Tandutinib Plus Bevacizumab to Treat Recurrent Brain Tumors
Condition: Glioblastoma; Gliosarcoma; Anaplastic Astrocytoma; Anaplastic Oligodendroglioma; Anaplastic Mixed Oligoastrocytoma
MeSH terms: Glioblastoma; Astrocytoma; Gliosarcoma; Oligodendroglioma
Intervention: Bevacizumab; MLN-518 (Tandutinib); Quality-of-life assessment
Intervention description: Bevacizumab 10 mg/kg dose intravenous repeated once every 2 weeks.; Tandutinib 500 mg by mouth daily dose twice a day.; Forty-five one-sentence questionnaire to assess health related quality of life in patients with brain cancer.
Intervention MeSH terms: Bevacizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 42.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Brain Tumor; Chemotherapy; Radiation; Anti-Angiogenesis; Glioblastoma; Glioma

Summary:

      Background:

      In order to survive, brain tumors must have a network of blood vessels to supply it with
      oxygen and nutrients. The tumors produce substances that enable new blood vessels to form.

      Tandutinib and Bevacizumab are experimental drugs that may prevent new blood vessel formation
      and thereby slow or stop tumor growth in the brain.

      Objectives:

      To determine the safety and side effects of Tandutinib in combination with Bevacizumab in
      patients with brain tumors.

      To evaluate the response of brain tumors to treatment with Tandutinib and Bevacizumab.

      Eligibility:

      Patients 18 years of age and older with a malignant brain tumor for whom standard treatments
      (surgery, radiation and chemotherapy) are no longer effective.

      Design:

      Patients receive treatment in 4-week cycles as follows: Tandutinib by mouth twice a day every
      day and intravenous (through a vein) infusions of Bevacizumab over 90 minutes (or less if
      well tolerated) every 2 weeks. Treatment may continue for up to 1 year, and possibly longer,
      as long as there are no signs of tumor growth or serious treatment side effects.

      Patients are evaluated with magnetic resonance imaging (MRI), computed tomography (CT) and
      positron emission tomography (PET) scans before starting treatment and then periodically to
      determine the response to treatment.

      Patients have physical and neurological examinations every 4 weeks and blood tests every 2
      weeks. They complete quality of life questionnaires every 4 weeks.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

          -  Patients with histologically proven intracranial malignant glioma will be eligible for
             this protocol.

        Malignant glioma includes glioblastoma multiforme (GBM), gliosarcoma, anaplastic
        astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic mixed oligoastrocytoma
        (AMO), or malignant astrocytoma NOS (not otherwise specified).

          -  Patients must have evidence for tumor progression by magnetic resonance imaging (MRI)
             or computed tomography (CT) scan.

        This scan should be 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, i.e. 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:

          -  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 21 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 progressed after radiation therapy and must have an interval of
             greater than or equal to 4 weeks from the completion of radiation therapy to study
             entry.

          -  All patients or their previously designated durable power of attorney (DPA) (if the
             patient is deemed by the treating physician to be 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 with a life expectancy
             greater than 8 weeks.

          -  Patients must have a Karnofsky performance status of greater than or equal to 60.

          -  Patients must have recovered from the toxic effects of prior therapy: 2 weeks from any
             investigational agent, 4 weeks from prior cytotoxic therapy, two weeks from
             vincristine, 6 weeks from nitrosoureas, 3 weeks from procarbazine administration, and
             1 week for non-cytotoxic agents, e.g., interferon, tamoxifen, thalidomide,
             cis-retinoic acid, etc. (radiosensitizer does not count). Any questions related to the
             definition of non-cytotoxic agents should be directed to the Study Chair.

          -  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 (serum glutamic
             oxaloacetic transaminase (SGOT) and bilirubin less than 2 times upper limit of normal
             (ULN)), and adequate renal function (creatinine less than 1.5 mg/dL and/or creatinine
             clearance greater than or equal to 60 cc/min) before starting therapy.

        Serum sodium, calcium, potassium, chloride, and magnesium must be in normal limits.

        These tests must be performed within 14 days prior to registration. Eligibility level for
        hemoglobin may be reached by transfusion.

          -  Patients must not have any significant medical illnesses that, in the investigator's
             opinion, cannot be adequately controlled with appropriate therapy or would compromise
             the patients' ability to tolerate this therapy

          -  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.

          -  Creatinine clearance or calculated creatinine clearance greater than or equal to 60
             mL/minute.

          -  Patients must practice adequate contraception.

          -  Head CT Scan without contrast (to rule out significant acute hemorrhage) within 7 days
             prior to starting treatment.

          -  A 12 lead electrocardiogram (ECG) to be performed within 2 weeks of trial entry with
             corrected QT interval (QTc) less than 460 msec.

        EXCLUSION CRITERIA:

          -  Patients who, in the view of the treating physician, have significant active cardiac,
             hepatic, renal, or psychiatric diseases are ineligible.

          -  No concurrent use of other standard chemotherapeutics or investigative agents.

          -  Patients known to have a malignancy that has required treatment in the last 12 months
             and/or is expected to require treatment in the next 12 months (except non-melanoma
             skin cancer or carcinoma in-situ in the cervix).

          -  Patients who have an active infection.

          -  Pregnant (positive pregnancy test) or nursing women. Fertile men and women must agree
             to use adequate contraceptive measures during study therapy and for at least 6 months
             after the completion of tandutinib plus bevacizumab therapy.

          -  Patients who have any disease that will obscure toxicity (i.e. vasculitis, congenital
             hypercoaguability syndromes, uncontrolled primary hypertension, idiopathic
             thrombocytopenia).

          -  Evidence of significant recent hemorrhage on mandatory CT scan (defined as 1 cm or
             more of acute blood) of the brain within 7 days of patient accrual with the following
             exceptions: resolving hemorrhagic changes related to surgery, and/or presence of
             punctate hemorrhages in the tumor.

          -  Concurrent anti-coagulation or anti-platelet medication (including aspirin,
             non-steroidal anti-inflammatories, cyclooxygenase -2 (COX-2) inhibitors).

          -  Serious or non-healing wound, ulcer or bone fracture.

          -  Proteinuria at screening as demonstrated by either:

          -  Urine protein:creatinine (UPC) ratio greater than or equal to 1.0 at screening OR

          -  Urine dipstick for proteinuria greater than or equal to 2+ (patients discovered to
             have greater than or equal to 2+ proteinuria on dipstick urinalysis at baseline should
             undergo a 24 hour urine collection and must demonstrate less than or equal to 1g of
             protein in 24 hours to be eligible).

          -  History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess
             within 6 months

          -  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 D1 therapy

          -  Patients with clinically significant cardiovascular disease

          -  History of cerebrovascular accident (CVA) or transient ischemic attack within 6 months

          -  Inadequately controlled hypertension (defined as systolic blood pressure greater than
             160 and/or diastolic blood pressure greater than 100 mmHg on antihypertensive
             medications)

          -  Any prior history of hypertensive crisis or hypertensive encephalopathy

          -  Myocardial infarction or unstable angina within 6 months

          -  New York Heart Association Grade II or greater congestive heart failure

          -  Serious cardiac arrhythmia requiring medication

          -  Unstable angina pectoris

          -  Symptomatic peripheral vascular disease

          -  Evidence of bleeding diathesis or coagulopathy

          -  Prothrombin time (PT)/partial thromboplastin time (PTT) greater than1.5 time the upper
             limit of normal

          -  Patients with known hypersensitivity of Chinese hamster ovary cell products or other
             recombinant human antibodies

          -  Inability to take oral medication

          -  Known gastrointestinal disease or history of gastrointestinal surgery that could
             interfere with the absorption of orally administered medication.

          -  Ongoing vomiting

          -  Active cardiac disease as defined by:

          -  Significant cardiac event (including symptomatic heart failure or evidence of cardiac
             ischemia within 3 months of first dose or presence of any cardiac disease that in the
             opinion of the Investigator increases the risk of ventricular arrhythmia.

          -  Clinically significant arrhythmia (multifocal premature ventricular contraction [PVC],
             bigeminy, trigeminy, ventricular tachycardia, bradycardia) that is symptomatic or
             requires treatment (Common Terminology Criteria for Adverse Events (CTCAE) grade 3),
             or asymptomatic sustained ventricular tachycardia.

          -  Previous history of QTc prolongation with other medication.

          -  Congenital long QT syndrome

          -  QTc with Bazett's correction that is unmeasurable, or greater than or equal to 460
             msec on screening ECG. If a patient has QTc greater than or equal to 460 msec on
             screening ECG, a second screen ECG may be repeated at least 24 hours apart. The
             average QTc from the 2 screening ECGs must be less than 460 msec in order for the
             patient to be eligible for the study. If the patient meets eligibility requirements in
             this way, the 'baseline' QTc for this patient will be the average of the 3 ECGs
             (screen 1, screen 2, and pre- 1 first dose).

          -  Previous history of left ventricular ejection fraction (LVEF) less than 45 percent as
             measured by multi-gated acquisition scan (MUGA) or by echocardiogram (ECHO) for
             patients with previous anthracycline therapy (total dose greater than 450 mg/m^2 or
             significant cardiovascular disease or chest irradiation, as determined by the
             investigator.

          -  A cardiac arrhythmia serious enough to require therapy (i.e. drugs, acquired immune
             deficiency (AID)), angina, symptomatic congestive heart failure and/or a cardiac
             ejection fraction less than 45 percent.

          -  Prior serious cardiac disease defined as prior coronary bypass surgery, angioplasty,
             or prior myocardial infarction unless a recent cardiac evaluation (within the last 3
             months) demonstrated no significant coronary artery disease (i.e. a negative stress
             test) and no myocardial wall dysfunction.

          -  Concurrent use of other standard chemotherapeutics or investigative agents or
             vasoconstrictors for the treatment of migraine (ergotamine, zolmitriptan, sumatriptan)
             because of the potential for exacerbation of coronary vasoconstriction.

          -  Known or suspected primary muscular or neuromuscular disease (e.g. muscular dystrophy,
             myasthenia gravis). This does not include steroid myopathy.

          -  Prior treatment with bevacizumab is not permitted.

          -  Concurrent use of other drugs that have been shown to potentially prolong the QTc
             interval.