Trial Information

A Phase IB/II Study of Sunitinib in Combination With Neoadjuvant Radiation in Patients With Resectable Soft-tissue Sarcoma

The presence of hypoxia has been documented in soft-tissue sarcomas, where it may contribute
to radioresistance. Combinations of radiosensitisers such as ifosfamide and doxorubicin
with radiotherapy have demonstrated promise in sarcomas, but with significant toxicity.

The rationale for this study is based on:

- the frequency of hypoxia in soft-tissue sarcomas

- the importance of radiotherapy in neoadjuvant treatment of soft-tissue sarcomas

- targeting hypoxic vasculature with sunitinib

- the single agent activity of sunitinib in soft-tissue sarcomas. This study will assess
the feasibility and tolerability of the combination of sunitinib with standard
preoperative radiotherapy. The surrogate endpoints of tumor necrosis and functional and
RECIST imaging response will provide early evidence of response rate. Toxicities will
be assessed both during chemoradiation and following surgery. The impact of treatment
on the hypoxic component of the tumor will be investigated with F18 azamycin
arabinoside PET scans.

Because the combination of sunitinib and radiotherapy has not been studied before, we
propose a phase Ib design with dose reductions in the event of excessive toxicity. Sunitinib
treatment will precede the commencement of radiotherapy by 2 weeks because there is
preclinical evidence that priming the tumor vasculature may increase synergy with
radiotherapy, and because sunitinib may have single agent activity in sarcomas, including
measurable effects on tumor vasculature. Because it is anticipated that the likelihood of
complications attributable to the combination of sunitinib and radiotherapy will be small,
the starting dose of sunitinib will be 50mg/day for the two week lead-in period and then
25mg for 5 weeks with concurrent radiotherapy.