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Published on: February 12, 2017
Phase 1 study of the novel vascular disrupting agent plinabulin (NPI-2358) and docetaxel
Michael Millward1, Paul Mainwaring, Alain Mita
1Department of Medical Oncology, Sir Charles Gairdner Hospital & University of Western Australia, Perth, Australia.
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/m(2) 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/m(2) to the standard single agent dose of 30 mg/m(2) 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/m(2) of plinabulin with 75 mg/m(2) 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.
Insights
The combination of plinabulin and docetaxel is tolerable and shows promising anti-tumor activity. The recommended Phase 2 dose (RP2D) was determined for further clinical trials.
Area of Science:
- Oncology
- Pharmacology
Background:
- Plinabulin (NPI-2358) is a vascular disrupting agent (VDA) targeting tumor vasculature.
- VDAs can be used alone or with chemotherapy for anti-tumor effects.
Purpose of the Study:
- To determine the recommended Phase 2 dose (RP2D) of plinabulin when combined with docetaxel.
- To assess the safety and tolerability of this combination therapy.
Main Methods:
- A "3+3" dose escalation design was used.
- Patients received escalating doses of plinabulin with a fixed dose of docetaxel (75 mg/m²).
- Dosing occurred over 21-day cycles with plinabulin administered on days 1 and 8.
Main Results:
- The recommended Phase 2 dose (RP2D) was established as 30 mg/m² of plinabulin with 75 mg/m² of docetaxel.
- Adverse events were consistent with known side effects of each agent.
- Of 8 evaluable non-small cell lung cancer (NSCLC) patients, 2 had partial responses and 4 showed tumor shrinkage.
Conclusions:
- The combination of plinabulin and docetaxel at full doses is tolerable.
- Encouraging anti-tumor activity supports further investigation of this combination therapy.
