Tamoxifen and Bortezomib to Treat Recurrent Brain Tumors
Condition: Glioma
MeSH terms: Glioma
Intervention: Tamoxifen citrate; Bortezomib
Intervention description: oral dose 120 mg twice a day, every day; intravenous (IV) injection 1.3 mg/m^2 days 3, 6, 10, 13, 24, 27,31,34 on every 6 week cycle
Intervention MeSH terms: Tamoxifen; Bortezomib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 43.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Brain; Tumor; Malignant; Therapy; Progression; Chemotherapy; Antiangiogenesis; Radiation; Malignant Brain Tumor; Malignant Glioma; Glioma

Summary:

      This study will determine whether the drugs tamoxifen and bortezomib can delay tumor growth
      in patients with recurrent glioma (malignant brain tumor). Tamoxifen may work by interfering
      with the internal signaling needed for the cancer to grow. Bortezomib may also interfere with
      tumor growth processes. Laboratory studies show that low doses of bortezomib significantly
      enhance glioma cell death when used with tamoxifen.

      Patients 18 years of age and older with glioma whose tumor does not respond to standard
      medical treatment and who are not taking enzyme-inducing anti-seizure medications such as
      Dilantin, phenobarbitol, or Tegretol, may be eligible for this study. Candidates are screened
      with a physical examination, blood tests, and magnetic resonance imaging (MRI) or computed
      tomography (CT). MRI and CT scans produce images of the brain that can show if the brain
      tumor is growing (see below).

      Participants receive treatment in 6-week cycles for up to 1 year. (The treatment duration may
      be extended in some patients who continue to tolerate the drug and show no signs of tumor
      growth after 1 year.) During each cycle, patients take six tamoxifen tablets twice a day
      every day and receive bortezomib by infusion into a vein on days 3, 6, 10, 13, 24, 27, 31 and
      34. Treatment may continue as long as the tumor does not grow and the patient does not
      develop unacceptable side effects. In addition to drug treatment, patients undergo the
      following tests and procedures:

        -  Periodic routine blood tests.

        -  MRI or CT scan of the head before starting each new cycle. MRI uses a magnetic field and
           radio waves to produce images of body tissues and organs. CT uses x-rays to provide
           3-dimensional views of the part of the body being studied. For both procedures, the
           patient lies on a table that slides into the cylindrical scanner.

        -  Blood test to measure levels of bortezomib. Blood is drawn before the bortezomib
           infusion on days 3 and 24, and 4 hours after the infusion on day 24 of the first
           treatment cycle only.

        -  Dynamic MRI with spectroscopy or positron emission tomography (PET). Patients may be
           asked to undergo one of these tests, which help distinguish live tumor from dying tumor.
           The experience of dynamic MRI with spectroscopy is the same as standard MRI and is done
           at the same time as the standard procedure (see above). PET uses a radioactive substance
           to show cellular activity in specific tissues of the body. The patient is given an
           injection of a sugar solution in which a radioactive isotope has been attached to the
           sugar molecule. A special camera detects the radiation emitted by the radioisotope, and
           the resulting images show how much glucose is being used in various parts of the body.
           Because rapidly growing cells, such as tumors, take up and use more glucose than normal
           cells do, this test can be used to show active tumors.

        -  Drug diary. Patients maintain a calendar to record when they take their study drugs and
           what side effects they develop.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

        Patients with histologically proven high-grade gliomas or patients with a clinical and
        radiographic diagnosis of brainstem glioma will be eligible for this protocol. High-grade
        gliomas include glioblastoma multiforme (GBM; stratum 1) and its variants such as
        gliosarcoma and anaplastic gliomas (AG; stratum 2), such as anaplastic astrocytoma (AA),
        anaplastic oligodendroglioma (AO), anaplastic mixed oligoastrocytoma (AMO), or malignant
        astrocytoma/glioma NOS (not otherwise specified).

        Patients must have unequivocal evidence for tumor progression by magnetic resonance imaging
        (MRI) or computerized tomography (CT) scan. This scan should be performed within 14 days
        prior to registration and on a steroid dosage 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
        MR/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:

          1. They have recovered from the effects of surgery.

          2. Residual disease following resection of recurrent tumor is 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 failed prior radiation therapy and must have an interval of greater
             than or equal to 4 weeks from the completion of radiation therapy to study entry.

             Ability of subjects or Legally Authorized Representative (LAR) to understand and the
             willingness to sign a written informed consent document.

             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, 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 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. 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.

             Patients must practice adequate contraception.

             EXCLUSION CRITERIA:

             Patients who, in the view of the treating physician, have significant active cardiac
             (documented coronary artery disease, congestive heart failure, arrhythmia requiring
             medication), hepatic (hepatocellular and/or cholestatic dysfunction as documented by
             liver biopsy, liver ultrasound, or abnormal liver function blood tests, renal (as
             documented by renal biopsy, ultrasound, CT/MRI scans or reflected in the blood tests
             or psychiatric diseases (requiring hospitalization or is of significant severity to
             impair the patients ability to cooperate with the study instructions).

             No concurrent use of other standard chemotherapeutics or investigative agents.

             Patients known to have an active malignancy other than their glioma (except
             non-melanoma skin cancer or carcinoma in-situ of the cervix).

             Patients who have an active infection requiring intravenous (IV) antibiotics.

             Patients who are pregnant or breast feeding.

             Patients who have any disease that will obscure toxicity or dangerously alter drug
             metabolism.

             Patients who have had clear tumor progression while being treated with tamoxifen
             and/or patients treated with tamoxifen within the past year.

             Patients who are taking EIAEDs (enzyme inducing anti-epileptic drugs) are not
             eligible.

             Patients who have had documented tumor progression while taking tamoxifen and/or any
             treatment with tamoxifen within 6 months of registration.

             Salicylates ARE permitted.

             Patients with grade 2 or greater peripheral neuropathy.

             Invasive procedures defined as follows:

               -  Major surgical procedures, open biopsy or significant traumatic injury within 28
                  days prior to Day ! therapy

               -  Anticipation of need for major surgical procedures during the course of the study

               -  Core biopsy within 7 days prior to D1 therapy