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An Exploratory Study of the Oral Selective Inhibitor of Nuclear Export (SINE) KPT-335 in Dogs with Lymphoma
Purpose of Study
The purpose of this study is to evaluate the safety and antitumor activity of KPT-335 in dogs with lymphoma in first relapse after completion of a single chemotherapy protocol (multi-agent or single agent).
In both normal and cancerous cells, proteins important in regulating cell growth and survival regularly move between the cell cytoplasm and the nucleus (center) of the cell. This shuttling of proteins is tightly controlled and helps to decide which genes get turned on and which genes get turned off. It is known that a specific protein in the membrane of the nucleus, CRM1, controls the shuttling of several key proteins in and out of the nucleus. In fact, over 150 proteins have been found to use CRM1 to leave the nucleus of the cell and enter the cytoplasm. In cancer cells, the function of CRM1 is critical to maintaining the uncontrolled growth and survival of these cells. Recent studies indicate that blocking CRM1 can induce death of cancer cells as they cannot recover function when the shuttling of proteins is disrupted; in contrast, normal cells appear to be less sensitive to this effect, likely because they are not growing in an uncontrolled manner. The novel compound KPT-335 is an irreversible inhibitor of CRM1; that is, once it binds, CRM1 cannot function unless new CRM1 protein is made. Studies in the laboratory have shown that KPT-335 kills a variety of cancer cell lines, even those known to be resistant to chemotherapy. KPT-335 has also demonstrated activity in mouse models of cancer when given by injection under the skin or orally. KPT-335 has also been tested in normal dogs where doses of 3-5 mg/kg were given Monday, Wednesday, Friday (MWF). Mild vomiting, diarrhea, and appetite loss did occur; this recovered with the addition of canned food to the diet and supportive care. In doses above 58 mg/kg, elevations in liver values were observed, although they recovered with discontinuation of drug and the use of a lower dose. A study of KPT-335 was performed in dogs with cancer and the dose of 1.5 mg/kg was found to be well-tolerated over 4-20 weeks of dosing when given on a Monday/Wednesday/Friday (MWF) basis. In dogs with lymphoma, partial shrinkage of lymph nodes and stable disease were noted in over half of the patients treated. Side effects from KPT-335 given at this dose on a MWF basis included mild loss of appetite, occasional vomiting, and diarrhea, with some dogs experiencing an increase in thirst and an increase in urination. All of these side effect were mild and well-controlled with additional medications.
To qualify for enrollment in this study, dogs must:
- Dogs with lymphoma, relapsed cases currently taking prednisone. Both B and T cell accepted.
- At least one peripherally located lymph node that measures
- Dogs must be at least 1 year of age
- Adequate organ function as indicated by standard laboratory tests
- Dogs must have an estimated life expectancy of at least 28 days.
- Prior chemotherapy or radiation must be completed at least 2 weeks prior
- Owner must be able to orally administer drug according to designated schedule
- No evidence of brain metastasis
- Can not be less than 2 weeks from a major surgical procedure
- Your dog will receive KPT-335 given at a dose of 1.25 mg/kg orally two days each week. Your dog will return weekly for the first 4 weeks, then every other week thereafter if your dog has experienced a complete response, partial response, or stable disease following treatment. Standard bloodwork will be performed at each visit. Analysis for tumor response will be performed by direct tumor measurement or through the use of x-rays or ultrasound.
If deemed eligible, the sponsor will cover study associated costs for screening, exam fees, labwork and adverse events.
Please contact the Clinical Trials Office at the Veterinary Medical Center for more information about this study.