Study of Platelet Derived Growth Factor Receptor (PDGFR) in Recurrent Malignant Gliomas
Condition: Glioma
MeSH terms: Glioma
Intervention: nilotinib
Intervention description: 400mg po (orally) BID (twice daily)
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 38.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: glioma; PDGFR; kinase; inhibitor; malignant; nilotinib

Summary:

      The purpose of this study is to determine the survival, disease response, and side effects of
      Tasigna® (nilotinib) in patients who have malignant gliomas and are positive for Platelet
      Derived Growth Factor Receptor (PDGFR) amplification. This study is designed to test the
      hypothesis that patients with malignant gliomas with PDGFR amplification are sensitive to
      PDGFR kinase inhibitors.
    

Eligibility criteria:

        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.

          -  Patients greater than 18 years of age.

          -  Histologically documented diagnosis of proven glioblastoma (GBM), or anaplastic
             astrocytoma (AA), anaplastic oligodendroglioma (AO), and anaplastic mixed
             oligoastrocytoma (AMO). Patients are eligible if the original local pathology was
             lower-grade glioma. Pathology will be read centrally to confirm diagnosis.

          -  Documentation of amplified PDGFRA by fluorescent in-situ hybridization (FISH),
             colorimetric in-situ hybridization (CISH), or quantitative PCR from tumor tissue (=>3
             copy number). Availability of unstained paraffin slides or the paraffin block of
             pretreatment baseline tissue is required for eligibility and for molecular analysis
             and would help to identify molecular predictors of outcome (all patients).

          -  Participants must have a Karnofsky Performance Status (KPS) ≥ 60.

          -  Adequate end organ function, defined as the following:

               -  Hematology:

                    -  Absolute neutrophil count (ANC) ≥ 1.5 x 109/L

                    -  Platelet count ≥ 100 x 109/L

                    -  Hemoglobin ≥ 9.0 g/dL

                    -  White blood cell (WBC) count ≥ 3.0 x 109/L

               -  Biochemistry:

                    -  AST/SGOT and ALT/SGPT ≤ 2.5 x institution's 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

          -  Patients must have the following laboratory values within normal limits (WNL) at the
             local institution lab or corrected to WNL with supplements prior to first dose of
             study medication.

               -  Potassium (WNL)

               -  Magnesium (WNL)

               -  Phosphorous (WNL)

               -  Calcium (WNL)

               -  Coagulation studies:

                    -  INR < 1.5

                    -  PTT within institution's normal range, unless receiving therapeutic low
                       molecular weight heparin

          -  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 an unequivocal progression by magnetic resonance imaging (MRI)
             or computed tomography (CT) scan. A scan must be performed within 14 days prior to
             registration 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 registration, 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 failed prior radiation therapy and 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. (radiosensitizer does not count).

          -  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 or surgical documentation of disease.

          -  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 anticoagulation therapy, only therapeutic low molecular weight
             heparin or factor Xa inhibitors are permitted.

          -  Due to the potential interaction between nilotinib and enzyme-inducing anti-epileptic
             drugs (EIAED), 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 (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.

          -  Patient received chemotherapy within 4 weeks (6 weeks for nitrosourea) prior to study
             entry, unless the disease is rapidly progressing.

          -  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 ECG

               -  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 CYP3A4 inhibitors and treatment
             cannot be either discontinued or switched to a different medication prior to starting
             study drug. See link for complete list of CYP3A4 inhibitors
             (http://medicine.iupui.edu/clinpharm/ddis/table.asp)

          -  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. See link for a comprehensive list of agents
             that prolong the QT interval
             (http://www.azcert.org/medical-pros/drug-lists/printable-drug-list.cfm).

          -  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.

          -  Treatment with other investigational agents within 30 days of Day 1.

          -  History of non-compliance to medical regimens or inability to grant consent.