Phase I trial of combretastatin A4 phosphate (CA4P) in combination with bevacizumab in patients with advanced cancer.
OBJECTIVE
The vascular disrupting agent (VDA) combretastatin A4 phosphate (CA4P) induces significant tumor necrosis as a single agent. Preclinical models have shown that the addition of an anti-VEGF antibody to a VDA attenuates the revascularization of the surviving tumor rim and thus significantly increases antitumor activity.


METHODS
Patients with advanced solid malignancies received CA4P at 45, 54, or 63 mg/m(2) on day 1, day 8, and then every 14 days. Bevacizumab 10 mg/kg was given on day 8 and at subsequent cycles four hours after CA4P. Functional imaging with dynamic contrast enhanced-MRI (DCE-MRI) was conducted at baseline, after CA4P alone, and after cycle 1 CA4P + bevacizumab.


RESULTS
A total of 63 mg/m(2) CA4P + 10 mg/kg bevacizumab q14 is the recommended phase II dose. A total of 15 patients were enrolled. Dose-limiting toxicities were grade III asymptomatic atrial fibrillation and grade IV liver hemorrhage in a patient with a history of hemorrhage. Most common toxicities were hypertension, headache, lymphopenia, pruritus, and pyrexia. Asymptomatic electrocardiographic changes were seen in five patients. Nine of 14 patients experienced disease stabilization. A patient with ovarian cancer had a CA125 response lasting for more than a year. DCE-MRI showed statistically significant reductions in tumor perfusion/vascular permeability, which reversed after CA4P alone but which were sustained following bevacizumab. Circulating CD34(+) and CD133(+) bone marrow progenitors increased following CA4P as did VEGF and granulocyte colony-stimulating factor levels.


CONCLUSIONS
CA4P in combination with bevacizumab appears safe and well tolerated in this dosing schedule. CA4P induced profound vascular changes, which were maintained by the presence of bevacizumab.
Mount Vernon Cancer Centre; Paul Strickland Scanner Centre, Northwood, Middlesex, United Kingdom. p.nathan@nhs.net
Paul
P
Nathan
Martin
M
Zweifel
Anwar R
AR
Padhani
Dow-Mu
DM
Koh
Matthew
M
Ng
David J
DJ
Collins
Adrian
A
Harris
Craig
C
Carden
Jon
J
Smythe
Nita
N
Fisher
N Jane
NJ
Taylor
J James
JJ
Stirling
Shiao-Ping
SP
Lu
Martin O
MO
Leach
Gordon J S
GJ
Rustin
Ian
I
Judson
D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D013267:Stilbenes / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
D061067:Antibodies, Monoclonal, Humanized; D013267:Stilbenes; D000068258:Bevacizumab; C058728:fosbretabulin