Blockade of platelet-derived growth factor receptor-beta by CDP860, a humanized, PEGylated di-Fab', leads to fluid accumulation and is associated with increased tumor vascularized volume.
OBJECTIVE
CDP860 is an engineered Fab' fragment-polyethylene glycol conjugate, which binds to and blocks the activity of the beta-subunit of the platelet-derived growth factor receptor (PDGFR-beta). Studies in animals have suggested that PDGFR-beta inhibition reduces tumor interstitial fluid pressure, and thus increases the uptake of concomitantly administered drugs. The purpose of this study was to determine whether changes in tumor vascular parameters could be detected in humans, and to assess whether CDP860 would be likely to increase the uptake of a concurrently administered small molecule in future studies.


METHODS
Patients with advanced ovarian or colorectal cancer and good performance status received intravenous infusions of CDP860 on days 0 and 28. Patients had serial dynamic contrast-enhanced magnetic resonance imaging studies to measure changes in tumor vascular parameters.


RESULTS
Three of eight patients developed significant ascites, and seven of eight showed evidence of fluid retention. In some patients, the ratio of vascular volume to total tumor volume increased significantly (P < .001) within 24 hours following CDP860 administration, an effect suggestive of recruitment of previously non-functioning vessels.


CONCLUSIONS
These observations suggest that inhibition of PDGFR-beta might improve delivery of a concurrently administered therapy. However, in cancer patients, further exploration of the dosing regimen of CDP860 is required to dissociate adverse effects from beneficial effects. The findings challenge the view that inhibition of PDGF alone is beneficial, and confirm that effects of PDGFR kinase inhibition mediate, to some extent, the fluid retention observed in patients treated with mixed tyrosine kinase inhibitors.
Cancer Research UK, Department of Medical Oncology, Christie Hospital, Manchester M20 4BX, United Kingdom. Gordon.Jayson@christie-tr.nwest.nhs.uk
G C
GC
Jayson
G J M
GJ
Parker
S
S
Mullamitha
J W
JW
Valle
M
M
Saunders
L
L
Broughton
J
J
Lawrance
B
B
Carrington
C
C
Roberts
B
B
Issa
D L
DL
Buckley
S
S
Cheung
K
K
Davies
Y
Y
Watson
K
K
Zinkewich-Péotti
L
L
Rolfe
A
A
Jackson
D000328:Adult; D000368:Aged; D001201:Ascites / Q000209:etiology; D002199:Capillary Permeability / Q000502:physiology; D003110:Colonic Neoplasms / Q000098:blood supply*; D003287:Contrast Media; D045604:Extracellular Fluid / Q000378:metabolism*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007091:Image Processing, Computer-Assisted / Q000379:methods; D007140:Immunoglobulin Fab Fragments / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000098:blood supply*; D010996:Pleural Effusion / Q000209:etiology; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors*; D012004:Rectal Neoplasms / Q000098:blood supply*; D012039:Regional Blood Flow / Q000502:physiology; D047368:Tumor Burden
C497445:CDP860; D003287:Contrast Media; D007140:Immunoglobulin Fab Fragments; D011092:Polyethylene Glycols; D020797:Receptor, Platelet-Derived Growth Factor beta