A PHASE-I PHARMACOKINETIC, TOXICITY AND DOSIMETRY STUDY OF I-131-LABELED IMMU-4 F(AB')2 IN PATIENTS WITH ADVANCED COLORECTAL-CARCINOMA

The I-131 labeled F(ab')2 fragment of the anti-CEA antibody IMMU-4 was administered to 13 patients with metastatic colorectal cancer in a ph ase I study. Patients received a single 1 hr infusion at activities of 40, 60, 90 115 and 135 mCi/m2. The maximum tolerated dose (MTD) of th e agent administered in the protocol was established in the range of 9 0-115 mCi/m2. Hematologic toxicity was the major dose-limiting side ef fect with redirection in absolute granulocyte and platelet counts dete cted at between 4 and 5 weeks after infusion. After 1 infusion, 5/13 p atients were HAMA positive by week 6-7. Two additional patients HAMA n egative after the first dose became HAMA positive after a second dose. Clearance of the total I-131 label from whole blood closely fit a one compartment mathematical model with half-lives ranging from 6.2 to 41 .7 hrs (x = 22.5 +/- 5). Similarly, the volume of distribution (Vd) wa s variable ranging from 4.3 to 12.9 1 (x = 8.3 +/- 11) suggesting vari able extravascular disposition of this agent. There was no apparent re lationship of total antibody dose and pharmacokinetics. In addition, t umor volume did not appear to directly correlate with half-life or wit h Cxt as individual parameters. Samples were assessed by gel permeatio n HPLC to determine the in vivo stability of the radiolabel. In the sa mples analyzed, a high molecular weight I-131 labeled peak was measure d which may be labeled antibody complexed in vivo with endogenous CEA. A low molecular weight peak was also detected which may be I-131-Fab monomer. These data suggest that the complex pharmacokinetics of I-131 labeled IMMU-4 F(ab')2 may lead to problems associated with the use o f this agent as a radiotherapeutic delivery vehicle.