Phase II Trial of Vandetanib in Children and Adults With Wild-Type Gastrointestinal Stromal Tumors
Condition: GIST
MeSH terms: Gastrointestinal Stromal Tumors
Study type: Interventional
Phase: Phase 2

Summary: 
      Background:

      -Some people with wild-type gastrointestinal stromal tumors (WT-GIST) have a deficiency in
      one of their proteins called succinate dehydrogenase (SDH). Vandetanib is a cancer drug that
      has been approved to treat thyroid cancer and has been used with some success in other tumors
      that have a similar loss of SDH. Researchers want to see if this drug can also decrease tumor
      growth in people with WT-GIST.

      Objectives:

      -To test whether the study drug will benefit people with WT-GIST.

      Eligibility:

      -Adults and children 3 years old and older with WT-GIST.

      Design:

        -  Researchers will test participants tumor tissue to confirm it is the wild type of GIST.

        -  Participants will be screened with a medical history, physical exam, and blood tests.
           They will also have electrical recording of the heart (Eastern Cooperative Oncology
           Group (ECOG)) and scans of the tumor.

        -  Participants will take the study drug in 28-day cycles. Their doctor will decide how
           many cycles they can complete.

             -  They will take the study drug once every day and record it in a diary.

             -  On Day 14, they will also visit their doctor to look for side effects.

        -  Before cycles 2, 3 and 4, participants will have a physical exam, urine tests, blood
           pressure check, and blood tests. These tests will then be done periodically for as long
           as they are in the study.

        -  Before cycle 4, scans will be done to check the size of the cancer. Most of these will
           be repeated every 3-6 cycles.

        -  When they stop taking the study drug, participants will return to the clinic for a
           physical exam and blood tests.
    

Detailed description: 
      Background:

        -  Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the
           gastrointestinal tract, resistant to cytotoxic chemotherapy and radiation therapy. KIT
           and platelet derived growth factor receptor alpha (PDGFRA) mutations have been
           identified as tumor initiating events in 85% of adult patients with GIST, but 85% of
           GISTs in pediatric patients lack KIT and PDGFRA mutations (wild-type) and imatinib is
           not as effective in eliciting objective responses.

        -  Recent work in the Pediatric and Wild-Type (wt) GIST Clinic at the National Cancer
           Institute (NCI) led to the identification of succinate dehydrogenase (SDH) germline
           mutations in 12% patients with wt-GIST (6/34). SDH protein expression evaluated using
           immunohistochemistry (IHC) was markedly decreased or absent in 18/18 patients with
           pediatric wt-GIST. Thus the majority of wt-GIST are SDH-deficient. Vandetanib (ZACTIMA;
           ZD6474; AstraZeneca) is an oral small molecule antineoplastic drug that inhibits
           vascular endothelial growth factor receptor 2 (VEGFR2), estimated glomerular filtration
           rate (EGFR), and rearranged during transfection (RET)-dependent signaling. Preliminary
           preclinical data demonstrate marked growth inhibition of SDH-mutant/deficient renal cell
           carcinoma cell lines when treated with vandetanib.

      Objective(s):

      -Primary: To assess the clinical activity (radiographic response Response Evaluation Criteria
      in Solid Tumors (RECIST v1.1) of vandetanib in children and adults with wt-GIST using RECIST
      (v1.1).

      Eligibility:

      -Adults and children with measurable localized or metastatic wt-GIST confirmed in a Clinical
      Laboratory Improvement Amendments (CLIA) laboratory will be eligible for trial participation.
      Patients must have measurable disease by RECISTv1.1 and adequate organ function.

      Design:

        -  This phase II trial will determine whether daily oral vandetanib is active in patients
           with wt-GIST. Vandetanib activity will be assessed primarily by radiographic response of
           measurable disease using RECISTv1.1.

        -  Vandetanib will be administered orally once daily continuously in the absence of
           toxicity or disease progression, using a 28-day cycle.

        -  Patients will be carefully monitored for toxicity and response. A small, optimal
           two-stage phase II design with a target response rate of 25% will be used. Nine
           evaluable patients will be enrolled initially. If 1 or more of the first 9 have a
           response, then accrual would continue until a total of 24 patients have enrolled. If
           there are 3 or more responses in 24 (12.5% or more) patients, then this would be
           sufficiently interesting activity to warrant further study.
    

Intervention name(s): Vandetanib
Intervention type(s): Drug
Intervention description(s): Vandetanib administered orally once per day continuously using a 28 day cycle until disease progression or unacceptable toxicity
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: GIST; Small Molecule; Mesenchymal Tumor; Receptor Tyrosine Kinase; Survival