Phase I trial of CYT997, a novel cytotoxic and vascular-disrupting agent.
BACKGROUND
CYT997 is a novel microtubule inhibitor and vascular-disrupting agent with marked preclinical anti-tumour activity.


METHODS
This phase I dose-escalation study assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of CYT997 administered by continuous intravenous infusion over 24 h every 3 weeks to patients with advanced solid tumours.


RESULTS
Thirty-one patients received CYT997 over 12 dose levels (7-358 mg m(-2)). Doses up to 202 mg m(-2) were well tolerated. Dose-limiting toxicities were observed at 269 and 358 mg m(-2), consisting of grade 3 prolonged corrected QT interval in two patients and grade 3 hypoxia and grade 4 dyspnea in one patient. All toxicities were reversible. The pharmacokinetics of CYT997 were linear over the entire dose range. Dynamic contrast-enhanced magnetic resonance imaging scans showed significant changes in tumour K(trans) values consistent with vascular disruption in 7 out of 11 evaluable patients treated at CYT997 doses of >or=65 mg m(-2). Moreover, plasma levels of von Willebrand factor and caspase-cleaved cytokeratin-18 increased post-treatment at higher dose levels. Among 22 patients evaluable for response, 18 achieved stable disease for >2 cycles.


CONCLUSIONS
CYT997 was well tolerated at doses that were associated with pharmacodynamic evidence of vascular disruption in tumours.
Lickliter
J D
JD
Department of Medical Oncology, Royal Brisbane and Women's Hospital, Herston 4029, Queensland, Australia. jason.lickliter@med.monash.edu.au
Francesconi
A B
AB
Smith
G
G
Burge
M
M
Coulthard
A
A
Rose
S
S
Griffin
M
M
Milne
R
R
McCarron
J
J
Yeadon
T
T
Wilks
A
A
Cubitt
A
A
Wyld
D K
DK
Vasey
P A
PA
D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002452:Cell Count; D042783:Endothelial Cells; D005260:Female; D006801:Humans; D053538:Keratin-18 / Q000032:analysis; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D014841:von Willebrand Factor / Q000032:analysis / Q000276:immunology
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; C543949:CYT997; D053538:Keratin-18; D011725:Pyridines; D011743:Pyrimidines; C029417:Von Willebrand antigen; D014841:von Willebrand Factor