Evaluation of four STA-1474 dosing regimens in dogs with mast cell tumors

Purpose

The goal of this study is to determine response rates in dogs with mast cell tumors recieving STA-1474 using 4 different dosing regimens.

Background 

Heat shock protein 90 (HSP90) is a chaperone protein important in the maintenance of several cellular proteins such as the oncogene Kit. Evidence suggests that its activity is upregulated in cancer cells to maintain appropriate folding and expression of client proteins, particularly when these proteins are over-expressed or mutated.  As such, adequate HSP90 activity is considered to be critical for the survival of several types of cancer cells.  STA-1474, a novel water-soluble resorcinol-containing compound, is metabolized to STA-9090, a potent HSP90 inhibitor that exhibits superior anti-tumor efficacy relative to HSP90 inhibitors of the geldanamycin class.   A Phase 1 trial of STA-1474 was performed in 25 dogs with spontaneous tumors. Measurable responses were observed in dogs with mast cell tumors, osteosarcoma, melanoma and thyroid carcinoma. The greatest biologic activity occured in a dosing cohort that received STA-1474 at 9.5 mg/kg over 8 hours resulting in plasma levels of STA-9090 greater than 50 ng/ml for 12 hours suggesting that long plasma exposures may be associated with greater biologic activity.  Given that an 8 hour infusion of STA-9090 in the human clinical setting is not possible, this study seeks to determine whether two consecutive days of treatment with STA-1474 is superior to other regimens with respect to target modulation and response to therapy.  

Inclusion criteria

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

  • a cytologic or histologic diagnosis of MCT.
  • be at least 1 year of age.
  • adequate organ function
  • not have evident of systemic disease
  • an estimated life expectancy of at least 8 weeks.
  • not received prior chemotherapy (including Kit inhibitors) or radiation therapy although can have received prednisone

Study Design

Dogs with MCT will undergo screening including complete blood count, chemistry panel, urinalysis and abdominal ultrasound to determine eligibility for the study.  A baseline tumor biopsy will then be obtained if your dog is found to be eligible.  Your dog will receive standard medications prior to getting STA-1474 to prevent any diarrhea or vomiting.  Following the biopsy, your dog will receive STA-1474 STA-1474 (Monday/Tuesday) with conventional chemotherapy (Vinblastine, a drug with known activity against MCT)a single dose of STA-1474 at 6 mg/kg over 1 hour

A tumor biopsy will be obtained 24 hrs and 72 hours after the last STA-1474 administration on the first cycle.  The treatments will then be repeated for another 3 cycles, although no further biopsies will be performed. If your dog has responded to therapy, then you will have the option of continuing treatment with STA-1474, although the costs for drug administration will not be covered for these subsequent treatments.  

Client Compensation

 All costs associated with this study are covered by the study including management of any side effects that may occur. 

 Contact Information

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