Pulse Toceranib plus Lomustine for the Treatment of Unresectable Canine Mast Cell Tumors: A Multicenter Study Led by Colorado State University

Purpose

 This study is a multi-center effort led by Dr. Doug Thamm at Colorado State University to determine the maximum tolerated dose, tolerability and adverse effect profile of combined treatment with pulse-dose toceranib and lomustine in dogs with MCT. He also would like to determine the response rate and progression-free interval in dogs with measurable MCT treated with combined pulse-dose toceranib and lomustine.

Background

Mast cell tumors (MCT) represent the most common cutaneous tumor in the dog, accounting for between 16 and 21% of all cutaneous tumors. In tumors localized to the skin in areas amenable to wide excision, surgery is the treatment of choice. However, locally recurrent, large or infiltrative tumors, those that have metastasized beyond the regional lymph node, or those in locations not amenable to wide surgical excision present a therapeutic challenge. A variety of medical therapies have been studied for canine MCT, including corticosteroids alone, lomustine, and prednisone and vinblastine. While generally well tolerated, response rates generally remain at or below 50% and are usually brief and incomplete. The tyrosine kinase inhibitor (TKI) toceranib (Palladia) has demonstrated encouraging single-agent antitumor activity against canine MCT; however most dogs do not experience complete remission. Extensive information exists demonstrating synergy between several different TKIs and chemotherapeutics in the treatment of human cancers, presumably owing to down regulation of important anti-apoptotic pathways. Therefore, we predict that pulse administration of TKI’s with chemotherapy may effectively chemosensitize while reducing toxicity and owner cost. Prior to toceranib’s approval, a pilot study was performed of pulse-administered imatinib combined with lomustine in dogs with MCT. While a dose reduction of lomustine was necessary, encouraging antitumor activity was observed. Based on these observations, we hypothesize that the combination of pulse-administered toceranib and lomustine will be well tolerated and efficacious.

Inclusion criteria

To qualify for enrollment in this study, dogs must have:

  • A histologically or cytologically confirmed, measurable mast cell tumor. Regional or distant metastatic disease is allowable, if the patient has expected survival duration of at least 6 weeks.
  • Mass must be a minimum of 1 cm in size, and can have disease anywhere as long as it is measureable. 
  • Adequate laboratory and clinical indices to safely undergo therapy (specifically: total bilirubin not exceeding 1.5x normal; transaminases not exceeding 2x normal; creatinine not exceeding 2x normal; at least 2,500 neutrophils/µL, 75,000 platelets/µL, and a hematocrit of at least 28%)
  • A performance status of 0-1

 Exclusion criteria

  • No  severe, complicating concurrent disease conditions
  • Prior chemotherapy and radiation therapy is allowable with a 2- and 6-week washout, respectively. No prior kinase inhibitors are allowed.  Concurrent NSAIDs are discouraged due to the potential for additive likelihood of GI ulceration.
  • No concurrent anti-neoplastic therapy allowed

Study Design

If, upon evaluation, the dog meets eligibility criteria, the owner must complete an Owner Consent Form of their pet’s initial clinical appearance. For baseline status, blood and urine will be sampled; target tumors identified, measured. Also thoracic radiographs and/or abdominal ultrasound will be performed, as well as, tumor and skin biopsies. 

  • Complete blood count and ALT will be evaluated prior to each treatment cycle; delay treatment if neutrophils <2,000/µL, if platelets <50,000/µL, or if ALT >2x ULN (or 2x pre-treatment value if elevation was detected prior to therapy)
  • Dogs will be treated with Palladia (2.75 mg/kg PO q 24h) on Days 1, 3, 5 and CCNU (lomustine; 60 mg/m2 PO) on Day 3
  • Treatment will be repeated every 3 weeks 

Client Compensation

This clinical trial provides free Lomustine and Palladia to dog owners, and provides a small amount of funds to cover some of the diagnostic tests. Adverse event costs are covered.

Contact Information

The clinical trials office at clinicaltrials [at] cvm [dot] osu [dot] edu