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

Study Overview
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Brief Summary
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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.

Detailed Description
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This is an international, randomized, open-label, double-arm, phase III trial that will be conducted in centers in Latin America, Asia, Europe and Canada. The study will be sponsored by Novartis Pharmaceuticals Corporation. Patient enrollment will be competitive and will have a duration of up to 30 months. An interim analysis is planned to occur when approximately 60% of the PFS events occurs. A total of 150 patients per arm will be enrolled in the study. Eligible patients will have advanced/metastatic, inoperable GIST of any anatomical location or recurrent GIST while on or post imatinib adjuvant therapy, with documented disease progression on therapy with imatinib 400 mg q.d.

Official Title
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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

Conditions
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Gastrointestinal Stromal Tumors

Intervention / Treatment
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* Drug: Nilotinib
* Drug: Imatinib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nilotinib<br>Patients who were assigned to this treatment group received 400 mg. nilotinib bid. | Drug: Nilotinib<br>* 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.<br>* Other names: Tasigna;|
| Active Comparator: Imatinib<br>Patients who were assigned to this treatment group received 400 mg. imatinib bid. | Drug: Imatinib<br>* 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).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | Progression-free survival (PFS) is the time from date of randomization to the date of first documented progression or death due to any cause. If a participant has not had an event, progression-free survival is censored at the time of last adequate tumor assessment. Progression is defined according to modified RECIST criteria as at least a 20% increase in the sum of the longest diameter of target lesions, worsening of the non-target lesions or the appearance of one or more new lesions. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Control Rate (DCR) | The Disease Control Rate (Complete Response(CR), Partial Response (PD) and Stable Disease (SD) rates for each treatment arm will be computed using the exact Clopper-Pearson interval estimation methodology. DCR is defined as the percentage of patients with a best overall response of • CR, i.e. at least two determinations of CR at least 4 weeks apart without loss of response between the determinations, • PR, i.e. at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR) and without loss of PR between the determinations, or • SD lasting at least 24 weeks, i.e. at least one SD or better response at least 24 weeks after randomization (and not qualifying for CR or PR). | every 2 months until 24 months (end of study) | 
| Time to Treatment Failure | TTF, defined as the time from date of randomization to the earliest of date of the first objective tumor progression, date of death due to any cause, or date of discontinuation due to reasons other than 'Protocol deviation' or 'Administrative problems'. | Time from date of radomization to the earliest date of the first objective tumor, death or discontinuation, assesed until 24 months. | 
| Overall Survival (OS) | . OS is defined as the time from the date of randomization to the date of death due to any cause or the date of last contact prior to or on the date of data cutoff. The median time to overall survival and its associated 95 % CI will be derived, for each treatment arm, using the time to event analysis based on Kaplan-Meier methodology. | time from the date of randomization to the date of death due to any cause or the date of last contact prior to or on the date of data cutoff, assesed until 24 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GIST