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Phase I safety evaluation of STA-12-8960 in dogs with spontaneous tumors
The objective of this study is to determine the maximum tolerated dose of STA-12-8960 in dogs with cancer, and to provide information about the ability of STA-12-8960 to induce responses in dogs with spontaneous tumors.
Heat shock protein 90 (Hsp90) is a “chaperone” protein that is important in maintenance of several proteins needed to promote cancer cell growth and survival. Hsp90 activity has been shown to be increased significantly in cancer cells. Hsp90 inhibitor drug conjugates (HDCs) are small molecules that link an anti-cancer drug to an Hsp90 inhibitor. The Hsp90 inhibitor helps bring the anti-cancer drug inside the cancer cells. The anti-cancer drug can then be slowly released inside the cancer cells. Synta Pharmaceuticals has developed STA-12-8960, an Hsp90 inhibitor linked to SN-38, an active metabolite of the anti-cancer (chemotherapy) drug irinotecan. At higher doses (20 mg/kg), healthy dogs receiving STA-12-8960 developed mild vomiting, diarrhea and decreased appetite that was self-limiting; the drug was better tolerated at 10 mg/kg with a limited loss of appetite. STA-12-8960 has demonstrated significant activity in mouse models of cancer and would therefore be expected to have activity in dogs with cancer.
- Dogs diagnosed with lymphoma (B-cell or T-cell), sarcomas, carcinomas and mast cell tumors are permitted. Metastatic disease to regional lymph nodes and lungs are permitted.
- Solid tumors must measure at least 2cm in the longest dimension. Dogs with lymphoma must have at least stage II disease with at least one measurable lymph node 2cm in size or larger.
- Dogs must be at least 1 year of age and > 8 kg.
- Adequate organ function as indicated by standard
laboratory tests (complete blood count, serum biochemistry profile,
- ANC ≥ 1000/μL and platelet count ≥ 100,000/μL
- Liver: Total bilirubin ≤ 1.5X the institutional upper limit of normal (ULN), ALT ≤ 3X ULN
- Renal: Serum creatinine ≤ 1.5X ULN
- ECOG performance score of 0-1
- Dogs must have an estimated life expectancy of at least 6 weeks.
- Prior radiation therapy or chemotherapy must
have been completed at least 2 weeks prior to study entry, and the patient must
have recovered from the acute toxicities of these treatments.
- Prednisone therapy is permitted, provided disease progression has not occurred during the course of prednisone administration
- Informed written consent obtained.
- Pregnant or lactating dogs
- Evidence of brain metastasis
- Dogs with uncontrolled autoimmune hemolytic anemia (IMHA) or immune mediated thrombocytopenia (ITP) are not eligible.
- Concurrent use of complementary or alternative medications that in the opinion of the principal investigators would confound the interpretation of toxicities and/or antitumor activity of the study drug.
- Dogs with significant cardiovascular disease.
- Less than 2 weeks from a major surgical procedure.
- Any serious systemic disorder incompatible with the study (at the discretion of the principal investigators).
- Use of any other investigational drug within 2 weeks of study entry.
If enrolled, dogs will receive STA-12-8960 intravenously once a week on days 0, 7 and 14 of the clinical trial. Additionally, a baseline tumor biopsy will be taken prior to treatment then again 2 and 24 hrs after the first treatment. On day 0, a small amount of blood will be collected before treatment then at 2, 4, 8 and 24 hours after treatment for a total of 10 ml (2 teaspoons) to check for blood levels of STA-12-8960. Recheck examination and bloodwork will be performed once weekly for 28 days.
- If enrolled, all costs associated with the clinical trial will be covered and any side effects will be covered by the study up to a $1,000.