A Phase I dose-escalation study of sibrotuzumab in patients with advanced or metastatic fibroblast activation protein-positive cancer.
OBJECTIVE
The purpose of this research was to determine the safety, immunogenicity, pharmacokinetics, biodistribution, and tumor uptake of repeat infusions of a complementarity-determining region grafted humanized antibody (sibrotuzumab) directed against human fibroblast activation protein (FAP).


METHODS
A Phase I open-label dose escalation study was conducted in patients with cancers epidemiologically known to be FAP positive. Patients were entered into one of four dosage tiers of 5, 10, 25, or 50 mg/m(2) sibrotuzumab, administered weekly for 12 weeks, with trace labeling with 8-10 mCi of (131)I in weeks 1, 5, and 9.


RESULTS
A total of 26 patients were entered into the trial (15 males and 11 females; mean age, 59.9 years; age range, 41-81 years). Twenty patients had colorectal carcinoma, and 6 patients had non-small cell lung cancer. A total of 218 infusions of sibrotuzumab were administered during the first 12 weeks of the study, with 24 patients being evaluable. One patient received an additional 96 infusions on continued-use phase for a total of 108 infusions over a 2-year period, and 1 patient received an additional 6 infusions on continued use. There were no objective tumor responses. Only one episode of dose-limiting toxicity was observed. Therefore, a maximum tolerated dose was not reached. Treatment-related adverse events were observed in 6 patients during the infusional monitoring period. Four of the 6 patients, 3 of whom had associated positive serum human antihuman antibody, were removed from the study because of clinical immune responses. Gamma camera images of [(131)I]sibrotuzumab demonstrated no normal organ uptake of sibrotuzumab, with tumor uptake evident within 24-48 h after infusion. Analysis of pharmacokinetics demonstrated a similar mean terminal t(1/2) of 1.4-2.6 days at the 5, 10, and 25 mg/m(2) dose levels, and with a longer mean t(1/2) of 4.9 days at the 50 mg/m(2) dose level.


CONCLUSIONS
Repeat infusions of the humanized anti-FAP antibody sibrotuzumab can be administered safely to patients with advanced FAP-positive cancer.
Ludwig Institute for Cancer Research, Melbourne Tumour Biology, Austin, and Repatriation Medical Centre, 3084 Australia. ams@austin.unimelb.edu.au
Andrew M
AM
Scott
Greg
G
Wiseman
Sydney
S
Welt
Alex
A
Adjei
Fook-Thean
FT
Lee
Wendie
W
Hopkins
Chaitan R
CR
Divgi
Lorelei H
LH
Hanson
Paul
P
Mitchell
Denise N
DN
Gansen
Steven M
SM
Larson
James N
JN
Ingle
Eric W
EW
Hoffman
Paul
P
Tanswell
Gerd
G
Ritter
Leonard S
LS
Cohen
Peter
P
Bette
Lisa
L
Arvay
Andree
A
Amelsberg
Dan
D
Vlock
Wolfgang J
WJ
Rettig
Lloyd J
LJ
Old
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000276:immunology / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000188:drug therapy / Q000556:secondary; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000556:secondary; D004305:Dose-Response Relationship, Drug; D010450:Endopeptidases; D005260:Female; D005500:Follow-Up Studies; D018093:Gelatinases; D006801:Humans; D007262:Infusions, Intravenous; D007457:Iodine Radioisotopes; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy / Q000556:secondary; D008297:Male; D020714:Maximum Tolerated Dose; D008565:Membrane Proteins; D008875:Middle Aged; D016499:Radioimmunotherapy; D012697:Serine Endopeptidases / Q000276:immunology / Q000378:metabolism*; D016896:Treatment Outcome; D000099167:Fibroblast Activation Protein Alpha
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D010450:Endopeptidases; D018093:Gelatinases; D007457:Iodine Radioisotopes; D008565:Membrane Proteins; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha; C476229:sibrotuzumab