Study Title: 3-Month Toxicity and Toxicokinetics (TK) Intravenous (IV) Infusion Study in Beagle Dogs Given RC-2 Beta (?) with a 4-Week Recovery (Target Animal Safety Study) Experimental Design: This GLP (Good Laboratory Practices) study is a controlled safety study of RC-2? in 20 male and 20 female purpose-bred beagle dogs, approximately 4 months at the age of initiation and weighing 5kg to 11kg. Dogs will be assigned to a group using a randomization procedure and treated in one of 4 groups: Saline Control, Low Dose (1x), Mid Dose (3x), and High Dose (5x). All dose groups will have RC-2? administered twice weekly via a 30-minute IV infusion for 13 weeks and an assessment of the reversibility of any effects after a 4-week recovery will be studied. The standard dosing of RC-2? is one dose per week;however, the study is designed in accordance with the CVM/ONADE agreement to use a compressed dosing schedule of two doses per week in order to reduce the overall study length. Data collected from all animals will be used in the final audited report. Objectives/Purpose of study: The purpose of this safety study is to evaluate the toxicity and determine the TK of RC-2? when administered twice weekly via a 30-minute IV infusion to dogs for 13 weeks and to assess the reversibility of any effects after a 4-week recovery. The primary objective is to establish the margin of safety for RC-2? in dogs using a condensed dosing schedule. The secondary objective is to determine the tolerability of the drug over a 3-month period including a 4-week recovery period. The data will be utilized for FDA Conditional Approval of RC-2? for Canine Lymphoma and Canine Mast Cell Tumors. Justification: This is a pivotal safety study for FDA Conditional Approval for the treatment of Canine Lymphoma and Canine Mast Cell Tumors. Canine Lymphoma is the most common malignancy diagnosed in canines representing up to 24% of all neoplasms seen in dogs, affecting over 21,900 dogs per year. This disease has a median survival of 12 months with chemotherapy and 4-8 weeks without treatment. Mast cell tumors are the most common malignant skin tumor of the dog and represent over 20% of the dermal and epidermal masses diagnosed in veterinary medicine. Over 65,000 dogs are diagnosed with Mast Cell Tumors per year. The median survival time for a dog with a grade III mast cell tumor with aggressive therapy is approximately 1 year, but it is reduced to 4-6 months in the face of metastasis. The justification for this study is that previous anecdotal use of RC-2? in the compassionate setting, has demonstrated effectiveness and hence, it may provide a completely new approach to the effective treatment of these two devastating cancers. The study will also be used to support the Investigational Drug Application for the treatment of human lymphoma with RC-2?. Study Site: Covance Laboratories, Inc., Madison, WI 53704-2523
