Randomized Phase III Trial Comparing Nilotinib 800mg to Imatinib 800 mg for the Treatment of Patients With Advanced and/or Metastatic Gastrointestinal Stromal Tumors Refractory to Imatinib 400 mg
- 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
- 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
- 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
- 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
- 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
- Prior use of imatinib doses higher than 400 mg q.d. or prior use of any other
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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