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Pilot study of a MEK inhibitor in dogs with histiocytic sarcoma

Status: Recruiting

Species: Dog

Veterinary Speciality: Oncology

Description

Histiocytic sarcoma represents a devastating disease in both dogs and humans, with little effective therapies for many patients.  While surgery, radiation and chemotherapy can be used to control disease for variable periods of time, most patients eventually fail treatment and die of tumor spread (metastasis) within 6-12 months of diagnosis. Published studies have shown that gene mutations (mostly the PTPN11 gene) in canine histiocytic sarcoma drive activation of a specific cell signaling pathway called the MAPK pathway.  One of the components of this pathway is a protein called MEK.  Studies of canine histiocytic tumor cells in the laboratory and in mouse models of disease show that an inhibitor of MEK called trametinib can slow or stop growth of this tumor.  The purpose of this clinical trial is to evaluate the effectiveness, safety and blood levels of the MEK inhibitor trametinib in dogs with histiocytic sarcoma. While trametinib was approved by the FDA in 2013 to treat people with melanoma (an aggressive skin cancer) and has now been used to treat people with several other kinds of cancers, it has not been studied formally in dogs (i.e., there have been no published studies with trametinib treatment in dog cancers).  However, trametinib has been used in dogs to treat a variety of cancers for the past 3 years in an unofficial setting (also known as “off label”, through compounding pharmacies) and a dose range has been determined that has been found to be well-tolerated by most dogs. In this study, we will determine whether trametinib can stop the growth of histiocytic sarcoma in dogs using this dose range and will determine what the trametinib blood levels.  The study will also look at the genetics of the tumor (provided by Fidocure) to determine what gene mutations are present and will assess whether the trametinib blocks MEK activation in the histiocytic sarcoma cells.  In this study, all dogs receive the trametinib (there is no placebo).

Inclusion Criteria

Eligible patients (any breed of dog) must meet all of the following criteria:

  • Dogs diagnosed with histologically or cytologically confirmed histiocytic sarcoma are eligible to enroll. The patient may have failed standard therapy or there may be no other known effective antineoplastic therapeutic options, or the owner may elect to enter the patient in lieu of standard therapy.
  • Dogs must be at least 1 year of age
  • Adequate organ function as indicated by standard laboratory tests (complete blood count, serum biochemistry profile, urinalysis).
    • 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 ≤5X ULN
    • ECOG performance score of 0-1
  • Dogs must have an estimated life expectancy of at least 28 days.
  • Prior chemotherapy or radiation must be completed 2 weeks prior to study entry and the patient must have recovered from the acute toxicities of these treatments.
  • Informed written consent must be obtained
  • The owner must be able to orally administer drug according to designated schedule.

Exclusion Criteria

Patients (dogs) meeting any of the following criteria will not be eligible for the study:

  • Pregnant or lactating dogs
  • Evidence of brain metastasis
  • Dogs with uncontrolled autoimmune hemolytic anemia (AIHA) or immune mediated thrombocytopenia (ITP) are not eligible.
  • Concurrent 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 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 1 week of study entry.

 

Client Benefits

The study will cover  all study related activities through the end of the last visit on Day 56.  This includes office visits, x-rays, needle aspiration of the tumor for diagnosis and blood work.  The study will cover any complications from the biopsy of the tumor or from administration of the trametinib (vomiting, diarrhea, etc).  The study will not cover costs associated with conditions unrelated to treatment of histiocytoc sarcoma (skin infection, ear infection, etc.). After Day 56, if your dog is responding to treatment (tumor has stopped growing or has gotten smaller) trametinib will be provided to you at no cost until such time as the disease becomes progressive.  However, the office visits and blood work will become your responsibility.  Medication refills will be provided once per month during this time period.

Sample or Data Requirements

.  At the first study day (Day 0) and after two weeks (Day 14) we will take needle biopsies of your dog’s tumor.  This is done using sedation (not anesthesia) and a local block, using a biopsy needle that is the width of the lead in a pencil (14 gauge).  No stitches are placed in the skin as the needle hole is very small (2-3 mm) and is closed with surgical glue.  On Day 0 we will also place an intravenous catheter so we can collect blood before and after the first dose of trametinib which we will give in the hospital.  This will allow us to determine what the blood levels of the drug are. Your dog will go home the same day (no overnight stay is needed).  We will follow your dog’s bloodwork to check cell counts and make sure that the liver and kidneys are functioning normally.  At each treatment, we will also collect a blood sample (approximately 1-2 tablespoons) that will allow us to look for markers that indicate response to treatment.

Contact Info

For questions regarding the clinical trial please email the clinical trials technician, Diane Welsh at: clinicaltrials@tufts.edu