A phase I pharmacokinetic study of the vascular disrupting agent ombrabulin (AVE8062) and docetaxel in advanced solid tumours

Abstract

Background:The vascular disrupting agent ombrabulin shows synergy with docetaxel in vivo. Recommended phase II doses were determined in a dose escalation study in advanced solid tumours.Methods:Ombrabulin (30-min infusion, day 1) followed by docetaxel (1-h infusion, day 2) every 3 weeks was explored. Ombrabulin was escalated from 11.5 to 42 mg m−2 with 75 mg m−2 docetaxel, then from 30 to 35 mg m−2 with 100 mg m−2 docetaxel. Recommended phase II dose cohorts were expanded.Results:Fifty-eight patients were treated. Recommended phase II doses were 35 mg m−2 ombrabulin with 75 mg m−2 docetaxel (35/75 mg m−2; 13 patients) and 30 mg m−2 ombrabulin with 100 mg m−2 docetaxel (30/100 mg m−2; 16 patients). Dose-limiting toxicities were grade 3 fatigue (two patients; 42/75, 35/100), grade 3 neutropaenic infection (25/75), grade 3 headache (42/75), grade 4 febrile neutropaenia (30/100), and grade 3 thrombosis (35/100). Toxicities were consistent with each agent; mild nausea/vomiting, asthaenia/fatigue, alopecia, and anaemia were common, as were neutropaenia and leukopaenia. Diarrhoea, nail disorders and neurological symptoms were frequent at 100 mg m−2 docetaxel. Pharmacokinetic analyses did not show any relevant drug interactions. Ten patients had partial responses (seven at 30 mg m−2 ombrabulin), eight lasting >3 months.Conclusions:Sequential administration of ombrabulin with 75 or 100 mg m−2 docetaxel every 3 weeks is feasible.

Coadministration of Vascular Disrupting Agents and Nanomedicines to Eradicate Tumors from Peripheral and Central Regions

“…VDAs have been extensively studied in combination therapy of cancer treatment. [31][32][33][34] In particular, Sengupta et al [ 35 ] reported a nanoscale codelivery system of combretastatin A4 (CA4) and doxorubicin for tumor therapy. The system enabled focal sequential release of CA4 and doxorubicin within a solid tumor, and resulted in improved therapeutic index with reduced toxicity.…”

Starvation tactics using natural compounds for advanced cancers: pharmacodynamics, clinical efficacy, and predictive biomarkers

“…In this trial, ombrabulin was well tolerated with limited cardiovascular side effects. Furthermore, in three additional phase I trials, ombrabulin has recently shown manageable and comparable overlapping toxicities to those observed in previous safety/pharmacokinetic studies . Von Pawel et al.…”

“…In this trial, ombrabulin was well tolerated with limited cardiovascular side effects. Furthermore, in three additional phase I trials, ombrabulin has recently shown manageable and comparable overlapping toxicities to those observed in previous safety/pharmacokinetic studies [122][123][124]. Von Pawel et al [125] randomized 176 patients with metastatic NSCLC in a phase II trial (DISRUPT) to receive ombrabulin (n = 88, 35 mg/m 2 ) or placebo (n = 88) followed by taxane-platinum doublet q3 wk as first-line therapy.…”

Phase I and pharmacokinetic study of the vascular‐disrupting agent CKD‐516 (NOV120401) in patients with refractory solid tumors

“…Vascular‐disrupting agents (VDAs) are a relatively new class of drugs that act on the established tumor vasculature, causing hypoxia and necrosis of the tumor mass . Tubulin colchicine binding site inhibitor VDAs have been most extensively tested in clinical trials . Common toxicities of these agents include nausea, diarrhea, tumor pain, and hypertension .…”

“…Tubulin colchicine binding site inhibitor VDAs have been most extensively tested in clinical trials . Common toxicities of these agents include nausea, diarrhea, tumor pain, and hypertension . CKD‐516 (NOV120401), developed by Chong Kun Dang (Seoul, Korea), is a VDA prodrug that is rapidly converted into the active moiety, S‐516 .…”