Gastrointestinal Stromal Tumors
Conditions
Keywords
GIST, Nilotinib
Brief summary
This is a phase II study of Nilotinib for patients with advanced GIST that cannot be surgically removed. Patients are candidates for the study if their tumors have progressed on imatinib and sunitinib or if they were intolerant to these drugs. Patients may have received other investigational therapies as well. We are testing the benefit of nilotinib in advanced GIST looking at the length of time disease is controlled as well as the response of the disease to the drug.
Detailed description
Nilotinib is an oral drug. The dose is 400 mg twice daily Patients are evaluated every 8 weeks for disease response. Blood work is assessed for safety initially weekly, then every 4 weeks. Physical exams are performed initially weekly and then decreased to every 4 weeks after the first month.
Interventions
DRUGNilotinib
400 mg orally twice daily until disease progression, intolerability or withdrawal of consent
Sponsors
Fox Chase Cancer Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have histologically or cytologically confirmed GIST * Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as \>= 20 millimeters (mm) with conventional techniques or as \>= 10 mm with spiral CT scan. * Patients may have received prior chemotherapy or radiation therapy. Patients must have recovered from any prior therapy and at least 4 weeks (6 weeks for nitrosoureas or mitomycin C; 2 weeks for limited field palliative radiation) must have elapsed since prior treatment. * Patients must have received and progressed on imatinib and sunitinib. Except for nilotinib, patients may have received additional tyrosine kinase inhibitors or additional targeted therapies. * Age \>= 18 years. * Life expectancy of greater than 12 weeks. * Eastern Cooperative Oncology Group (ECOG) performance status 0-2 * Patients must have normal organ and marrow function as defined below: * absolute neutrophil count \>= 1,500/mcL * platelets \>= 100,000/mcL * total bilirubin \<= 1.5 times Upper Limits of Normal (ULN) * AST(SGOT)/ALT(SGPT) \<= 2.5 X ULN OR \<= 5.0 X ULN if considered due to tumor * Potassium, magnesium normal or corrected to normal limits prior to initiating drug * Calcium, phosphorus normal or corrected to normal limits prior to initiating drug * creatinine within normal institutional limits * creatinine clearance 24 hour creatinine clearance \>= 50 mL/min (calculation by cockroft formula is acceptable) * The effects of Nilotinib on the developing human fetus at the recommended therapeutic dose are unknown. Men or women of childbearing potential (WOCBP), to include female partners of heterosexual or bisexual patients, must agree to use an effective method of contraception during the study and for up to three months following termination of the study. Post menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. * Ability to understand and the willingness to sign a written informed consent document.
Exclusion criteria
* Patients may not be receiving any other investigational agents within 4 weeks. * Prior or concomitant malignancies (with a relapse in the last 5 years or requiring active treatment) other than GIST and with the exception of previous or concomitant basal cell skin cancer, previous cervical carcinoma in situ * Impaired cardiac function at baseline, including any one of the following: * Left Ventricular Ejection Fraction (LVEF)\< 45% or below the institutional Lower Limits of Normal (LLN) range (whichever is higher) * Complete left bundle branch block * Use of a ventricular paced cardiac pacemaker * Congenital long QT syndrome or family history of long QT syndrome * History of or presence of significant ventricular or atrial tachyarrhythmias * Clinically significant resting bradycardia (\< 50 beats per minute) * QTc \> 450 msec on screening ECG (using the QTcF formula). If QTc \> 450 msec and electrolytes are not within normal ranges (electrolytes should be corrected and then the patient rescreened for QTc. * Right bundle branch block plus left anterior hemiblock, bifascicular block * Myocardial infarction within 12 months prior to Visit 1 * Other clinically significant heart disease (e.g., unstable angina, congestive heart failure or uncontrolled hypertension) * Patients with severe and/or uncontrolled concurrent medical disease that in the opinion of the investigator could cause unacceptable safety risks or compromise compliance with the protocol e.g. impairment of gastrointestinal (GI) function, or GI disease that may significantly alter the absorption of the study drugs, uncontrolled diabetes * Use of therapeutic coumarin derivatives (i.e. warfarin, acenoucumarol, phenprocoumon) * Use of any medications that prolong the QT interval and CYP3A4 inhibitors if the treatment cannot be either safely discontinued or switched to a different medication prior to starting study drug administration. Please see http://www.torsades.org/medical-pros/drug-lists/printable-drug-list.cfm for a comprehensive list of agents that prolong the QT interval as well as * Patients who have undergone major surgery \<= 2 weeks prior to Visit 1 or who have not recovered from side effects of such surgery * A history of noncompliance to medical regimens or inability or unwillingness to return for scheduled visits, patients who are pregnant or breast feeding, and patients unwilling or unable to comply with the requirements for the protocol. * Patient has known chronic liver disease (i.e., chronic active hepatitis, and cirrhosis). * Patient has a known diagnosis of human immunodeficiency virus (HIV) infection.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival Rate at 6 Months | 6 months | Number of participants that demonstrate progression free survival at 6 months |
| Response Rate | 1year | Response rate of nilotinib by RECIST criteria evaluated every 2 months for the first 6 months then every 3 months for the duration of treatment period. |
Countries
United States
Participant flow
Recruitment details
Patients were accrued between 7/03/2008 and 9/24/2009 at Fox Chase Cancer Center outpatient medical oncology clinics.
Pre-assignment details
Advanced GIST with measurable disease; previously treated with at least imatinib and sunitinib; a 5-day washout from prior tyrosine kinase inhibitor therapy. Normal cardiac function with LVEF 45% or \>, no history of significant heart disease,arrhythmias,congenital long QT sydrome, heart block, MI within 12 mos of visit 1 or unstable angina, CHF
Participants by arm
| Arm | Count |
|---|---|
| Nilotinib Arm All patients treated with nilotinib 400 mg BID orally daily; 4 weeks = one cycle | 15 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Treatment Phase | fibrous tumor not GIST | 1 |
Baseline characteristics
| Characteristic | Nilotinib Arm |
|---|---|
| Age Categorical <=18 years | 0 participants |
| Age Categorical >=65 years | 4 participants |
| Age Categorical Between 18 and 65 years | 9 participants |
| Gender Female | 4 participants |
| Gender Male | 9 participants |
| Primary Site of Cancer Colon | 1 Participants |
| Primary Site of Cancer Rectum | 1 Participants |
| Primary Site of Cancer Small Bowel | 5 Participants |
| Primary Site of Cancer Stomach | 6 Participants |
| Prior Tyrosine Kinase Inhibitor (TKI) IM and SU | 11 Participants |
| Prior Tyrosine Kinase Inhibitor (TKI) IM, SU and NA | 1 Participants |
| Prior Tyrosine Kinase Inhibitor (TKI) IM, SU, RT and CT | 1 Participants |
| Region of Enrollment United States | 13 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 13 / 13 |
| serious Total, serious adverse events | 12 / 13 |
Outcome results
Primary
Progression Free Survival Rate at 6 Months
Number of participants that demonstrate progression free survival at 6 months
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nilotinib Arm | Progression Free Survival Rate at 6 Months | 13 Participants |
Primary
Response Rate
Response rate of nilotinib by RECIST criteria evaluated every 2 months for the first 6 months then every 3 months for the duration of treatment period.
Time frame: 1year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nilotinib Arm | Response Rate | 5 Participants |