A Randomized Phase II Trial of Vandetanib (ZD6474) in Combination With Carboplatin Versus Carboplatin Alone Followed by Vandetanib Alone in Adults With Recurrent High-Grade Gliomas
Condition: Glioblastoma Multiforme; Gliosarcoma; Anaplastic Astrocytoma; Anaplastic Oligodendroglioma; Anaplastic Mixed Oligoastrocytoma
MeSH terms: Glioblastoma; Astrocytoma; Gliosarcoma; Oligodendroglioma
Intervention: ZD6474 (Vandetanib); Carboplatin
Intervention description: Vandetanib is an oral medication known to block angiogenesis and has shown significant antitumor activity in laboratory and animal studies. Vandetanib appears to be well tolerated by patients at specific daily doses.; Carboplatin is a drug that interrupts division of cancer cells and has been shown to be a useful drug in treatment of tumors known as gliomas. It is a useful drug for treating brain tumors, but researchers are interested in gathering more information about how it works as a treatment for patients who have not responded to initial surgery, radiation, or chemotherapy.
Intervention MeSH terms: Carboplatin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 112.0
Sex: All
Minimum age: 18 Years
Maximum age: 100 Years
Healthy volunteers: No
Keywords: Brain Tumor; Chemotherapy; Antiangiogenesis; Radiation; Progression; Glioma; Glioblastoma Multiforme

Summary:

      Background:

        -  Growth of new blood vessels (angiogenesis) provides many tumors, including brain tumors,
           with needed nutrients and oxygen for cancer cells to survive. One possible treatment for
           different kinds of cancer involves treatment with drugs that slow or stop angiogenesis
           and prevent further tumor growth.

        -  Vandetanib is an oral medication known to block angiogenesis and has shown significant
           antitumor activity in laboratory and animal studies. Vandetanib appears to be well
           tolerated by patients at specific daily doses.

        -  Carboplatin is a drug that interrupts division of cancer cells and has been shown to be
           a useful drug in treatment of tumors known as gliomas. It is a useful drug for treating
           brain tumors, but researchers are interested in gathering more information about how it
           works as a treatment for patients who have not responded to initial surgery, radiation,
           or chemotherapy.

      Objective:

      - To determine the safety and effectiveness of vandetanib and carboplatin, given together or
      sequentially, against recurrent high-grade gliomas.

      Eligibility:

      - Adults diagnosed with a malignant glioma who have received standard treatments that no
      longer appear to be effective.

      Design:

        -  Patients will be assigned to one of two groups. Group 1 patients (combination group)
           will receive oral vandetanib for 28 days and intravenous (IV) carboplatin (once at the
           beginning of the 28-day cycle). Group 2 patients (sequential group) will receive IV
           carboplatin alone (once at the beginning of the 28-day cycle) and then oral vandetanib
           (300 mg daily) for 28 days if the tumor grows or the patient develops unacceptable
           carboplatin toxicity.

        -  Treatment will continue in 28-day cycles for 1 year for both groups.

        -  Patients will undergo a number of tests and procedures during the treatment cycle,
           including physical examinations, routine laboratory tests, electrocardiograms, and
           magnetic resonance imaging (MRI) scans

        -  At the end of 1 year of treatment, patients will be reevaluated for possible
           continuation of drug therapy.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

        Patients with histologically proven malignant primary gliomas who have progressive disease
        after radiotherapy will be eligible for this protocol. These include glioblastoma
        multiforme (GBM), gliosarcoma, anaplastic astrocytoma (AA), anaplastic oligodendroglioma
        (AO), anaplastic mixed oligoastrocytoma (AMO), and malignant glioma/astrocytoma NOS.

        Patients must have an magnetic resonance imaging (MRI)/computed tomography (CT) scan
        performed within 14 days prior to registration and on a fixed dose of steroids 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, that is, MRI or CT must be used
        throughout the period of protocol treatment for tumor measurement.

        Patients having undergone recent resection of recurrent or progressive tumor will be
        eligible as long as all of the following conditions apply:

        Patients will be eligible four weeks after surgery if they have recovered from the effects
        of surgery.

        Residual disease following resection of recurrent tumor is not mandated for eligibility
        into the study. To best assess the extent of residual disease post-operatively, a CT/MRI
        should be done:

          -  no later than 96 hours in the immediate post-operative period or

          -  at least 4 weeks post-operatively, and

          -  within 14 days of registration, and

          -  on a steroid dosage that has been stable for at least 5 days.

        If the 96 hour scan is more than 14 days before registration, the scan needs to be
        repeated. If the steroid dose is increased between the date of imaging and registration, a
        new baseline MRI/CT is required on a stable steroid dosage for at least 5 days.

        Patients must have failed prior radiation therapy.

        All patients or their previously designated durable power of attorney (DPA) (if the patient
        is deemed by the treating physician to be cognitively impaired or questionably impaired in
        such a way that the ability of the patient to give informed consent is questionable) must
        sign an informed consent indicating that they are aware of the investigational nature of
        this study.

        Patients must be greater than or equal to 18 years old, and must have a life expectancy
        greater than 8 weeks.

        Patients must have a Karnofsky performance status of greater than or equal to 60.

        Patients must be at least six weeks from radiation therapy. Additionally, patients must be
        at least 6 weeks from nitrosoureas, 4 weeks from temozolomide, 3 weeks from procarbazine,
        and 2 weeks from last vincristine administration. Patients must be at least 4 weeks from
        other cytotoxic therapies not listed above and 2 weeks for non-cytotoxic agents (e.g.,
        interferon, tamoxifen) including investigative agents.

        Patients must have adequate bone marrow function (white blood cell (WBC) greater than or
        equal to 3,000/microL, absolute neutrophil count (ANC) greater than or equal to
        1,500/mm(3), platelet count of greater than or equal to 100,000/mm(3), and hemoglobin
        greater than or equal to 10 gm/dl), adequate liver function (aspartate aminotransferase
        (AST), alanine aminotransferase (ALT) and alkaline phosphatase 2.5 less than or equal to
        upper limit of normal (ULN) and bilirubin less than or equal to 1.5 times ULN), and
        adequate renal function (creatinine less than or equal to 1.5 mg/dL and/or creatinine
        clearance greater than or equal to 60 cc/min) before starting therapy. Patients must also
        have serum potassium greater than or equal to 3.5 mg/dL, magnesium greater than or equal to
        0.75 mmol/L and calcium levels within normal levels; supplementation is allowed. In cases
        where the serum calcium is below the normal range, 2 options would be available: 1) the
        calcium adjusted for albumin is to be obtained and substituted for the measured serum
        value. Exclusion is to then be based on the adjusted for albumin values falling below the
        normal limit. 2) Determine the ionized calcium levels. Exclusion is then to be based if
        these ionized calcium levels are out of normal range despite supplementation. These tests
        must be performed within 14 days prior to registration. Eligibility level for hemoglobin
        may be reached by transfusion.

        Patients must either not be receiving steroids, or be on a stable dose of steroids for at
        least five days prior to registration.

        This study was designed to include women and minorities, but was not designed to measure
        differences of intervention effects. Males and females will be recruited with no preference
        to gender. No exclusion to this study will be based on race. Minorities will actively be
        recruited to participate.

        Patients must not be pregnant or nursing, and all patients (both men and women) must be
        willing to practice birth control during and for 2 months after treatment with vandetanib
        and/or carboplatin. Women of childbearing potential (WCBP) must have a negative serum or
        urine pregnancy test. In addition, WCBP patients must agree to use adequate contraceptive
        methods (oral, injectable, or implantable hormonal contraceptive; tubal ligation;
        intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner).

        A 12 lead electrocardiogram (ECG) to be performed within 2 weeks of trial entry with
        corrected QT interval (QTc) less than 480 msec. If a patient has a QT interval corrected
        for heart rate using Bazett's) QTcB interval > 480 ms on screening ECG, the screening ECG
        may be repeated twice [at least 24 hours apart] for a total of 3 ECGs. The average QTcB
        from the 3 screening ECGs must be less than or equal to 480 ms in order for the patient to
        be eligible for the study).

        EXCLUSION CRITERIA:

        Patients who, in the view of the treating physician, have significant active hepatic,
        renal, or psychiatric diseases are ineligible.

        Prior treatment with vandetanib.

        Prior treatment with platinum-based therapy.

        Patients known to have an allergic response to mannitol.

        Clinically significant cardiovascular event (e.g. myocardial infarction, superior vena cava
        syndrome (SVC), New York Heart Association (NYHA) classification of heart disease greater
        than or equal to 2 within 3 months before entry; or presence of cardiac disease that, in
        the opinion of the investigator, increases the risk of ventricular arrhythmia.

        History of arrhythmia (multifocal premature ventricular contractions PVCs), bigeminy,
        trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation) which is
        symptomatic or requires treatment (Common Terminology Criteria for Adverse Events (CTCAE)
        grade 3) or asymptomatic sustained ventricular tachycardia. Atrial fibrillation, controlled
        on medication is not excluded.

        QTc prolongation with other medications that required discontinuation of that medication.

        Congenital long QT syndrome, or 1st degree relative with unexplained sudden death under 40
        years of age.

        Presence of left bundle branch block (LBBB.)

        QTc with Bazett's correction that is unmeasurable, or greater than or equal to 480 msec on
        screening ECG. (Note: If a subject has a QTc interval greater than or equal to 480 msec on
        screening ECG, the screen ECG may be repeated twice (at least 24 hours apart). The average
        QTc from the three screening ECGs must be less than 480 msec in order for the subject to be
        eligible for the study. Patients who are receiving a drug that has a risk of QTc
        prolongation excluded if QTc is greater than or equal to 460 msec.

        Any concurrent medication that may cause QTc prolongation or induce Torsades de Pointes.
        Drugs listed in Appendix E, Table 2, that in the investigators opinion cannot be
        discontinued are allowed; however, must be monitored closely with additional ECGs and
        laboratory assessments of electrolytes to ensure the patients safety.

        Concomitant medications that are potent inducers (rifampicin, rifabutin, St. Johns Wort and
        Enzyme-Inducing Anti-Epileptic Drugs (EIAEDs) of cytochrome P450 3A4 (CYP3A4) function.
        EIAEDs are allowed.

        Hypertension not controlled by medical therapy (systolic blood pressure greater than 160 mm
        Hg or diastolic blood pressure greater than 100 mm Hg)

        Currently active diarrhea that may affect the ability of the patient to absorb the
        vandetanib or tolerate diarrhea.

        Women who are currently pregnant or breast feeding.

        Patients known to have a malignancy (other than their malignant glioma) that has required
        treatment in the last 12 months and/or is expected to require treatment in the next 12
        months (except for non-melanoma skin cancer, carcinoma in situ in the cervix or ductal
        carcinoma in situ).

        Invasive procedures defined as follows:

          -  Major surgical procedure, open biopsy or significant traumatic injury within 28 days
             prior to Day 1 therapy

          -  Anticipation of need for major surgical procedures during the course of the study

          -  Core biopsy within 7 days prior to Day 1 (D1) therapy

        Patients should not be on anti-platelet medications (aspirin, clopidogrel, ticlopidine,
        prasugel). Non-steroidal anti-inflammatory drugs should be used with caution if medically
        necessary.

        Restrictions

          -  Patients who are blood donors should not donate blood during the trial and for 3
             months following their last dose of trial treatment.

          -  Due to the experimental nature of vandetanib, all patients of childbearing potential
             must be one year post-menopausal, surgically sterile, or using an acceptable method of
             contraception (oral contraceptives, barrier methods in conjunction with spermicide,

        approved contraceptive implant, long-term injectable contraception, intrauterine device or
        tubal ligation) during and continued after the last dose of study medication. Contraceptive
        use will continue for at least two months, five half-lives, after the last dose on study
        medication.