A phase I pharmacokinetic, toxicity and dosimetry study of ¹³¹I labeled IMMU-4 F(ab')₂ in patients with advanced colorectal carcinoma

The ¹³¹I labeled F(ab')₂ fragment of the anti-CEA antibody IMMU-4 was administered to 13 patients with metastatic colorectal cancer in a phase 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 the agent administered in the protocol was established in the range of 90-115 mCi/m². Hematologic toxicity was the major dose-limiting side effect with redirection in absolute granulocyte and platelet counts detected at between 4 and 5 weeks after infusion. After 1 infusion, 5/13 patients were HAMA positive by week 6-7. Two additional patients HAMA negative after the first dose became HAMA positive after a second dose. Clearance of the total ¹³¹I 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) was variable ranging from 4.3 to 12.9 l (x = 8.3 ± 1 l) suggesting variable extravascular disposition of this agent. There was no apparent relationship of total antibody dose and pharmacokinetics. In addition, tumor volume did not appear to directly correlate with half-life or with Cxt as individual parameters. Samples were assessed by gel permeation HPLC to determine the in vivo stability of the radiolabel. In the samples analyzed, a high molecular weight ¹³¹I labeled peak was measured which may be labeled antibody complexed in vivo with endogenous CEA. A low molecular weight peak was also detected which may be ¹³¹I-Fab monomer. These data suggest that the complex pharmacokinetics of ¹³¹I labeled IMMU-4 F(ab')₂ may lead to problems associated with the use of this agent as a radiotherapeutic delivery vehicle.