Modulating The Tumor Microenvironment In Osteosarcoma

The purpose of this study is to evaluate the use of a new immune therapy in combination with chemotherapy 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, typically either carboplatin or doxorubicin. 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 that combines both chemotherapy and immunotherapy to stimulate the immune system both before and after amputation of the affected limb. In the current study, a cocktail of three of drugs given orally to stimulate the immune system will be combined with doxorubicin chemotherapy. The 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 already completed a clinical trial of the three drugs used alone in dogs with osteosarcoma both before and after amputation and have found that approximately 40% of dogs treated will survive longer than on year, demonstrating that the drug combination has activity against this disease. By adding the doxorubicin into the treatment regimen, it is predicted that survival times will be further improved.

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 15 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 ≤ 1.5X the institutional upper limit of normal (ULN), ALT ≤ 3X ULN
• Renal function: Serum creatinine ≤ 1.5X 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 pathologic 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 antitumor 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 potential benefit to your dog is that the combination of doxorubicin, toceranib, losartan and ladarixin will prevent or delay the development of tumor spread. The hope is that this will be more effective than the currently recommended chemotherapy treatment with carboplatin or doxorubicin alone.

The study will cover the office visit, x-rays, and bloodwork prior to amputation to determine eligibiltiy; the study will not cover the needle aspiration required for diagnosis (approximately $350). The study will cover $1500 of the approximate $4000-4500 total cost for amputation of the affected leg. The study will also cover all of the costs associated with drug administration, bloodwork, and x-rays for up to one year (12 months) after amputation up to a total of $5000 (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. Bloodwork 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 14 days so that the oral drugs and first dose of chemotherapy can administered 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 a dose of doxorubicin chemotherapy by intravenous injection and the combination of toceranib/losartan/ladarixin at home. Approximately 72 hours prior to the amputation, the toceranib will be stopped, although 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 post-amputation, where the second dose of doxorubicin will be given. Your dog will continue on the toceranib/losartan/ladarixin at home and then receive another 3 doses of doxorubicin (one dose every 3 weeks), for a total of 5 doses of doxorubicin. Following the last dose of doxorubicin, your dog will be monitored monthly with physical exam, bloodwork and chest x-rays; study blood will also be collected to perform studies that check the immune response and other study-related parameters (total amount of blood drawn is approximately 2-3 tablespoons). At 12 months post-amputation, the recheck exams will be changed to every 2 months for another 12 months.