Optimizing Novel Immunotherapy Combinations Targeting the Tumor Microenvironment in Canine Spontaneous Osteosarcoma

The purpose of this study is to evaluate the use of a new immune therapy in dogs with osteosarcoma, a malignant tumor that affects the long bones in dogs. The standard treatment for dogs with osteosarcoma is amputation of the affected leg followed by generally 4 treatments with a chemotherapy drug called carboplatin. Unfortunately, 25-30% of affected dogs will develop spread of the osteosarcoma to the lungs before chemotherapy treatment is completed, and 50% of all dogs will have spread within 6-8 months following amputation. Only 15% of dogs will live for two years after amputation. Therefore, new therapies for this cancer are desperately needed. There is increasing evidence that the immune system can recognize and kill osteosarcoma cells. A few recent studies in dogs with osteosarcoma using different ways to stimulate the immune systen have been promising. However, most of them are not used until after the amputation/surgical site has healed or until after the chemotherapy treatments have been finished. This gives the remaining tumor cells a chance to continue growing and find ways to evade the immune system. The purpose of this study is to use a new method to stimulate the immune system prior to amputation and then immediately after amputation wtihout the need for chemotherapy. This is the time when remaining tumor cells are most vulnerable to attack by the immune system and when it is easiest to prevent them from taking up residence in the lungs and other organs. In the current study, a combination of drugs that are given orally will be used to stimulate the immune system. This combination of three drugs includes: 1) Toceranib  (Palladia), a drug that is approved to treat cancer in dogs. Toceranib has been shown to decrease two types of immune cells that actively block activation of other immune cells against the cancer. 2) Losartan, a blood pressure medication that has been shown block also help regulate the flow of immune cells into the tumor. And 3) Ladarixin, a drug that blocks a key receptor (IL-8 receptor) immune cells use to help block the action of other immune cells. These three drugs work together to target key parts of the immune system and retool their functions so that they can now kill the tumor cells. We have seen evidence that these three drugs can work in dogs with osteosarcoma that have already failed chemotherapy treatment with carboplatin after amputation. Based on these findings, we believe that the drug combination will work better when the number of cancer cells is much lower and before they have been exposed to chemotherapy and given a chance to become resistant to treatment.

Inclusion Criteria

Eligible dogs (all breeds) must meet all of the following criteria:

• Suspected diagnosis of primary OS of one appendicular limb; must be confirmed histologically at amputation
• Dogs must be at least 1 year of age and body weight of 10 kg or higher
• Adequate organ function by standard laboratory tests (CBC, serum biochemistry profile, urinalysis).
• ANC≥1000/μL and platelet count ≥ 100,000/μL
• Liver function: Total bilirubin < 5X the institutional upper limit of normal (ULN), ALT < 3X ULN
• Renal function: Serum creatinine < 5X ULN, with USG > 1.012
• ECOG performance score of 0-1
• Otherwise healthy with no underlying clinically significant cardiac, renal or hepatic disease
• Informed written consent must be obtained

Exclusion Criteria

Dogs with any of the following will not be eligible for the study:

• Evidence of pathological fracture
• Pregnant or lactating dogs
• Abnormal CNS function suggestive of tumor metastasis to the brain (seizures or dementia of recent onset)
• Uncontrolled or recently diagnosed IMHA or IMTP
• Concurrent or recent use of complementary or alternative medicines that in the opinion of the principal investigators would confound the interpretation of toxicities and/or anti-tumor activity of the study drugs
• Dogs with significant cardiovascular disease.
• Any other serious systemic disorder incompatible with completing the 1-year study (at the discretion of the principal investigators)
• Concurrent immune dysregulation due to an underlying condition (eg, hyperadrenocorticism, diabetes mellitus, renal disease)
• Treatment with immune suppressive medications (other than ocular) for any condition

Client Benefits

The study will cover the office visit, x-rays, and blood work prior to amputation to determine eligibility; the study will not cover the needle aspiration required for diagnosis (approximately $350). The study will cover $1500 of the approximate $4000-5000 total cost for amputation of the affected leg. The study will also cover all of the costs associated with drug administration, blood work, and x-rays for up to one year (12 months) after amputation up to a total of $5500 (including the $1500 for amputation). The study will not cover costs associated with complications secondary to amputation (i.e., infection), but will cover all costs associated with side effects from the drug therapy. The study will not cover costs associated with conditions unrelated to the osteosarcoma treatment (skin infection, ear infection, etc.).

Sample or Data Requirements

Your dog will need to have a diagnosis of osteosarcoma based on either a biopsy of the tumor or a needle aspiration of the tumor. Blood work and chest x-rays will also need to be performed to make sure that there is no obvious evidence of tumor spread in the lungs and that the liver, kidneys and other body systems are functioning normally. Your dog also needs to be comfortable enough to delay amputation for 10-14 days so that that the oral drugs can be started before the tumor is removed (i.e., your dog cannot have a fracture of the bone or be unable to bear any weight at all/be in substantial pain). Once enrolled, your dog will receive the combination of toceranib/losartan/ladarixin at home. Approximately 72 hours prior to the amputation, the toceranib will be stopped, although the losartan and ladarixin will continue to be given. At 1 week post amputation, the toceranib will be re-started. Your dog will be evaluated 2 weeks following the toceranib re-start, then monthly for the first year. The toceranib/losartan/ladarixin will be continued for a total of 6 months, after which the drug regimen will be stopped. At 12 months post amputation, the recheck exams will be changed to every 2 months for another 12 months. At each study visit beginning at week 5, chest x-rays will be taken and blood will be drawn to evaluate cell counts and organ function, as well as for assays to monitor the immune response.