| Abstract: |
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/m2 sibrotuzumab, administered weekly for 12 weeks, with trace labeling with 8-10 mCi of 131I 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 [131I]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 t1/2 of 1.4-2.6 days at the 5, 10, and 25 mg/m2 dose levels, and with a longer mean t1/2 of 4.9 days at the 50 mg/m2 dose level. Conclusion: Repeat infusions of the humanized antiFAP antibody sibrotuzumab can be administered safely to patients with advanced FAP-positive cancer. |
| Keywords: |
adult; clinical article; treatment outcome; aged; aged, 80 and over; middle aged; unclassified drug; clinical trial; advanced cancer; area under the curve; dose response; drug safety; hypertension; cancer radiotherapy; follow-up studies; anorexia; colorectal cancer; metastasis; lung non small cell cancer; carcinoma, non-small-cell lung; lung neoplasms; tumor markers, biological; cell protein; dose-response relationship, drug; enzyme linked immunosorbent assay; backache; coughing; dyspnea; fever; flushing; hypoxia; colorectal neoplasms; antibodies, monoclonal; rigor; antigens, neoplasm; serine endopeptidases; iodine 131; drug distribution; drug uptake; isotope labeling; iodine radioisotopes; multicenter study; immunogenicity; drug clearance; open study; maximum tolerated dose; phase 1 clinical trial; drug half life; radioimmunotherapy; infusions, intravenous; antibody; fibroblast activation protein; scintillation camera; complementarity determining region; sibrotuzumab; humans; human; male; female; priority journal; article
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