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

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1065-1073
Number of pages9
JournalInvestigational New Drugs
Volume30
Issue number3
DOIs
StatePublished - Jun 1 2012

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

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