A phase I radioimmunotherapy trial evaluating (90)yttrium-labeled anti-carcinoembryonic antigen (CEA) chimeric T84,66 in patients with metastatic CEA-producing malignancies

Chimeric T84.66 (cT84.66) is a genetically engineered human/murine chimeric IgG(1) with high affinity and specificity to carcinoembryonic antigen (CEA ), The purpose of this Phase I dose escalation therapy trial was to evaluat e the toxicities, biodistribution, pharmacokinetics, tumor targeting, immun ogenicity, and organ and tumor absorbed dose estimates of cT84.66 labeled w ith Y-90, Patients with metastatic CEA-producing malignancies were first ad ministered 5 mCi In-111-labeled DTPA-cT84.66 (5 mg), followed by administra tion of the therapy dose of Y-90-labeled DTPA-cT84.66 1 week later, The the rapy infusion was immediately followed by a 72-h administration of DTPA at 250 mg/m(2)/24 h, Dose levels of administered activity ranged from 5 to 22 mCi/m(2) with three to six patients per level. Serial nuclear scans, blood samples, and 24-h urine collections were performed out to 5 days after infu sion. Human antichimeric antibody response was assayed out to 6 months, Pat ients were administered up to 3 cycles of therapy every 6 weeks. Radiation absorbed doses to organs were estimated using a five compartment model and MIRDOSE3, Twenty-two patients received at least one cycle of therapy, with one individual receiving two cycles and two receiving three cycles of thera py, All mere heavily pretreated and had progressive disease prior to entry in this trial. Reversible leukopenia and thrombocytopenia were the primary dose-limiting toxicities observed. Maximum tolerated dose was reached at 22 mCi/m(2). In general, patients with liver metastases demonstrated more rap id blood clearance of the antibody. Thirteen patients developed an immune r esponse to the antibody. Average radiation doses to marrow, liver, and whol e body were 2.6, 29, and 1.9 cGy/mCi Y-90, respectively. Dose estimates to tumor ranged from 66 to 1670 cGy (8.7 to 52.2 cGy/mCi Y-90) for each cycle of therapy delivered. Although no major responses were observed, three pati ents demonstrated stable disease of 12-28 weeks duration and two demonstrat ed a mixed response. In addition, a 41-100% reduction in tumor size was obs erved with five tumor lesions. Y-90-labeled cT84,66 was well tolerated, wit h reversible thrombocytopenia and leukopenia being dose limiting. Patients with extensive hepatic involvement by tumor demonstrated unfavorable biodis tribution for therapy with rapid blood clearance and poor tumor targeting. Average tumor doses when compared with red marrow doses indicated a favorab le therapeutic ratio. Stable disease and mixed responses were observed in t his heavily pretreated population with progressive disease. This trial repr esents an important step toward further improving the therapeutic potential of this agent through refinements in the characteristics of the antibody a nd the treatment strategies used. Future trials will focus on the use of pe ripheral stem cell support to allow for higher administered activities and the use of combined modality strategies with radiation-enhancing chemothera py drugs. Further efforts to reduce immunogenicity through humanization of the antibody are also planned. Finally, novel engineered, lower molecular w eight, faster clearing constructs derived from cT84,66 continue to be evalu ated in preclinical models as potential agents for radioimmunotherapy.