Phase I trial of 131I-huA33 in patients with advanced colorectal carcinoma.
OBJECTIVE
Humanized monoclonal antibody A33 (huA33) targets the A33 antigen which is expressed on 95% of colorectal cancers. A previous study has shown excellent tumor-targeting of iodine-131 labeled huA33 (131I-huA33). Therefore, we did a phase I dose escalation trial of 131I-huA33 radioimmunotherapy.


METHODS
Fifteen patients with pretreated metastatic colorectal carcinoma each received two i.v. doses of 131I-huA33. The first was an outpatient trace-labeled "scout" dose for biodistribution assessment, followed by a second "therapy" dose. Three patients were treated at 20, 30, and 40 mCi/m2 dose levels, and six patients at 50 mCi/m2 to define the maximum tolerated dose.


RESULTS
Hematologic toxicity was 131I dose-dependent, with one episode of grade 4 neutropenia and two episodes of grade 3 thrombocytopenia observed at 50 mCi/m2. The maximum tolerated dose was determined to be 40 mCi/m2. There were no acute infusion-related adverse events, and gastrointestinal toxicity was not observed despite uptake of 131I-huA33 in bowel. Seven patients developed pruritus or rash, which was not related to 131I dose. There was excellent tumor-targeting of 131I-huA33 shown in all patients. The serum T1/2beta of 131I-huA33 was (mean +/- SD) 135.2 +/- 46.9 hours. The mean absorbed tumor dose was 6.49 +/- 2.47 Gy/GBq. Four patients developed human anti-human antibodies. At restaging, 4 patients had stable disease, whereas 11 patients had progressive disease.


CONCLUSIONS
Radioimmunotherapy using 131I-huA33 shows promise in targeting colorectal tumors, and is deliverable at a maximum tolerated dose of 40 mCi/m2. Further studies of 131I-huA33 in combination with chemotherapy are planned.
Chong
Geoffrey
G
Ludwig Institute for Cancer Research, Melbourne, Australia.
Lee
Fook Thean
FT
Hopkins
Wendie
W
Tebbutt
Niall
N
Cebon
Jonathan S
JS
Mountain
Angela J
AJ
Chappell
Bridget
B
Papenfuss
Anthony
A
Schleyer
Paul
P
U
Paul
P
Murphy
Roger
R
Wirth
Veronika
V
Smyth
Fiona E
FE
Potasz
Nicole
N
Poon
Aurora
A
Davis
Ian D
ID
Saunder
Tim
T
O'keefe
Graeme J
GJ
Burgess
Antony W
AW
Hoffman
Eric W
EW
Old
Lloyd J
LJ
Scott
Andrew M
AM
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy*; D005076:Exanthema / Q000209:etiology; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology*; D008875:Middle Aged; D009503:Neutropenia / Q000209:etiology; D011537:Pruritus / Q000209:etiology; D016499:Radioimmunotherapy / Q000009:adverse effects / Q000379:methods*; D011879:Radiotherapy Dosage; D014018:Tissue Distribution; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; C104258:GPA33 protein, human; D007457:Iodine Radioisotopes; D008562:Membrane Glycoproteins