Clinical Trials /

Study of Platelet Derived Growth Factor Receptor (PDGFR) in Recurrent Malignant Gliomas

NCT01140568

Description:

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.

Related Conditions:
  • Glioma
Recruiting Status:

Terminated

Phase:

Phase 2

Trial Eligibility

Document

Study of Platelet Derived Growth Factor Receptor (<span class="go-doc-concept go-doc-biomarker">PDGFR</span>) in Recurrent Malignant Gliomas

Title

  • Brief Title: Study of Platelet Derived Growth Factor Receptor (PDGFR) in Recurrent Malignant Gliomas
  • Official Title: A Phase II Study of PDGFR Kinase Inhibitor in Biomarker-Enriched Recurrent Malignant Gliomas
  • Clinical Trial IDs

    NCT ID: NCT01140568

    ORG ID: 091728

    Trial Conditions

    Glioma

    Trial Interventions

    Drug Synonyms Arms
    nilotinib Tasigna nilotinib

    Trial Purpose

    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.

    Detailed Description

    Malignant gliomas (MG), including anaplastic gliomas (AG) and glioblastoma (GBM), are the
    most common primary brain tumor. Standard of care (surgery, radiotherapy, and temozolomide
    at initial diagnosis) results in a median survival of only 14 months. For patients with
    recurrent disease, conventional chemotherapy is generally ineffective with response rates
    <20%. Clearly there is need for improved treatments. Recent genome-wide studies have
    confirmed that GBM is a heterogeneous group of diseases that can be subclassified by shared
    genetic aberrations. The implication is that, in part, the underlying genetics may determine
    responsiveness to treatments and thus allow us to personalize therapy.

    This is an, open-label, non-randomized, phase II study with oral nilotinib in adult patients
    with biomarker-enriched, recurrent malignant gliomas who have developed tumor progression
    after standard therapy. Patients will be treated with oral nilotinib (starting with the
    labeled dose of 400 mg) daily until disease progression or intolerance. One cycle is defined
    as 28 days.

    Approximately 50 evaluable patients will be enrolled in this study, with 32 (grade IV) and
    18 (grade III) in separate arms.

    All patients will undergo clinical evaluation after each 28-day cycle. Neuroimaging studies
    (MRI) will be performed at baseline, 4 weeks, 8 weeks and then after every 2 cycles (8
    weeks). If a contraindication for MRI's exists, patients will undergo contrast-enhanced CT
    scans. Laboratory tests will be obtained weekly during the first 4 weeks, and then on days 1
    and 15 of all subsequent cycles. Patients will remain on study medication unless they
    develop tumor progression or unacceptable toxicity.

    Trial Arms

    Name Type Description Interventions
    nilotinib Experimental nilotinib

    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.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    To determine the efficacy of nilotinib in patients with recurrent malignant gliomas with PDGFR amplification as measured by 6-month progression-free survival.

    Secondary Outcome Measures

    To define the safety of nilotinib in this population based on frequency of adverse events leading to study discontinuation and number of significant laboratory abnormalities.

    To characterize the pharmacokinetics of nilotinib in this population by serum and cerebrospinal fluid (CSF) examination of drug and metabolites.

    Trial Keywords

    glioma

    PDGFR

    kinase

    inhibitor

    malignant

    nilotinib