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The RDIF method for DCE analysis offers an alternative, easy-to-implement method for estimating the input function in tumors. The method assumes that during the DCE experiment, the changes observed by MRI result solely from vascular perfusion and permeability kinetics, and that information can be used to model the input function. Importantly, the method is demonstrated in a murine xenograft study to yield K results consistent with literature values and suitable for compound studies.

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11095 Background: Epidermal growth factor receptor variant III (EGFRvIII) is a constitutively active mutant of EGFR present in thirty to fifty percent of glioblastoma (GBM) patients. AMG 595, currently in Phase I trials, is composed of a fully human anti-EGFRvIII-specific antibody conjugated to the maytansinoid DM1 via a non-cleavable linker. The MRI apparent diffusion coefficient (MRI ADC) has been shown to correlate with tissue cellularity, and changes in MRI ADC can be an early indicator of therapeutic efficacy. The aim of this work is to evaluate MRI ADC as a clinically translatable early readout of tissue changes due to AMG 595 treatment in a murine orthotopic GBM model. Methods: D317 human GBM cells were intracranially injected into in female CB17 SCID mice at Day 0. Mice were randomized at Day 7, using tumor volumes calculated by MRI, and were treated with vehicle, 6.5, 11, or 22 mg/kg AMG 595 i.v. twice per week, or temozolomide 10 mg/kg p.o. daily five days per week (N=8/group). MRI was repeated at days 14 and 21. Tumor volumes were manually traced on multi-slice T2-weighted RARE images covering the entire tumor volume. The mean MRI apparent diffusion coefficients for each tumor in the vehicle and 22 mg/kg AMG 595-treated groups were calculated from diffusion-weighted spin echo images (b = 100-1200 s/mm2). Results: A dose-dependent effect of AMG 595 on tumor volume was observed at Day 21; growth was inhibited in both the temozolomide and AMG 595-treated groups (22 and 11 mg/kg) relative to vehicle (p<0.0001). At Day 14, this significant treatment effect on tumor volume was not yet detectable. However, mean MRI ADC values were already significantly higher in the AMG 595 (22 mg/kg) treated group than in the vehicle group (23% higher at Day 14, p<0.01 vs vehicle; 32% higher at Day 21, p<0.0001 vs vehicle). The increase in MRI ADC in the AMG 595-treated group preceded observable tumor growth inhibition in the AMG 595-treated animals. Conclusions: Increases in tumor MRI ADC in response to AMG 595 treatment precede measurable inhibition of tumor growth, supporting the use of MRI ADC as a clinically relevant early biomarker for therapeutic efficacy.