Dose escalation of first in human alpha radioimmunotherapy with 212Pb-TCMC-trastuzumab

Objectives To study toxicity, biodistribution, and pharmacokinetics of intra-peritoneal (IP) 212Pb-TCMC-trastuzumab in patients with HER-2 expressing malignancy. This phase I trial provides IP therapy for patients with peritoneal carcinomatosis who have failed standard therapies.

Methods 212Pb-TCMC-trastuzumab was delivered IP <4h after 4mg/kg IV trastuzumab.

Results Four dose levels (7.4, 9.6, 12.6, 16.3 MBq/m2) have shown minimal toxicity at >1 year for 1st group & >2-10 mo for others. Imaging and pharmacokinetics in the 1st cohort (n=3) showed little redistribution of radioactivity out of the peritoneal cavity, no significant uptake in major organs and serum levels <1-23% injected dose of antibody conjugate by 63 hours based on decay corrected values. Non-decay corrected cumulative urinary excretion was <6% in 24h (2.3 half lives). A similar range of serum levels has been observed at 2 and 24h measures in all patients. External radiation dose-rate measurements over the abdomen dropped to 13+/- 4% by 24 h. The 24h data points correlate closely with 212Pb physical decay (T1/2 =10.6 h) but are slightly less when not corrected for urinary loss. Similar loss was noted at 3 other body sites, where the percent of activity was proportional to the distance from the abdomen. Patients tolerated therapy at 7-16 MBq/m2 with minimal, asymptomatic laboratory abnormality (transient Grade 1 in 5/13 patients) and no late cardiac, liver or renal toxicity > 2-12 mo.

Conclusions Four dose levels of IP 212Pb-TCMC-trastuzumab treatment of patients with peritoneal carcinomatosis showed minimal distribution outside the peritoneal cavity and good tolerance with minimal related toxicity.

Research Support AREVA Med, NIH 1UL1RR025777-01