Phase II radioimmunotherapy trial with131I-CC49 in colorectal cancer

Abstract

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 131I‐CC49 to determine its overall toxicity and the response to therapy of patients treated with it. Methods. Patients received 75 mCi/m2 131I‐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 anti‐mouse antibody (range, 161 to > 20,000 ng/ml) at 6–8 weeks postinfusion. Mean ± SD whole‐body half‐life (whole‐body retention) of 131I‐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 anti‐mouse 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.

Application of cytokine intervention for improved radio-antibody dose delivery

“…Clinically, RAIT is quite effective in the treatment of lymphoma (Denardo et al, 1988;Goldenberg et al, 1991;Kaminski et al, 1993;Press et al, 1989) and is considered a promising adjuvant for treating occult micrometastatic disease (Blumenthal et al, 1992b). Several clinical trials are assessing the potential utility of RAIT for solid tumor therapy Hird et al, 1993;Juweid et al, 1997;Meredith et al, 1992;Murray et al, 1994). To improve the outcome, one must select an appropriate radionuclide based on the size of the lesion(s) to be treated and an appropriate form of Ab such that the biological decay is matched with the physical decay of the nuclide (Wessels and Rogus, 1984;Wheldon et al, 1991).…”

Structural Correlates of an Anticarcinoma Antibody: Identification of Specificity-Determining Residues (SDRs) and Development of a Minimally Immunogenic Antibody Variant by Retention of SDRs Only

“…CC49 is a potentially useful diagnostic and therapeutic reagent for carcinomas because radiolabeled CC49 has shown efficient tumor targeting of a variety of carcinomas in several clinical trials. Radiolabeled murine CC49 has now been shown to successfully target human colorectal (27)(28)(29)(30)(31)(32), breast (33,34), prostate (31,35,36) and ovarian (37)(38)(39) carcinomas in phase I/II clinical trials. Objective responses have been observed in ovarian cancer patients receiving 177 Lu-CC49 (murine) (37,40); several patients with microscopic disease have remained disease-free Ͼ18 mo (37).…”

Antibody-guided radiation therapy of cancer

“…Registration in the USA includes imaging using 111 In-ibritumomab following the first rituximab infusion. Zevalin's product information mentions that 90 Y-ibritumomab should not be administered to patients with altered biodistribution as determined by imaging with 111 In-ibritumomab. In the European Union, imaging using 111 In-ibritumomab is thought to be unnecessary, although opinions differ [79].…”