title: 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.
abstract: Safety, targeting, and antitumor efficacy of pretargeted radioimmunotherapy using anti-carcinoembryonic antigen (CEA) hMN-14 x m734 bispecific antibody (BsmAb) and 131I-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/m2 (11 patients) or 40 mg/m2 (11 patients) dose of BsmAb and escalating activities of (131)I-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/m2 of BsmAb and in 1 patient (11%) injected with 40 mg/m2. No other nonhematologic toxicity was observed. With 75 mg/m2 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/m2 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/m2 of BsmAb (64%) than with 40 mg/m2 (22%) (P = 0.04). Human antimouse antibody elevation was observed in 1 patient (8%) and human antihuman antibody in 4 (33%).
  
  
  CONCLUSIONS
  A BsmAb dose of 40 mg/m2 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 131I-di-DTPA-indium in MTC patients. In non-MTC patients, dose escalation should continue.
authors.affiliation: Nuclear Medicine Department, René Gauducheau Cancer Center, Nantes, France. francoise.bodere@chu-nantes.fr
authors.forename: Françoise
authors.initials: F
authors.lastname: Kraeber-Bodéré
authors.forename: Caroline
authors.initials: C
authors.lastname: Rousseau
authors.forename: Caroline
authors.initials: C
authors.lastname: Bodet-Milin
authors.forename: Ludovic
authors.initials: L
authors.lastname: Ferrer
authors.forename: Alain
authors.initials: A
authors.lastname: Faivre-Chauvet
authors.forename: Loïc
authors.initials: L
authors.lastname: Campion
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Vuillez
authors.forename: Anne
authors.initials: A
authors.lastname: Devillers
authors.forename: Chien-Hsing
authors.initials: CH
authors.lastname: Chang
authors.forename: David M
authors.initials: DM
authors.lastname: Goldenberg
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Chatal
authors.forename: Jacques
authors.initials: J
authors.lastname: Barbet
mesh_terms: D000328:Adult; D000368:Aged; D018033:Antibodies, Bispecific / Q000008:administration & dosage* / Q000009:adverse effects; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D019583:Dose Fractionation, Radiation; D005260:Female; D006241:Haptens / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D007457:Iodine Radioisotopes / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D011832:Radiation Injuries / Q000175:diagnosis / Q000209:etiology; D016499:Radioimmunotherapy / Q000009:adverse effects / Q000379:methods*; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000009:adverse effects; D011879:Radiotherapy Dosage; D018570:Risk Assessment / Q000379:methods; D013964:Thyroid Neoplasms / Q000175:diagnosis / Q000532:radiotherapy*; D016896:Treatment Outcome
chemical_list: D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D006241:Haptens; D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals