Our purpose was to study the safety, distribution, pharmacokinetics, immunogenicity, and tumor response of intraperitoneal 212Pb-TCMC-trastuzumab (TCMC is S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraaza-1,4,7,10-tetra(2-carbamoylmethyl)cyclododecane) in patients with human epidermal growth factor receptor type 2 (HER-2)–expressing malignancy. Methods: In a standard 3 1 3 phase 1 design for dose escalation, 212Pb-TCMC-trastuzumab was delivered intraperitoneally less than 4 h after administration of trastuzumab (4 mg/kg intravenously) to patients with peritoneal carcinomatosis who had failed standard therapies. Results: Five dosage levels (7.4, 9.6, 12.6, 16.3, and 21.1 MBq/m2) showed minimal toxicity at more than 1 y for the first group and more than 4 mo for others. The lack of substantial toxicity was consistent with the dosimetry assessments (mean equivalent dose to marrow, 0.18 mSv/MBq).
Radiation dosimetry assessment was performed using pharmacokinetics data obtained in the initial cohort (n 5 3). Limited redistribution of radioactivity out of the peritoneal cavity to circulating blood, which cleared via urinary excretion, and no specific uptake in major organs were observed in 24 h. Maximum serum concentration of the radiolabeled antibody was 22.9% at 24 h (decay-corrected to injection time) and 500 Bq/mL (decay-corrected to collection time).
Non–decay-corrected cumulative urinary excretion was 6% or less in 24 h (2.3 half-lives). Dose rate measurements performed at 1 m from the patient registered less than 5μSv/h (using portable detectors) in the latest cohort, significantly less than what is normally observed using nuclear medicine imaging agents. Antidrug antibody assays performed on serum from the first 4 cohorts were all negative.
Conclusion: Five dose levels of intraperitoneal 212Pb-TCMC-trastuzumab treatment of patients with peritoneal carcinomatosis showed little agent-related toxicity, consistent with the dosimetry calculations.