Nilotinib 800 Mg And Imatinib 800 Mg For The Treatment Of Patients With Gastrointestinal Stromal Tumors (Gist) Refractory To Imatinib 400 Mg

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