Abstract
14517 Background: In pre-clinical models the combination of radioimmunotherapy (RIT) with 131I-A5B7 and the vascular disruptive agent (VDA) CA4P was more effective than either agent alone, curing mice with CEA-positive colon carcinoma xenografts. Previous single agent phase I trials have defined the MTD for 131I-A5B7 at 2400MBq/m2 and CA4P between 60- 68mg/m2. We performed a Phase I/II trial to determine the DLT, MTD and efficacy of this combination in patients with advanced gastrointestinal cancer. Methods: Patients had advanced gastrointestinal adenocarcinoma, CEA 10–1000μg/L, disease measurable by RECIST, QTc ≤450 ms, no cardiac arrhythmia/ischaemia and adequate haematology/biochemistry. Disease had to be suitable for evaluation by dynamic MRI (DCE-MRI). All patients received a test dose of CA4P up to 2 weeks prior to Day 1, to document blood flow response. The starting dose was 1800MBq/m2 of 131I-A5B7 given on day 1 and 45mg/m2 CA4P given 48 and 72 hours post A5B7, and then weekly for up to seven weeks. Results: Twelve patients were treated; eleven colorectal and one pancreatic adenocarcinoma, mean age 63 (32–77), WHO PS 0(6) and 1(6). 2/6 patients at the first dose level had DLTs (grade 4 neutropenia) attributed to 131I-A5B7. The dose was reduced to 1600MBq/m2 and CA4P escalated to 54mg/m2. Again, 2/6 patients had DLTs attributable to 131I-A5B7 (grade 4 neutropaenia), and one patient had grade 3 ataxia (non-DLT). Of ten evaluable patients 1 had SD and 9 had PD, confirmed by FDG-PET in four. CA4P and A5B7 pharmacokinetics were similar to previous studies. SPECT confirmed tumour antibody uptake in all 5 patients studied. DCE-MRI confirmed falls in the kinetic parameters (Ktrans/IAUGC60) in 9/12 patients, statistically significant in 3/12 (p<0.05), 4 hours after the test dose of CA4P. Conclusions: This is the first clinical trial reporting on the combination of RIT and a VDA; each therapy component was shown to function but with dose-limiting myelosuppression from the combination at 66% of the single agent antibody MTD. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Cancer Research UK
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