Safety of First in Human Intraperitoneal Alpha Radioimmunotherapy with ²¹²Pb-TCMC-trastuzumab

Objectives To determine the long term safety of salvage intra-peritoneal (IP) ²¹²Pb-TCMC-trastuzumab in patients with HER-2 expressing malignancy.

Methods ²¹²Pb-TCMC-trastuzumab was delivered IP <4h after 4mg/kg IV trastuzumab. Toxicity monitoring was done for 1 year. Monitoring included clinical findings, laboratory values, cardiac studies and immunologic assays^.

Results Sixteen patients at five dose levels (7.4, 9.6, 12.6, 16.3, 21.1 MBq/m²⁾ were monitored up to for 1 year (10-11mo for. #14,#15) or until death. There were no clinical signs or symptoms of an immune response, and assays to detect an immune response to ²¹²Pb-TCMC-trastuzumab were negative for all 13 of 16 tested (no sample for 3 patients). Most adverse events were related to disease or medications other than the ²¹²Pb-TCMC-trastuzumab. Patients tolerated therapy at 7-21 MBq/m² with minimal, asymptomatic laboratory abnormality (transient Grade 1 in 5/16 patients). Whereas hematologic toxicity has been dose-limiting in prior IP radionuclide conjugate studies, the mean platelet counts, total white blood cell counts and neutrophil counts remained normal after a mean equivalent dose to marrow of 0.006cGy/MBq. Only 2 patients had a transient decreased counts to Grade 1(Platelets 142,000/µL, WBC 3500/ µL without neutropenia). No late cardiac, liver or renal toxicity was found.

Conclusions Five dose levels of IP ²¹²Pb-TCMC-trastuzumab appear safe for patients with peritoneal carcinomatosis who have failed standard therapies. Monitoring up to 1 year showed minimal, transient toxicity within 6 weeks and no late toxicity.

Research Support AREVA Med, and NIH 1UL1RR025777-01