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Published on: February 12, 2017
Phase 1 first-in-human trial of the vascular disrupting agent plinabulin(NPI-2358) in patients with solid tumors or
Monica M Mita1, Matthew A Spear, Lorrin K Yee
1Institute for Drug Development, San Antonio, Texas, USA.
Purpose:
Plinabulin (NPI-2358) is a vascular disrupting agent that elicits tumor vascular endothelial architectural destabilization leading to selective collapse of established tumor vasculature. Preclinical data indicated plinabulin has favorable safety and antitumor activity profiles, leading to initiation of this clinical trial to determine the recommended phase 2 dose (RP2D) and assess the safety, pharmacokinetics, and biologic activity of plinabulin in patients with advanced malignancies.
Experimental Design:
Patients received a weekly infusion of plinabulin for 3 of every 4 weeks. A dynamic accelerated dose titration method was used to escalate the dose from 2 mg/m² to the RP2D, followed by enrollment of an RP2D cohort. Safety, pharmacokinetic, and cardiovascular assessments were conducted, and Dynamic contrast-enhanced MRI (DCE-MRI) scans were performed to estimate changes in tumor blood flow.
Results:
Thirty-eight patients were enrolled. A dose of 30 mg/m² was selected as the RP2D based on the adverse events of nausea, vomiting, fatigue, fever, tumor pain, and transient blood pressure elevations, with DCE-MRI indicating decreases in tumor blood flow (Ktrans) from 13.5 mg/m² (defining a biologically effective dose) with a 16% to 82% decrease in patients evaluated at 30 mg/m². Half-life was 6.06 ± 3.03 hours, clearance was 30.50 ± 22.88 L/h, and distributive volume was 211 ± 67.9 L.
Conclusions:
At the RP2D of 30 mg/m², plinabulin showed a favorable safety profile, while eliciting biological effects as evidenced by decreases in tumor blood flow, tumor pain, and other mechanistically relevant adverse events. On the basis of these results additional clinical trials were initiated with plinabulin in combination with standard chemotherapy agents.
Insights
Plinabulin effectively reduced tumor blood flow and showed a good safety profile in patients with advanced cancers. Further trials are ongoing to combine it with chemotherapy.
Area of Science:
- Oncology
- Pharmacology
- Radiology
Background:
- Plinabulin (NPI-2358) is a vascular disrupting agent targeting tumor vasculature.
- Preclinical studies suggested favorable safety and antitumor activity.
Purpose of the Study:
- Determine the recommended phase 2 dose (RP2D) of plinabulin.
- Assess safety, pharmacokinetics, and biologic activity in advanced malignancies.
Main Methods:
- Weekly plinabulin infusions over 3 of 4 weeks.
- Dynamic accelerated dose titration to identify RP2D.
- Safety, pharmacokinetic, and DCE-MRI assessments.
Main Results:
- 30 mg/m² selected as RP2D due to manageable adverse events.
- DCE-MRI showed decreased tumor blood flow (Ktrans) from 13.5 mg/m².
- Pharmacokinetics: half-life 6.06 hrs, clearance 30.50 L/h, volume 211 L.
Conclusions:
- Plinabulin at 30 mg/m² demonstrated a favorable safety profile.
- Biological effects, including reduced tumor blood flow and pain, were observed.
- Clinical trials combining plinabulin with chemotherapy were initiated.
