Introduction

Canine hemangiosarcoma (HSA) is an aggressive cancer that is poorly responsive to chemotherapy. Ethos-PUSH seeks to identify novel treatments for dogs with splenic HSA that improve clinical outcomes, molecular biomarkers of prognosis, and biomarker-drug matches associated with exceptional drug response. A necessary step in successful oncology drug development includes drug selection criteria and studies of drug tolerability in tumor-bearing patients.

Methods

Criteria for drug selection in this Umbrella study design included: biological rationale from hemangiosarcoma studies, novel mechanism of action, or hints of activity in canine HSA or human angiosarcoma. Walk-in studies were performed in cancer-bearing dogs to establish the safety/tolerability and pharmacokinetic (PK) parameters for oral paclitaxel (Oraxol), sorafenib, and a novel, oil-based formulation of rapamycin.

Results

Paclitaxel has demonstrated broad activity against canine and human cancers (including angiosarcoma). Using a rolling-6 tolerability study design, we established a clinically relevant dose/schedule of Oraxol (90 mg/m2 on 3 consecutive days weekly) in pet dogs with cancer. Sorafenib is a dual inhibitor of VEGF and RAF/MAPK and has unique value amongst multi-targeting TKIs as it may circumvent the problem of evasive resistance associated with VEGF inhibition alone. We defined the tolerability and PK-based dosing of sorafenib (3 mg/kg daily) in tumor-bearing dogs. Aberrant mTOR signaling is a biological feature of HSA. We report on the tolerability and desired PK of an oil-based formulation of rapamycin designed to overcome challenges associated with poor oral bioavailability.

Conclusion

These data establish the tolerability, PK parameters, and dosing schemes for Ethos-PUSH anticancer agents in cancer-bearing dogs.

Funding Information

Ethos Discovery, San Diego, CA, USA.