Dovitinib for Imatinib/Sumitinib-failed Gastrointestinal Stromal Tumors (GIST): TKI258
Condition: Gastrointestinal Stromal Tumors
MeSH terms: Gastrointestinal Stromal Tumors
Intervention: dovitinib
Intervention description: TKI258 at 500 mg/day on a 5 days on/2 days off dosing schedule
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 30.0
Sex: All
Minimum age: 20 Years
Healthy volunteers: No
Keywords: This is a single-center; prospective; single-arm; open-label phase II study

Summary:

      With discovery of KIT mutations and the advent of KIT tyrosine kinase inhibitor imatinib
      (GlivecTM, Novartis), there has been substantial improvement in overall survival in patients
      with advanced and/or metastatic gastrointestinal tumors (GIST). Recently, sunitinib
      (SuteneTM, Pfizer) showed activity as second-line therapy in GIST patients after failure with
      imatinib. However, virtually all patients will eventually progress or become intolerable
      after the first-line imatinib and the second-line sunitinib. Dovitinib (TKI258, Novartis) is
      a multi-kinase inhibitor. TKI258 is a potent inhibitor of the VEGFR 1, 2, and 3, FGFR1, 2 and
      3, PDGFRβ, Kit, RET, TrkA, CSF 1R, and FLT3 with inhibitory concentration 50% (IC50s) of less
      than 40nM. Stem cell factor (SCF) also termed KIT ligand, or steel factor has been shown to
      modulate tumor angiogenesis. In cultured human endothelial cells and Kit expressing cancer
      cells, TKI258 inhibits VEGF- and SCF-stimulated mitogenesis. .
    

Eligibility criteria:

        Inclusion criteria

          -  Age 20 years or older

          -  Histologically confirmed metastatic and/or advanced GIST with CD117(+), DOG-1(+), or
             mutation in KIT or PDGFRα gene

          -  Failed (progressed and/or intolerable) after prior treatments for GIST, including at
             least both imatinib and sunitinib .

          -  ECOG performance status of 0~2

          -  Resolution of all toxic effects of prior treatments to grade 0 or 1 by NCI-CTCAE
             version 3.0

          -  At least one measurable lesion as defined by RECIST version 1.0.

          -  Adequate bone marrow, hepatic, renal, and other organ functions

               -  Neutrophil > 1,500/mm3

               -  Platelet > 75,000/mm3

               -  Hemoglobin > 8.0 g/dL

               -  Total bilirubin < 1.5 x upper limit of normal (ULN)

               -  AST/ALT < 2.5 x ULN (or < 5 x ULM in case of liver metastases)

               -  Creatinine < 1.5 x ULN

               -  Amylase, lipase < ULN

          -  Electrolytes should be within normal limits.

          -  Urine dipstick reading: Negative for proteinuria or, if documentation of +1 results
             for protein on dipstick reading, then total urinary protein ≤ 500 mg and measured
             creatinine clearance ≥ 50 mL/min/1.73m2 from a 24-hour urine collection

          -  Life expectancy > 12 weeks

          -  Women with reproductive potential must have a negative serum or urine pregnancy test

          -  Washout period of previous TKIs or chemotherapy for more than 4 times the half life.

          -  Provision of a signed written informed consent

        Exclusion criteria

          -  Women of child-bearing potential who are pregnant or breast feeding or adults of
             reproductive potential not employing an effective method of birth control.

          -  Clinically significant cardiac disease (New York Heart Association, Class III or IV)
             or impaired cardiac function or clinically significant cardiac diseases,

          -  Uncontrolled infection.

          -  Diabetes mellitus (insulin dependent or independent disease, requiring chronic
             medication) with signs of clinically significant peripheral vascular disease.

          -  Previous pericarditis; clinically significant pleural effusion in the previous months
             or current ascites requiring two or more interventions/month.

          -  Known pre-existing clinically significant disorder of the hypothalamic-pituitary axis,
             adrenal or thyroid glands.

          -  Prior acute or chronic pancreatitis of any etiology.

          -  Acute and chronic liver disease and all chronic liver impairment.

          -  Malabsorption syndrome or uncontrolled gastrointestinal toxicities with toxicity
             greater than NCI CTCAE grade 2.

          -  Other severe, acute, or chronic medical or psychiatric condition or laboratory
             abnormality.

          -  Treatment with any of the medications that have a potential risk of prolonging the QT
             interval or inducing Torsades de Points and the treatment cannot be discontinued or
             switched to a different medication prior to starting study drug.

          -  Use of ketoconazole, erythromycin, carbamazepine, phenobarbital, rifampin, phenytoin
             and quinidine 2 weeks prior baseline.

          -  Major surgery ≤ 28 days prior to starting study drug or who have not recovered from
             side effects of such therapy.

          -  Known diagnosis of HIV infection .

          -  History of another primary malignancy that is currently clinically significant or
             currently requires active intervention.

          -  Patients with brain metastases as assessed by radiologic imaging

          -  Alcohol or substance abuse disorder.

          -  no other inhibitor of FGFR except sunitinib