia
  2. 2.Division of Cancer ServicesMater HospitalBrisbaneAustralia
  3. 3.Cancer Therapy and Research CenterInstitute for Drug DevelopmentSan AntonioUSA
  4. 4.Nereus Pharmaceuticals, IncSan DiegoUSA
  5. 5.Haematology and Oncology Clinics of AustraliaBrisbaneAustralia

Personalised recommendations