Sunitinib to Treat Recurrent Brain Cancer
Condition: Glioblastoma Multiforme; Malignant Gliomas; Anaplastic Gliomas
MeSH terms: Glioblastoma; Glioma
Intervention: Sutent (sunitinib)
Intervention description: Oral dose 37.5 mg daily on a continuous 4 week cycle
Intervention MeSH terms: Sunitinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 87.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Glioblastoma; Chemotherapy; Anti-Angiogenesis; Radiation; Brain Tumor; Malignant Glioma; Glioblastoma Multiforme

Summary:

      Background:

      One way tumors are able to grow is by forming new blood vessels that supply them with
      nutrients and oxygen.

      Sunitinib blocks certain proteins on the surface of tumor and blood vessel cells that are
      involved with the formation of new blood vessels.

      Blocking these proteins may prevent the tumor cells or blood vessels from continuing to grow.

      Objectives:

      To determine whether sunitinib can cause tumors to shrink or stabilize in patients with
      recurrent brain cancer.

      Eligibility:

      Patients 18 years of age or older with brain cancer whose disease has worsened after standard
      treatment with surgery, radiation.

      Design:

      Patients take a sunitinib pill once a day in 4-week treatment cycles. Treatment may continue
      as long as the tumor remains stable or decreases in size and the side effects of treatment
      are tolerated.

      Routine blood tests are done every 2 weeks during the first 8 weeks of treatment and then
      every 4 weeks after that.

      Magnetic resonance imaging (MRI) scans are done before starting treatment (at baseline) and
      at the end of every 4-week cycle to monitor tumor growth.

      Positron emission tomography (PET) scans are done at baseline and at the end of the first
      cycle.

      Neurological and physical examinations are done at baseline, at week 2 of treatment and at
      the end of every treatment cycle.

      Health-related quality of life is assessed every 4 weeks.

      Pregnancy tests, electrocardiograms and echocardiograms are repeated as needed.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

               1. Patients with histologically proven intracranial malignant glioma will be
                  eligible for this protocol. Malignant gliomas include glioblastoma multiforme
                  (GBM), gliosarcoma (GS), anaplastic astrocytoma (AA), anaplastic
                  oligodendroglioma (AO), anaplastic mixed oligoastrocytoma (AMO), or malignant
                  astrocytoma NOS (not otherwise specified).

               2. Patients may have received prior therapy with bevacizumab, but not within six
                  weeks of starting treatment with sunitinib. Patients who received prior therapy
                  with bevacizumab must have demonstrated radiographic disease progression while
                  being treated with bevacizumab.

               3. Patients must have progressed after radiation and temozolomide therapy and have
                  an interval of greater than or equal to 4 weeks from the completion of radiation
                  therapy to study entry. If the patient has had prior stereotactic radio surgery,
                  true tumor progression must be corroborated by fludeoxyglucose 18F (FDG)-positron
                  emission tomography (PET) or magnetic resonance (MR) spectroscopy imaging.

               4. Patients must have evidence of tumor progression by contrast enhanced perfusion
                  magnetic resonance imaging (MRI) or computed tomography (CT) scan. This scan
                  should be performed within 14 days prior to registration and on a five-day stable
                  dose of steroids. 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.

               5. 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.

                  f) Normal organ and marrow function defined as: total leukocyte count greater
                  than or equal to 3000 cells/ul, absolute neutrophil count (ANC) greater than or
                  equal to 1500 cells/ul, platelet count greater than or equal to 100,000 cells/ul,
                  serum creatinine less than or equal to 2.0 times the upper limit of normal, and
                  bilirubin less than or equal to 1.5 times the upper limit of normal, hemoglobin
                  greater than or equal to 9.0 g/dL , serum calcium less than or equal to 12.0
                  mg/dL, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) less than
                  or equal to 1.5 times the upper limit of normal, prothrombin time (PT) less than
                  or equal to 1.5 upper limits of normal (ULN). Eligibility level for hemoglobin
                  may be reached by transfusion.

                  g) The effects of sunitinib on the developing human fetus at the recommended
                  therapeutic dose are unknown. Women of child-bearing potential and men must agree
                  to use adequate contraception (hormonal or barrier method of birth control;
                  abstinence) prior to study entry and for the duration of study participation.
                  Should a woman become pregnant or suspect she is pregnant while participating in
                  this study, she should inform her treating physician immediately.

                  h) 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.

                  i) Patients must be greater than or equal to 18 years old, and with a life
                  expectancy greater than 8 weeks.

                  j) Patients must have a Karnofsky performance status of greater than or equal to
                  60.

                  k) Patients must have recovered from the toxic effects of prior therapy: 2 weeks
                  from any investigational agent, two weeks from vincristine, 6 weeks from
                  nitrosoureas, 3 weeks from procarbazine, 1 week for non-cytotoxic agents, (e.g.,
                  interferon, tamoxifen, thalidomide, cis-retinoic acid, etc.), and 4 weeks from
                  other cytotoxic therapy. Any questions related to the definition of non-cytotoxic
                  agents should be directed to the Study Chair.

                  l) 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.

                  m) 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.

        EXCLUSION CRITERIA:

          1. Patients who, in the view of the treating physician, have significant active cardiac,
             hepatic, renal, or psychiatric diseases are ineligible.

          2. Patients with a history of prior therapy directed against vascular endothelial growth
             factor (VEGF) (e.g. sorafenib, pazopanib, Zactima (ZD6474), AZD2171), with the
             exception of bevacizumab, will not be allowed to enroll.

          3. Concurrent use of other standard chemotherapeutics or investigative agents.

          4. Patients known to have a malignancy (other than their malignant glioma) that has
             required treatment in the last 12 months and/or are expected to require treatment in
             the next 12 months (except non-melanoma skin cancer or carcinoma in-situ in the
             cervix).

          5. Patients who have an active infection.

          6. Pregnant (positive pregnancy test) or nursing women. Both fertile men and women must
             agree to use adequate contraceptive measures during study therapy and for at least 3
             months after the completion of sunitinib therapy.

          7. Concurrent anti-coagulation or anti-platelet medication (including aspirin,
             non-steroidal anti-inflammatory agents, cyclooxygenase -2 (COX-2) inhibitors).

          8. Serious or non-healing wound, ulcer or bone fracture

          9. History of any of the following within 6 months of study entry: abdominal fistula,
             gastrointestinal perforation, intra-abdominal abscess, stroke, myocardial infarction
             or unstable angina. Patients will not undergo diagnostic screening for any of these
             conditions.

         10. 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 start of therapy

         11. Uncontrolled hypertension (greater than 150/100 mmHg) while on antihypertensive
             medications.

         12. New York Heart Association class II or greater congestive heart failure.

         13. Serious cardiac arrhythmia requiring medication.

         14. Evidence of bleeding diathesis, coagulopathy, or international normalized ratio (INR)
             greater than 1.5.

         15. History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to sunitinib.

         16. Patients receiving any enzyme inducing anti-epileptic drugs (EIAEDs) and other potent
             cytochrome P450 3A4 (CYP3A4) modulators (per Appendixes B and C) within two weeks
             prior to treatment start are ineligible.

         17. Baseline echocardiogram with ejection fraction less than 50% or greater than or equal
             to 20% decrease from a prior study

         18. corrected QT interval(QTc) interval greater than 500 msec on baseline
             electrocardiogram (EKG).

         19. Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
             therapy are ineligible because of the potential for pharmacokinetic interactions with
             sunitinib.