Pharmacodynamic Study of Axitinib in Patients With Solid Tumors

We hypothesize that the rapid tumor recovery observed after temporary cessation of
VEGF-directed therapy is secondary to a transient increase in tumor proliferation (increased
DNA synthesis, cell division, and cell growth in tumor). We have shown that this hypothesis
is likely correct with our current sunitinib pharmacodynamic study (ongoing study; PI: G.
Liu). We believe that a similar observation will be evident with axitinib as well. Given
the shorter half life of axitinib (compared to sunitinib), this effect will likely be
evident sooner. Thus, axitinib is a more ideal drug to synchronize with cytotoxic
chemotherapy, in order to exploit this apparent proliferative index flair during acute VEGFR
TKI withdrawal.

To refine the schedule for chemotherapy administration, we propose performing a
pharmacodynamic trial assessing FLT-PET/CT imaging in patients with lung cancer and other
solid malignancies, in order to determine the optimal duration of axitinib exposure, and
ideal timing after withdrawal to add chemotherapy.

The implications of this hypothesis, if proven true, would be to exploit this rapid tumor
growth period following VEGFR TKI cessation and then add S-phase specific chemotherapy for
improved cytotoxic effect.