A phase I trial of radioimmunotherapy with 131I-A5B7 anti-CEA antibody in combination with combretastatin-A4-phosphate in advanced gastrointestinal carcinomas.
OBJECTIVE
In preclinical models, radioimmunotherapy with (131)I-A5B7 anti-carcinoembryonic antigen (CEA) antibody ((131)I-A5B7) combined with the vascular disruptive agent combretastatin-A4-phosphate (CA4P) produced cures unlike either agent alone. We conducted a phase I trial determining the dose-limiting toxicity (DLT), maximum tolerated dose, efficacy, and mechanism of this combination in patients with gastrointestinal adenocarcinomas.


METHODS
Patients had CEA of 10 to 1,000 microg/L, QTc < or =450 ms, no cardiac arrhythmia/ischaemia, and adequate hematology/biochemistry. Tumor was suitable for blood flow analysis by dynamic contrast enhanced-magnetic resonance imaging (MRI). The starting dose was 1,800 MBq/m(2) of (131)I-A5B7 on day 1 and 45 mg/m(2) CA4P given 48 and 72 hours post-(131)I-A5B7, then weekly for up to seven weeks.


RESULTS
Twelve patients were treated, with mean age of 63 years (range, 32-77). Two of six patients at the first dose level had DLTs (grade 4 neutropenia). The dose was reduced to 1,600 MBq/m(2), and CA4P escalated to 54 mg/m(2). Again, two of six patients had DLTs (neutropenia). Of ten assessable patients, three had stable disease and seven had progressive disease. Single-photon emission computed tomography confirmed tumor antibody uptake in all 10 patients. DCE-MRI confirmed falls in kinetic parameters (K(trans)/IAUGC(60)) in 9 of 12 patients. The change of both pharmacokinetic parameters reached a level expected to produce efficacy in one patient who had a minor response on computed tomography and a reduced serum tumor marker level.


CONCLUSIONS
This is believed to be the first trial reporting the combination of radioimmunotherapy and vascular disruptive agent; each component was shown to function, and myelosuppression was dose-limiting. Optimal dose and timing of CA4P, and moderate improvements in the performance of radioimmunotherapy seem necessary for efficacy.
Meyer
Tim
T
UCL Cancer Institute, University College London, United Kingdom. t.meyer@ucl.ac.uk
Gaya
Andrew M
AM
Dancey
Gairin
G
Stratford
Michael R L
MR
Othman
Shokri
S
Sharma
Surinder K
SK
Wellsted
David
D
Taylor
N Jane
NJ
Stirling
J James
JJ
Poupard
Linda
L
Folkes
Lisa K
LK
Chan
Pei-San
PS
Pedley
R Barbara
RB
Chester
Kerry A
KA
Owen
Karen
K
Violet
John A
JA
Malaroda
Alessandra
A
Green
Alan J
AJ
Buscombe
John
J
Padhani
Anwar R
AR
Rustin
Gordon J
GJ
Begent
Richard H
RH
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D002272:Carcinoembryonic Antigen / Q000276:immunology; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000532:radiotherapy*; D006801:Humans; D007457:Iodine Radioisotopes / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D016499:Radioimmunotherapy / Q000379:methods; D011879:Radiotherapy Dosage; D013267:Stilbenes / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome
C518613:A5B7 monoclonal antibody; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D002272:Carcinoembryonic Antigen; D007457:Iodine Radioisotopes; D013267:Stilbenes; C058728:fosbretabulin