Targeting, toxicity, and efficacy of 2-step, pretargeted radioimmunotherapy using a chimeric bispecific antibody and 131I-labeled bivalent hapten in a phase I optimization clinical trial

Safety, targeting, and antitumor efficacy of pretargeted radioimmunotherapy using anti-carcinoembryonic antigen (CEA) hMN-14 x m734 bispecific antibody (BsmAb) and I-131-di-diethylenetriamine pentaacetic acid (DTPA)-indium hapten were evaluated in a phase I study performed on patients with CEA-expressing tumors. Methods: Twenty-two patients with nonmedullary thyroid carcinoma (non-MTC) (group I, 13 patients) or medullary thyroid carcinoma (MTC) (group II, 9 patients) were enrolled. These patients received a 75 mg/m(2) (11 patients) or 40 mg/m(2) (11 patients) dose of BsmAb and escalating activities of I-131-di-DTPA-indium 5 d later. Toxicity and tumor response were assessed in 20 patients who received a therapeutic (>2.2 GBq) hapten dose of radioactivity. Results: The percentage of lesions detected by immunoscintigraphy after injection of the therapeutic dose of hapten was 70% on an anatomic-site basis. High bone uptake was relatively frequent. A transient grade I or II hepatic toxicity was observed in 5 patients (45%) injected with 75 mg/m(2) of BsmAb and in 1 patient (11%) injected with 40 mg/m(2). No other nonhematologic toxicity was observed. With 75 mg/m(2) of BsmAb, hematologic toxicity was high: 5 cases of grade III or IV leukopenia (45%) and 5 cases of grade III or IV thrombopenia (45%). With a 40 mg/m(2) dose of BsmAb, hematologic toxicity was reduced significantly: 3 cases of grade III or IV leukopenia (33%) and 1 case of grade III or IV thrombopenia (11%) (P = 0.02). Toxicity was significantly higher in MTC patients than in non-MTC patients (P = 0.019). Nine cases of tumor stabilization of 3 mo to more than 12 mo were observed (45%), 6 in the MTC group and 3 in the non-MTC group. The rate of disease stabilization was significantly higher with 75 mg/m(2) of BsmAb (64%) than with 40 mg/m(2) (22%) (P = 0.04). Human antimouse antibody elevation was observed in 1 patient (8%) and human antihuman antibody in 4 (33%). Conclusion: A BsmAb dose of 40 mg/m(2) and a 5-d interval appeared to be a better dose/schedule regimen, with acceptable toxicity. Under these conditions, the maximal tolerated activity was 3 GBq of I-131-di-DTPA-indium in MTC patients. In non-MTC patients, dose escalation should continue.