Nilotinib in Advanced Gastrointestinal Stromal Tumors (GIST)
Condition: Gastrointestinal Stromal Tumors
MeSH terms: Gastrointestinal Stromal Tumors
Intervention: Nilotinib
Intervention description: 400 mg orally twice daily until disease progression, intolerability or withdrawal of consent
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 13.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: GIST; Nilotinib

Summary:

      This is a phase II study of Nilotinib for patients with advanced GIST that cannot be
      surgically removed. Patients are candidates for the study if their tumors have progressed on
      imatinib and sunitinib or if they were intolerant to these drugs. Patients may have received
      other investigational therapies as well. We are testing the benefit of nilotinib in advanced
      GIST looking at the length of time disease is controlled as well as the response of the
      disease to the drug.
    

Eligibility criteria:

        Inclusion Criteria

          -  Patients must have histologically or cytologically confirmed GIST

          -  Patients must have measurable disease, defined as at least one lesion that can be
             accurately measured in at least one dimension (longest diameter to be recorded) as >=
             20 millimeters (mm) with conventional techniques or as >= 10 mm with spiral CT scan.

          -  Patients may have received prior chemotherapy or radiation therapy. Patients must have
             recovered from any prior therapy and at least 4 weeks (6 weeks for nitrosoureas or
             mitomycin C; 2 weeks for limited field palliative radiation) must have elapsed since
             prior treatment.

          -  Patients must have received and progressed on imatinib and sunitinib. Except for
             nilotinib, patients may have received additional tyrosine kinase inhibitors or
             additional targeted therapies.

          -  Age >= 18 years.

          -  Life expectancy of greater than 12 weeks.

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-2

          -  Patients must have normal organ and marrow function as defined below:

               -  absolute neutrophil count >= 1,500/mcL

               -  platelets >= 100,000/mcL

               -  total bilirubin <= 1.5 times Upper Limits of Normal (ULN)

               -  AST(SGOT)/ALT(SGPT) <= 2.5 X ULN OR <= 5.0 X ULN if considered due to tumor

               -  Potassium, magnesium normal or corrected to normal limits prior to initiating
                  drug

               -  Calcium, phosphorus normal or corrected to normal limits prior to initiating drug

               -  creatinine within normal institutional limits

               -  creatinine clearance 24 hour creatinine clearance >= 50 mL/min (calculation by
                  cockroft formula is acceptable)

          -  The effects of Nilotinib on the developing human fetus at the recommended therapeutic
             dose are unknown. Men or women of childbearing potential (WOCBP), to include female
             partners of heterosexual or bisexual patients, must agree to use an effective method
             of contraception during the study and for up to three months following termination of
             the study. Post menopausal women must be amenorrheic for at least 12 months to be
             considered of non-childbearing potential.

          -  Ability to understand and the willingness to sign a written informed consent document.

        Exclusion Criteria

          -  Patients may not be receiving any other investigational agents within 4 weeks.

          -  Prior or concomitant malignancies (with a relapse in the last 5 years or requiring
             active treatment) other than GIST and with the exception of previous or concomitant
             basal cell skin cancer, previous cervical carcinoma in situ

          -  Impaired cardiac function at baseline, including any one of the following:

               -  Left Ventricular Ejection Fraction (LVEF)< 45% or below the institutional Lower
                  Limits of Normal (LLN) range (whichever is higher)

               -  Complete left bundle branch block

               -  Use of a ventricular paced cardiac pacemaker

               -  Congenital long QT syndrome or family history of long QT syndrome

               -  History of or presence of significant ventricular or atrial tachyarrhythmias

               -  Clinically significant resting bradycardia (< 50 beats per minute)

               -  QTc > 450 msec on screening ECG (using the QTcF formula). If QTc > 450 msec and
                  electrolytes are not within normal ranges (electrolytes should be corrected and
                  then the patient rescreened for QTc.

               -  Right bundle branch block plus left anterior hemiblock, bifascicular block

               -  Myocardial infarction within 12 months prior to Visit 1

               -  Other clinically significant heart disease (e.g., unstable angina, congestive
                  heart failure or uncontrolled hypertension)

          -  Patients with severe and/or uncontrolled concurrent medical disease that in the
             opinion of the investigator could cause unacceptable safety risks or compromise
             compliance with the protocol e.g. impairment of gastrointestinal (GI) function, or GI
             disease that may significantly alter the absorption of the study drugs, uncontrolled
             diabetes

          -  Use of therapeutic coumarin derivatives (i.e. warfarin, acenoucumarol, phenprocoumon)

          -  Use of any medications that prolong the QT interval and CYP3A4 inhibitors if the
             treatment cannot be either safely discontinued or switched to a different medication
             prior to starting study drug administration. Please see
             http://www.torsades.org/medical-pros/drug-lists/printable-drug-list.cfm for a
             comprehensive list of agents that prolong the QT interval as well as

          -  Patients who have undergone major surgery <= 2 weeks prior to Visit 1 or who have not
             recovered from side effects of such surgery

          -  A history of noncompliance to medical regimens or inability or unwillingness to return
             for scheduled visits, patients who are pregnant or breast feeding, and patients
             unwilling or unable to comply with the requirements for the protocol.

          -  Patient has known chronic liver disease (i.e., chronic active hepatitis, and
             cirrhosis).

          -  Patient has a known diagnosis of human immunodeficiency virus (HIV) infection.