Status:
TERMINATED
Nilotinib 800 Mg And Imatinib 800 Mg For The Treatment Of Patients With Gastrointestinal Stromal Tumors (Gist) Refractory To Imatinib 400 Mg
Lead Sponsor:
Novartis Pharmaceuticals
Conditions:
Gastrointestinal Stromal Tumors
Eligibility:
All Genders
18+ years
Phase:
PHASE3
Brief 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 establis...
Detailed Description
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 Pharm...
Eligibility Criteria
Inclusion
- 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
- 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
Key Trial Info
Start Date :
June 1 2009
Trial Type :
INTERVENTIONAL
Allocation :
ACTUAL
End Date :
August 1 2012
Estimated Enrollment :
94 Patients enrolled
Trial Details
Trial ID
NCT00751036
Start Date
June 1 2009
End Date
August 1 2012
Last Update
March 26 2014
Active Locations (32)
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1
Novartis Investigative Site
Buenos Aires, Buenos Aires, Argentina, C1264AAA
2
Novartis Investigative Site
Caba, Buenos Aires, Argentina, C1426ANZ
3
Novartis Investigative Site
Fortaleza, Ceará, Brazil, 60430-230
4
Novartis Investigative Site
Belo Horizonte, Minas Gerais, Brazil, 30130-100