Nilotinib 800 Mg And Imatinib 800 Mg For The Treatment Of Patients With Gastrointestinal Stromal Tumors (Gist) Refractory To Imatinib 400 Mg
Condition: Gastrointestinal Stromal Tumors
MeSH terms: Gastrointestinal Stromal Tumors
Intervention: Nilotinib; Imatinib
Intervention description: Nilotinib hard gel capsules were supplied to the Investigators at dose strengths of 200 mg. Nilotinib is a novel agent, which has been approved for the treatment of chronic phase and accelerated phase Philadelphia-chromosome-positive CML in adult patients resistant to or intolerant to prior therapy that included imatinib.; Imatinib tablets were supplied at 100 mg and/or 400 mg dose strength. Imatinib is an approved agent for GIST. Efficacy of imatinib at a dose of 400 mg bid has been established in the setting of disease progression after the use of the conventional dose (400 mg qd).
Intervention MeSH terms: Imatinib Mesylate
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 94.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: GIST

Summary:

      The study will investigate the comparative efficacy and safety of two oral inhibitors of Kit
      and PDGFR: nilotinib 400 mg bid, a novel agent, and imatinib 400 mg bid, an approved agent
      with an established efficacy.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Provide a written informed consent.

          -  Male or female patients ≥ 18 years of age.

          -  Histologically confirmed diagnosis of GIST of any anatomical location, which is
             unresectable and/ or metastatic or recurrent.

          -  Documented disease progression according to RECIST 1.0. Documentation of progression
             required by either 2 CT scans or 2 MRI scans within 6 months prior to randomization
             (one image will document the lesion and the other will document the progression by
             lesion(s) growth or the presence of new lesion(s)). The interval between the 2 images
             should be no greater than 6 months apart. Scans will be provided to the selected
             imaging CRO.

          -  Documented disease progression must occur while on imatinib 400 mg PO q.d. Imatinib
             therapy could be for (1) unresectable GIST; (2) metastatic GIST; or (3) recurrent GIST
             while on imatinib adjuvant therapy or recurrent GIST post adjuvant imatinib therapy.

          -  Positive immunohistochemical staining for c-KIT (CD117) or negative staining for KIT,
             but with either positive staining for DOG1 or an identified mutation on KIT or PDGFR
             genes.

          -  Presence of at least one measurable lesion according to RECIST 1.0, defined as a
             lesion that can be accurately measured in at least one dimension (longest diameter) as
             ≥ 20 mm with conventional techniques (conventional CT or MRI scan) or as ≥ 10 mm with
             spiral CT scan. Lesions in previously irradiated areas can be considered measurable
             only if they have demonstrated clear evidence of progression since the radiotherapy.

          -  A performance status of 0, 1 or 2 according to the Eastern Cooperative Oncology Group
             (ECOG) scale (Oken et al 1982)(Appendix A).

          -  Adequate organ function, as indicated by all of the following:

          -  White blood cell (WBC) count ≥ 3500/mm3;

          -  Absolute neutrophil count (ANC) ≥1500/mm3;

          -  Hemoglobin ≥ 9.0 g/dL;

          -  Platelet count ≥ 100 x 109/L;

          -  Total bilirubin ≤ 1.5 X ULN (< 3.0 X ULN if related to disease);

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 times the
             ULN, unless liver metastases present, in which case AST and ALT have to be ≤ 5 times
             the ULN;

          -  Serum creatinine ≤ 1.5 times the ULN;

          -  Serum amylase and lipase ≤1.5 X ULN;

          -  Alkaline phosphatase ≤2.5 X ULN (≤ 5.0 X ULN if related to disease);

          -  Serum potassium, phosphorus, magnesium and calcium ≥ LLN [lower limit of normality] or
             correctable with supplements prior to first dose of study drug. (Total calcium
             corrected for serum albumin)

          -  Female patients of childbearing potential must have a negative serum pregnancy test
             within 7 days prior to registration.

          -  Fertile patients (female) must agree to use an acceptable method of contraception to
             avoid pregnancy for the duration of the study and for 3 months after study
             termination.

        Exclusion Criteria:

          -  Prior use of imatinib doses higher than 400 mg q.d. or prior use of any other
             tyrosine-kinase inhibitor.

          -  Tumor progression after stopping imatinib 400 mg q.d.

          -  No investigational cytotoxic drug ≤ 4 weeks (6 weeks for nitrosurea or mitomycin C)
             prior to the Screening Visit (V100) is allowed with the exception of imatinib therapy.

          -  Cytotoxic, or antineoplastic treatments, such as chemotherapy, immunotherapy,
             biological response modifiers, or radiotherapy.

          -  If the only measurable lesion was previously irradiated and has not shown clear
             evidence of progression since the radiotherapy, the patient cannot be included.

          -  Serious uncontrolled concomitant medical or psychiatric illness.

          -  Impaired cardiac function including any one of the following:

          -  LVEF < 45% or below the institutional lower limit of the normal range (whichever is
             higher) confirmed by ECHO or Muga

          -  Inability to determine the QT interval on ECG

          -  Complete left bundle branch block

          -  Right bundle branch block plus left anterior or posterior hemiblock

          -  Use of a ventricular-paced pacemaker

          -  Congenital long QT syndrome or a known family history of long QT syndrome

          -  History of or presence of clinically significant ventricular or atrial
             tachyarrhythmias

          -  Clinically significant resting bradycardia (<50 bpm);

          -  QTcF >450 msec on screening ECG (using the QTcF formula). If QTc >450 and electrolytes
             are not within normal ranges, electrolytes should be corrected and then the patient
             re-screened for QTc;

          -  History or clinical signs of myocardial infarction within 1 year of study entry

          -  History of unstable angina within 1 year of study entry

          -  Other clinically significant heart disease (e.g., congestive heart failureor
             uncontrolled hypertension).

          -  Treatment with strong CYP3A4 inhibitors (e.g., erythromycin, ketoconazole,
             itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, mibefradil) and
             the treatment cannot be discontinued or switched to a different medication prior to
             starting study drug. (Appendix B).

          -  Treatment with strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine,
             rifampin, rifabutin, rifapentin, phenobarbitol, St John's Wort), and the treatment
             cannot be discontinued or switched to a different medication prior to starting study
             drug.

          -  Patients using medication that have been documented to prolong QT interval (see
             Appendix B for complete list).

          -  Grade 3 or higher impairment of gastrointestinal (GI) function or GI disease that may
             significantly alter the absorption of study drug (e.g., ulcerative disease,
             uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome).

          -  History of acute pancreatitis within one year of study entry or medical history of
             chronic pancreatitis.

          -  Patients with a history of another primary malignancy that is currently clinically
             significant or currently requires active intervention.

          -  Patients with any other clinically significant medical or surgical condition which,
             according to investigators' discretion, should preclude participation; (i.e.: severe
             renal disease unrelated to tumor, active or chronic liver disease- hepatitis B or C
             virus carriers with normal liver function tests, as described above, can be included).
             This includes patient with an acquired bleeding disorder unrelated to cancer.

          -  Use of any investigational agent within 28 days prior to enrollment in the study or
             foreseen use of an investigational agent during the study.

          -  History of non-compliance to medical regimens or inability to grant consent.

          -  Women who are pregnant, breast feeding, or of childbearing potential without a
             negative serum pregnancy test at baseline. Male or female patients of childbearing
             potential unwilling to use effective barrier contraceptives throughout the trial and
             for 3 months following discontinuation of study drug. Post-menopausal women must have
             been amenorrheic for at least 12 months to be considered of non-childbearing
             potential.

          -  Inability to comply with the study protocol.

          -  Patients with a history of CNS metastasis. Note: Patients without clinical signs and
             symptoms of CNS involvement are not required to have CT/MRI of the brain.

          -  Major surgery within 4 weeks prior to randomization or those who have not recovered
             from prior surgery

        Other protocol-defined inclusion/exclusion criteria may apply