Defining Actionable Targets for Osteosarcoma

Osteosarcoma represents a challenging disease to treat in both dogs and humans. In dogs with osteosarcoma, despite 30 years of effort and multiple clinical studies, the median survival time after amputation of the affected leg followed by carboplatin chemotherapy remains 11 months; only 25% of dogs will live to 2 years. With advances in technology, we now have a much better understanding of the underlying genetic changes that help drive osteosarcoma growth. The purpose of this study is to use this information and determine whether specific drugs that target key defects in osteosarcoma cells are effective for preventing the development of tumor spread (metastasis) following amputation of the affected limb. We will be testing three different drugs that target individual proteins/pathways known to be abnormal in osteosarcoma. These are 1) olaparib, a drug that targets a protein called PARP which is most effective in cells that have defective DNA repair which is common in osteosarcoma; 2) temozolomide, a chemotherapy drug that targets cells with defective DNA repair; and 3) VLS-1488, a drug that targets cells with defective Rb protein, a common finding in osteosarcoma. In the current study, we will be testing how well each of these drugs work in dogs after the tumor has been removed, instead of using carboplatin chemotherapy.

• Group A: Dogs with newly diagnosed OS will receive treatment with the drug of interest prior to amputation (tumor removal) and then continue on this treatment after tumor removal in place of standard chemotherapy.
• Group B: Dogs that have failed treatment (either standard of care therapy [amputation + carboplatin chemotherapy] or novel drug therapy [amputation + novel drug]) and have developed metastasis will receive the drug(s) of interest until progression of disease is noted.

Inclusion Criteria

Eligibility for Group A:

• Presumptive diagnosis of Osteosarcoma in a limb bone based on cytology or biopsy
• No obvious evidence of tumor spread based on chest x-rays or CT scan
• No concurrent health conditions (heart, kidney, liver disease, among others) that may interfere with either treatment or overall survival
• Weigh at least 15 kg
• No clinically significant abnormalities on baseline bloodwork (CBC/chemistry).
• No prior diagnosis of a malignant tumor that is likely to impact overall survival.
• Not receiving any other small molecule therapies (i.e., oclacitinib, etc.) that may interfere with the planned drug treatments.

Eligibility for Group B:

• Prior diagnosis of OS with amputation and either carboplatin chemotherapy or study drug therapy
• Metastasis to the lungs, skin/subcutaneous tissue and/or abdomen with no evidence of bone metastasis
• No concurrent health conditions (heart, kidney, liver disease, among others) that may interfere with either treatment or overall survival.
• Weigh at least 15 kg
• No clinically significant abnormalities on baseline bloodwork (CBC/chemistry).
• No prior diagnosis of a malignant tumor that is likely to impact overall survival.
• Not receiving any other small molecule therapies (i.e., oclacitinib, etc.) that may interfere with the planned drug treatments.
• Have a life expectancy of at least 1 month

Exclusion Criteria

For participation in the clinical study, all costs associated with study screening are covered and you will receive a $1500 credit toward amputation of your dog’s leg. Additionally, all costs associated with treatment post-amputation will be covered, including those associated with any potential side effects. Treatment of conditions unrelated to the study (i.e., ear infection) are not covered by the study.

Sample or Data Requirements

Baseline screening tests include routine bloodwork (complete blood count, chemistry panel), a urine exam, and whole body CT exam. Once enrolled in the study, your dog will have a tumor biopsy performed under sedation (this is not general anesthesia). Your dog will then receive 6 days of the oral study drug. Your dog will return to the hospital on day 7, where we will administer the study drug, then take samples of blood at 0, 2, 4, 6 and 8 hours after drug to measure blood levels of the drug. The following day, your dog will undergo limb amputation. Your dog will return to the clinic 7 days post-amputation for a recheck exam and to restart the study drug. We will then see your dog monthly post amputation for a physical exam and routine bloodwork, with a whole-body CT scan performed under sedation every 2 months to monitor for tumor spread. Throughout the study, we will take blood samples from your dog to investigate potential biomarkers that could indicate response or resistance to treatment and help determine which osteosarcoma subtypes are more likely to respond to the study drug. The maximum blood volume drawn at any study visit is 40 ml, (2 tablespoons + 2 teaspoons). We will also do two buccal swabs on the first visit, which are used to collect normal DNA from the mouth by rotating a swab in the cheek pouch for 30-60 seconds.

Contact Information

For questions regarding the clinical trial, please email clinicaltrials@tufts.edu.