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A Phase I Dose-Escalation Study of Sibrotuzumab in Patients with Advanced or Metastatic Fibroblast Activation Protein-positive Cancer¹

Ludwig Institute for Cancer Research, Melbourne Tumour Biology Austin, and Repatriation Medical Centre, Melbourne, 3084 Australia [A. M. S., F-T. L., W. H., P. M.]; Mayo Clinic, Rochester, Minnesota 55905 [G. W., A. Ad., L., H. H., D. N. G., J. N. I.]; Memorial Sloan Kettering Cancer Center, New York, New York 10021 [S. W., C. R. D., S. M. L.]; Ludwig Institute for Cancer Research, New York, New York 10158 [S. W., E. W. H., G. R., L. S. C., L. J. O.]; Boehringer Ingelheim Pharma KG, Biberach, 88397 Germany [P. T., P. B., W. J. R.]; and Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut 06877-0368 [L. A., A. Am., D. V.]

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 t_1/2 of 1.4–2.6 days at the 5, 10, and 25 mg/m² dose levels, and with a longer mean t_1/2 of 4.9 days at the 50 mg/m² dose level.

Conclusion: Repeat infusions of the humanized anti-FAP antibody sibrotuzumab can be administered safely to patients with advanced FAP-positive cancer.

Commentary

Tumors and Their Microenvironments: Tilling the Soil: Commentary re: A. M. Scott et al., A Phase I Dose-Escalation Study of Sibrotuzumab in Patients with Advanced or Metastatic Fibroblast Activation Protein-positive Cancer. Clin. Cancer Res., 9: 1639–1647, 2003.

Jonathan D. Cheng and Louis M. Weiner
Clin. Cancer Res. 2003 9: 1590-1595. [Full Text] [PDF]

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