Background. Radiolabeled CC49, a second generation high affinity monoclonal antibody (MoAb) reactive with tumor-associated glycoprotein 72 (TAG72) has undergone previous Phase I testing in patients with colon cancer. Based on this report, the authors treated 15 refractory metastatic colon cancer patients with I-131-CC49 to determine its overall toxicity and the response to therapy of patients treated with it.Methods. Patients received 75 mCi/m(2 131) I-CC49 (20 mg MoAb) intravenously for a period of 30-60 minutes. Whole body retention was derived from the measured dose-rate of I-131 monitored daily at 1 m using an ion chamber. Two whole-body and static-gamma camera images were taken of patients on days 4 and 7 after the infusion.Results. Nonhematologic toxicity (Grade 1-2) consisted of nausea (two patients), arthralgias (three patients), transient fever and chills (two patients), and transient blood pressure changes (two patients). At 4-5 weeks posttreatment, reversible Grade 3-4 thrombocytopenia was observed in 7 of 15 patients, and reversible Grade 3-4 granulocytopenia was observed in 6 of 15 patients. Twelve of 13 patients tested developed human antimouse antibody (range, 161 to >20,000 ng/ml) at 6-8 weeks postinfusion. Mean +/- SD whole-body half-life (whole-body retention) of I-131-CC49 was 57.3 +/- 13.4 hours. Tumors were seen in all patients. In two of three patients treated a second time, an increased whole body clearance rate correlated with elevated human antimouse antibody, reduced uptake in tumor, and enhanced uptake in the thyroid. Estimated tumor doses ranged from 19-667 rads. Red marrow dose estimated from whole body retention ranged from 60 to 117 rads and correlated with decreases in platelet count. No objective tumor responses (i.e., partial or complete) were observed.Conclusions. Despite minimal toxicity and favorable tumor uptake, efficacy has been limited at this dose and schedule. Cancer 1994; 73:1057-66.

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 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 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) was variable ranging from 4.3 to 12.9 1 (x = 8.3 +/- 11) 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 I-131 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 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 of this agent as a radiotherapeutic delivery vehicle.

PURPOSEA phase I trial was undertaken to determine the toxicity and biologic effects of a combination of murine monoclonal antibody L6 (MoAb L6) plus subcutaneous (SC) interleukin-2 (IL-2).PATIENTS AND METHODSFifteen patients with refractory adenocarcinoma (five breast, five lung, five colorectal), received L6 at 200 mg/m2 intravenously (IV) daily on days 1 to 7, followed by a 1-week rest period. IL-2 was given at either 2, 3, or 4.5 x 10(6) U/m2 daily doses times 4 days for a total duration of 3 weeks.RESULTSSide effects of L6 consisted of mild fever and chills along with a rash and serum sickness in one patient. One patient developed dyspnea and urticaria, that resolved with antihistamines. Maximum-tolerated dose (MTD) of SC IL-2 was 3 x 10(6) U/m2, with dose-limiting toxicities that consisted of grade 4 fatigue and dyspnea. Significant decreases in complement levels along with increases in absolute lymphocyte count and eosinophil count were observed. Mean antibody-dependent cellular cytotoxicity from mononuclear cells taken from patients who received IL-2 was elevated significantly compared with baseline in all patients independent of IL-2 dose (P less than .05). Serum IL-2 levels were elevated in 13 of 14 patients (range, 0.9 to 100 U/mL). Human antimouse antibody (HAMA) titers were elevated in nine of 14 (64%) patients who were tested between 3 and 8 weeks after L6 infusion. One patient with breast cancer had a transient mixed response, and one patient with colorectal cancer had a partial response.CONCLUSIONSL6 and SC IL-2 were well tolerated in the majority of patients when given in the outpatient setting. In view of the clinical efficacy of this combination, more phase II trials are warranted.