Phase 1 first-in-human trial of the vascular disrupting agent plinabulin(NPI-2358) in patients with solid tumors or lymphomas.
OBJECTIVE
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.


METHODS
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.
Institute for Drug Development, San Antonio, Texas, USA.
Monica M
MM
Mita
Matthew A
MA
Spear
Lorrin K
LK
Yee
Alain C
AC
Mita
Elisabeth I
EI
Heath
Kyriakos P
KP
Papadopoulos
Kristine C
KC
Federico
Steven D
SD
Reich
Ofelia
O
Romero
Lisa
L
Malburg
MaryJo
M
Pilat
G Kenneth
GK
Lloyd
Saskia T C
ST
Neuteboom
Gillian
G
Cropp
Edward
E
Ashton
Patricia M
PM
LoRusso
D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D054659:Diketopiperazines; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006207:Half-Life; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007262:Infusions, Intravenous; D008223:Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010865:Pilot Projects; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
D020533:Angiogenesis Inhibitors; D054659:Diketopiperazines; D007093:Imidazoles; C514351:NPI 2358; D010879:Piperazines