PHASE-I II RADIO-IMMUNOTHERAPY STUDY WITH IODINE-131-LABELED ANTI-CEAMONOCLONAL-ANTIBODY F6 F(AB')(2) IN PATIENTS WITH NONRESECTABLE LIVERMETASTASES FROM COLORECTAL-CANCER/

Experimental studies in nude mice with human colon-carcinomas grafts d emonstrated the therapeutic efficiency of F(ab')(2) fragments to carci noembryonic antigen (CEA) labeled with a high dose of (131)Iodine. A p hase I/II study was designed to determine the maximum tolerated dose o f I-131-labeled F(ab')(2) fragments ((131)-F(ab')(2)) from anti-CEA mo noclonal antibody F6, its limiting organ toxicity and tumor uptake. Te n patients with non-resectable liver metastases from colorectal cancer (9 detected by CT scan and 1 by laparotomy) were treated with I-131-F (ab')(2), doses ranging from 87 mCi to 300 mCi for the first 5 patient s, with a constant 300-mCi dose for the last 5 patients. For all the p atients, autologous bone marrow was harvested and stored before treatm ent. Circulating CEA ranged from 2 to 126 ng/ml. No severe adverse eve nts were observed during or immediately following infusion of therapeu tic doses. The 9 patients with radiologic evidence of liver metastases showed uptake of I-131-F(ab')(2) in the metastases, as observed by si ngle-photon-emission tomography. The only toxicity was hematologic, an d no severe aplasia was observed when up to 250 mCi was infused. At th e 300-mCi dose, 5 out of 6 patients presented grade-3 or -4 hematologi c toxicity, with a nadir for neutrophiles and thrombocytes ranging fro m 25 to 35 days after infusion. In these 5 cases, bone marrow was re-i nfused. No clinical complications were observed during aplasia The tum or response could be evaluated in 9 out of 10 patients. One patient sh owed a partial response of one small liver metastasis (2 cm in diamete r) and a stable evolution of the other metastases, 2 patients had stab le disease, and 6 showed tumor progression at the time of evaluation ( 2 or 3 months after injection) by CT scan. This phase-I/II study demon strated that a dose of 300 mCi of I-131-F(ab')(2) from the anti-CEA Na b F6 is well tolerated with bone-marrow rescue, whereas a dose of 200 mCi can be infused without severe bone-marrow toxicity. (C) 1998 Wiley -Liss, Inc.