Nilotinib in Treating Patients with Recurrent Glioblastoma

Inclusion Criteria

• Ability to provide written informed consent prior to participation in the study and any related procedures being performed
• Participants must have agreed to and signed an authorization for the release of their protected health information
• Subjects must be able to adhere to the dosing and visit schedules, and agree to record medication times accurately and consistently in a daily diary
• Participants must have a life expectancy of at least 8 weeks
• Histologically documented diagnosis of proven glioblastoma (GBM)
• Patients must have undergone prior standard therapy of radiation therapy, and adjuvant chemotherapy
• Documentation of amplified PDGFR by fluorescent in-situ hybridization (FISH), colorimetric in-situ hybridization (CISH), or quantitative polymerase chain reaction (PCR) from tumor tissue (>= 3 copy number), or over expression by immunohistochemistry (IHC)
• Participants must have a Karnofsky Performance Status (KPS) >= 60
• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
• Platelet count >= 100 x 10^9/L
• Hemoglobin >= 9.0 g/dL
• White blood cell (WBC) count >= 3.0 x 10^9/L
• Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) =< 2.5 x institution's upper limit of normal (ULN)
• Total bilirubin =< 1.5 x institution's ULN
• Serum creatinine =< 1.5 x institution's ULN or 24-hour creatinine clearance >= 50 ml/min
• Alkaline phosphatase (ALP) =< 2.5 x ULN unless considered tumor related
• International normalized ratio (INR) < 1.5 x institutional ULN
• Partial thromboplastin time (PTT) =< 1.2 x institutional ULN
• Female patients of childbearing potential must have negative pregnancy test within 7 days before initiation of study drug dosing; postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential; male and female patients of reproductive potential must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drug
• Participants must have a progression by MRI or computed tomography (CT) scan; a scan must be performed within 21 days prior to cycle 1, day 1 (C1d1) and on a steroid dose that has been stable for at least 5 days; if the steroid dose is increased between the date of imaging and C1d1, a new baseline MRI/CT is required; the same type of scan, i.e., MRI or CT must be used throughout the period of protocol treatment for tumor measurement; a patient who develops a contraindication to undergo an MRI scan during study treatment may remain on study and undergo contrast enhanced CT scans
• Patients must have an interval of greater than or equal to 60 days from the completion of radiation therapy to study entry
• Subjects must have recovered from the toxic effects of prior therapy; residual toxicity from any previous treatment must be =< Grade 1
• Patients must have sufficient time for recovery from prior therapy: 28 days from any investigational agent, 28 days from prior cytotoxic therapy (except 23 days from prior temozolomide, 14 days from vincristine, 42 days from nitrosoureas, 21 days from procarbazine administration), and 7 days for non-cytotoxic agents, e.g., interferon, tamoxifen, thalidomide, cis-retinoic acid, etc.
• Patients with prior therapy that included interstitial brachytherapy or stereotactic radiosurgery must have confirmation of true progressive disease rather than radiation necrosis based upon positron emission tomography (PET), Thallium scanning, MR spectroscopy/perfusion, progression outside of radiation field, or surgical documentation of disease; if the additional imaging is unable to be performed for insurance or other reasons, the principal investigator (PI) will review the available imaging to determine if patients is eligible
• Subjects who have undergone recent resection of recurrent or progressive tumor will be eligible as long as all of the following conditions apply: * Prior to initiating therapy, 4 weeks must have elapsed since surgery; * Subjects must have recovered from surgical-related trauma; * Wound healing needs to have occurred

Exclusion Criteria

• Patients who received PDGFR inhibitors (imatinib, sunitinib, nilotinib, etc.) previously are excluded (patients who received PDGFR antibody based treatment however are allowed)
• History of intratumoral or peritumoral hemorrhage if deemed significant by the treating physician
• For patients requiring anti-coagulation therapy, only therapeutic low molecular weight heparin, direct thrombin inhibitors, or factor Xa inhibitors are permitted
• Due to the potential interaction between nilotinib and enzyme-inducing anti-epileptic drugs (EIAED - phenytoin, fosphenytonin, carbamazepine, oxcarbazepine, phenobarbital, primidone, felbamate), only patients on non-enzyme inducing anti-epileptic drugs (NEIAED) or on no anti-epileptic drugs are eligible
• Patient is < 3 years free of another primary malignancy except: if the other primary malignancy is not currently clinically neither significant nor requiring active intervention, or if other primary malignancy is a basal cell skin cancer or a cervical carcinoma in situ; existence of any other malignant disease is not allowed
• Female patients who are pregnant or breast-feeding, or intends to become pregnant during the study
• Any significant medical illnesses that in the investigator's opinion cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate this therapy
• Patient has a rare hereditary problem of galactose intolerance, severe lactase deficiency or of glucose-galactose malabsorption
• Patients with any disease that will obscure toxicity or dangerously alter drug metabolism
• Patient with electrolyte abnormality deemed clinically significant by the investigator (e.g., hypokalemia, hypomagnesemia, hypophosphatemia, hyperkalemia, hypocalcemia, hyponatremia) unless the level can be corrected to normal levels prior to initiating study drug
• Patient has a known diagnosis of human immunodeficiency virus (HIV) infection
• Concomitant use of any anti-cancer therapy or radiation therapy, or any other investigational agent
• Impaired cardiac function including any of the following: * Congenital long QT syndrome or a known family history of long QT syndrome * History or presence of clinically significant ventricular or atrial tachyarrhythmias * Clinically significant resting bradycardia (< 50 beats per minute) * Inability to monitor the QT interval by electrocardiogram (ECG) * Corrected QT (QTc) > 450 msec on baseline ECG; if QTc > 450 and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTc * Myocardial infarction within 1 year of starting study drug * Other clinically significant heart disease (e.g., unstable angina, congestive heart failure, or uncontrolled hypertension)
• Patients currently receiving treatment with strong cytochrome P450 3A4 (CYP3A4) inhibitors and treatment cannot be either discontinued or switched to a different medication prior to starting study drug
• Patient currently receiving treatment with any medications that have the potential to prolong the QT interval and cannot be either discontinued or switched to a different medication prior to starting study drug
• Impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection or gastric bypass surgery)
• Acute or chronic pancreatic disease
• Another malignancy that is clinically significant or requires active intervention (chemotherapy or radiation)
• Severe or uncontrolled medical conditions (i.e., uncontrolled diabetes, active or uncontrolled infection)
• Acute or chronic liver or severe renal disease
• History of significant congenital or acquired bleeding disorder
• Major surgery within 4 weeks prior to Day 1 of study or who have not recovered from prior surgery
• History of non-compliance to medical regimens or inability to grant consent