A Phase I Dose-Escalation Study of Sibrotuzumab in Patients with Advanced or Metastatic Fibroblast Activation Protein-positive Cancer

Purpose: 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). Exp...

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Bibliographic Details
Published in:	Clinical cancer research Vol. 9; no. 5; pp. 1639 - 1647
Main Authors:	SCOTT, Andrew M, WISEMAN, Greg, LARSON, Steven M, INGLE, James N, HOFFMAN, Eric W, TANSWELL, Paul, RITTER, Gerd, COHEN, Leonard S, BETTE, Peter, ARVAY, Lisa, AMELSBERG, Andree, VLOCK, Dan, WELT, Sydney, RETTIG, Wolfgang J, OLD, Lloyd J, ADJEI, Alex, LEE, Fook-Thean, HOPKINS, Wendie, DIVGI, Chaitan R, HANSON, Lorelei H, MITCHELL, Paul, GANSEN, Denise N
Format:	Journal Article
Language:	English
Published:	Philadelphia, PA American Association for Cancer Research 01-05-2003
Subjects:	Adult Aged Aged, 80 and over Antibodies, Monoclonal - adverse effects Antibodies, Monoclonal - pharmacokinetics Antibodies, Monoclonal - therapeutic use Antibodies, Monoclonal, Humanized Antigens, Neoplasm - immunology Antigens, Neoplasm - metabolism Antineoplastic agents Biological and medical sciences Biomarkers, Tumor - immunology Biomarkers, Tumor - metabolism Carcinoma, Non-Small-Cell Lung - blood Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - secondary Colorectal Neoplasms - blood Colorectal Neoplasms - drug therapy Colorectal Neoplasms - secondary Dose-Response Relationship, Drug Female Follow-Up Studies Gelatinases Humans Immunotherapy Infusions, Intravenous Iodine Radioisotopes Lung Neoplasms - blood Lung Neoplasms - drug therapy Lung Neoplasms - secondary Male Maximum Tolerated Dose Medical sciences Membrane Proteins Middle Aged Pharmacology. Drug treatments Radioimmunotherapy Serine Endopeptidases - immunology Serine Endopeptidases - metabolism Treatment Outcome Antineoplastic agent Human Immune response Toxicity Monoclonal antibody Malignant tumor Sibrotuzumab Treatment Immunotherapy Phase I trial Advanced stage Metastatic Pharmacokinetics Fibroblast
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Summary:	Purpose: 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). Experimental Design: 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. Conclusion: Repeat infusions of the humanized anti-FAP antibody sibrotuzumab can be administered safely to patients with advanced FAP-positive cancer.
ISSN:	1078-0432 1557-3265