EFFECT OF RECOMBINANT ALPHA-INTERFERON ON PHARMACOKINETICS, BIODISTRIBUTION, TOXICITY, AND EFFICACY OF I-131-LABELED MONOCLONAL-ANTIBODY CC49 IN BREAST-CANCER - A PHASE-II TRIAL

Preclinical studies have demonstrated that recombinant IFN-alpha (rIFN -alpha) can enhance the tumor associated glycoprotein 72 (TAG-72) on t umors, To determine whether rIFN-alpha could enhance TAG-72 expression iii vivo in patients, 15 women with breast cancer were randomized to receive daily injections of rIFN-alpha (3 x 10(6) units/m(2) for 13 da ys) beginning on day 1 (group I = 7 patients) or on day 6 (group 2 = 8 patients), On day 3, all patients received a 10-20-mCi tracer dose of I-131-CC49, a high-affinity murine monoclonal antibody reactive again st TAG-72, followed by a therapy dose of 60-75 mCi/m(2) of I-131-CC49 on day 6. Whole body and single-photon emission computed tomography sc ans along with whole blood pharmacokinetics were performed following t racer and treatment phases, Hematological toxicity was considerable; r eversible grade 3-4 neutropenia and thrombocytopenia was observed in 1 2 of 15 patients, Twelve of 14 patients tested developed human antimou se antibodies 3-6 weeks after treatment, For group 1 patients, whole b lood residence time increased significantly between that predicted fro m the tracer doses and therapy doses (42.6 +/- 4.7 versus 51.5 +/- 4.8 h, respectively; P < 0.01). The calculated radiation absorbed dose to red marrow from therapy compared to tracer activity was also signific antly higher for this group (1.25 +/- 0.35 versus 1.07 +/- 0.26 cGy/mC i; P < 0.05). Treatment with rIFN-alpha was found to enhance TAG-72 ex pression in tumors from patients receiving rIFN-alpha (group 1) by 46 +/- 19% (P < 0.05) compared to only 1.3 +/- 0.95% in patients not init ially receiving IFN (group 2). The uptake of CC49 in tumors was also s ignificantly increased in rIFN-alpha-treated patients, One partial and two minor tumor responses were seen, In summary, rIFN-alpha treatment altered the pharmacokinetics and tumor uptake of I-131-CC49 in patien ts at the expense of increased toxicity.