Oral Pazopanib Plus Oral Topotecan Metronomic Antiangiogenic Therapy for Recurrent Glioblastoma Multiforme (A) Without Prior Bevacizumab Exposure and (B) After Failing Prior Bevacizumab

* General Inclusion Criteria
* Patients with histologically proven intracranial glioblastoma multiforme (GBM) or gliosarcoma (GS). Patients will be eligible if the original histology was low-grade glioma and a subsequent histological diagnosis of a GBM or GS is made. Patients must have evidence of progression of the GBM or GS on magnetic resonance imaging (MRI) or computed tomography (CT) scan. Patient must have failed prior chemoradiation with temozolomide and any other therapies except BEV (group A), or must have failed primary chemoradiation and a BEV-incorporating treatment (group B).
* Patients may have had treatment for no more than 2 prior relapses. Relapse is defined as progression following initial therapy (i.e. radiation+/- chemo if that was used as initial therapy). The intent therefore is that patients had no more than 3 prior therapies

(initial and treatment for 2 relapses). If the patient had a surgical resection for relapsed disease and no anti-cancer therapy was instituted for up to 12 weeks, and the patient undergoes another surgical resection, this is considered as 1 relapse.

For patients who had prior therapy for a low-grade glioma, the surgical diagnosis of a high-grade glioma will be considered the first relapse.

* Patients must be greater than 12 weeks following completion of chemoradiation or any additional radiation to reduce the chance of pseudoprogression.
* Measurable disease is required unless patient is post-operative and in that case patient can have no evidence of disease.
* All patients must sign an informed consent indicating that they are aware of the investigational nature of this study.
* Archived tumor tissue must be available for all subjects for confirmation of the diagnosis before or during treatment. Samples must be provided within 4 weeks of enrollment.
* Patients must be greater than or equal to 18 years old.
* Patients must have a Karnofsky performance status of greater than or equal to 60.
* At the time of registration: Patients must have recovered from the toxic effects of prior therapy: greater than or equal to 28 days from any investigational agent, greater than or equal to 28 days from prior cytotoxic therapy, greater than or equal to 14 days from vincristine, greater than or equal to 42 days from nitrosoureas, greater than or equal to 21 days from procarbazine administration, \>21 days from bevacizumab administration and greater than or equal to 7 days for non-cytotoxic agents, e.g., interferon, tamoxifen, thalidomide, cis-retinoic acid, etc. (radiosensitizer does not count). Any questions related to the definition of noncytotoxic agents should be directed to Academic Principal Investigator (PI).
* Patients must have adequate organ function:

  * 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).

    ---Eligibility level for hemoglobin may be reached by transfusion.
  * Liver function (alanine amino transferase (ALT) and aspartate aminotransferase (AST) \< 2.5 X upper limit of normal (ULN), and total bilirubin \< 1.5 X ULN), prothrombin time (PT) or international normalized ratio (INR), and activated partial thromboplastin time (aPTT) less than or equal to 1.2 X ULN.

    * Concomitant elevations in bilirubin and AST/ALT above 1.0 x ULN (upper limit of normal) are not permitted.
    * Subjects receiving anticoagulant therapy are eligible if their INR is stable and within the recommended range for the desired level of anticoagulation.
  * Renal function (creatinine less than or equal to 1.5 mg/dL (133 micromol/L), or if \> 1.5 mg/dL, calculated creatinine clearance greater than or equal to 50 cc/min), and urine protein to creatinine ratio of \< 1 prior to registration.
* Patients must have shown unequivocal radiographic evidence for tumor progression by MRI or CT scan as defined by Section 6.4.1.4.5. A scan should be performed within 14 days prior to registration and on a steroid dose that has been stable or decreasing 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:

  --They have recovered from the effects of surgery and be \> 28 days from surgery.
* Residual disease following resection of recurrent GBM or GS 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, within 14 days prior to registration. 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 and must have an interval of greater than or equal to 12 weeks from the completion of radiation therapy to study entry.
* Patients with prior therapy that included interstitial brachytherapy or stereotactic radiosurgery must have confirmation of true progressive disease rather than radiation necrosis based upon either positron emission tomography (PET) or Thallium scanning, MR spectroscopy or surgical/pathological documentation of disease.
* A female is eligible to enter and participate in this study if she is of:

  * Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who has had:

    * A hysterectomy
    * A bilateral oophorectomy (ovariectomy)
    * A bilateral tubal ligation
    * Is post-menopausal
    * Subjects not using hormone replacement therapy (HRT) must have experienced in questionable cases, have a follicle stimulating hormone (FSH) value \>40 mIU/mL and an estradiol value \< 40pg/mL (\<140 pmol/L).
    * Subjects using HRT must have experienced total cessation of menses for \>= 1year and be greater than 45 years of age OR have had documented evidence of menopause based on FSH and estradiol concentrations prior to initiation of HRT
  * Childbearing potential, including any female who has had a negative serum pregnancy test within 2 weeks prior to the first dose of study treatment, preferably as close to the first dose as possible, and agrees to use adequate contraception. Novartis acceptable contraceptive methods, when used consistently and in accordance with both the product label and the instructions of the physician, are as follows:

    * Complete abstinence from sexual intercourse for 14 days before exposure to investigational product, through the dosing period, and for at least 21 days after the last dose of investigational product. Oral contraceptive, either combined or progestogen alone.
    * Injectable progestogen.
    * Implants of levonorgestrel.
    * Estrogenic vaginal ring.
    * Percutaneous contraceptive patches.
    * Intrauterine device (IUD) or intrauterine system (IUS) with a documented failure rate of less than 1% per year.
    * Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study, and this male is the sole partner for that subject.
    * Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository).
    * Female subjects who are lactating should discontinue nursing prior to the first dose of study drug and should refrain from nursing throughout the treatment period and for 14 days following the last dose of study drug.

General Exclusion Criteria

* Patients must not have any significant medical illnesses that in the investigators opinion cannot be adequately controlled with appropriate therapy or would compromise the patients ability to tolerate this therapy.
* Patients with a history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix), unless in complete remission and off of all therapy for that disease for a minimum of 3 years are ineligible.
* Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding including, but not limited to:

  * Active peptic ulcer disease.
  * Known intraluminal metastatic lesion/s with risk of bleeding.
  * Inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease), or other gastrointestinal conditions with increased risk of perforation.
  * History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior to beginning study treatment.
* Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product including, but not limited to:

  * Malabsorption syndrome
  * Major resection of the stomach or small bowel.
  * Presence of uncontrolled infection.
  * Corrected QT interval (QTc) \> 480 msecs using Bazett's formula. Bazett's Formula: QTc (Bazett)=QT/RR
* History of any one or more of the following cardiovascular conditions within the past 6 months:

  * Cardiac angioplasty or stenting
  * Myocardial infarction
  * Unstable angina
  * Coronary artery bypass graft surgery
  * Symptomatic peripheral vascular disease
  * Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA), see appendix 13.7
  * Poorly controlled hypertension \[defined as systolic blood pressure (SBP) of greater than or equal to 140 mmHg or diastolic blood pressure (DBP) of less than or equal to 90mmHg\]. Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry. BP must be re-assessed on two occasions that are separated by a minimum of 1 hour; on each of these occasions, the mean (of 3 readings) SBP/DBP values from each BP assessment must be less than or equal to 140/90 mmHg in order for a subject to be eligible for the study.
  * History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months. Note: Subjects with recent DVT who have been treated with therapeutic anticoagulating

agents for at least 6 weeks are eligible.

* Prior major surgery or trauma within 28 days and/or presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement not considered to be major).
* Evidence of active bleeding or bleeding diathesis.
* Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels
* Hemoptysis in excess of 2.5 mL (or one half teaspoon) within 8 weeks of first dose of study drug.
* Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with subjects safety, provision of informed consent, or compliance to study procedures.
* Unable or unwilling to discontinue use of inducers and inhibitors of Cytochrome P450 (CYP450) listed in Appendix 13.4 and breast cancer resistance protein (BCRP) and P-glycoprotein (PgP) inducers and inhibitors for at least 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of study drug and for the duration of the study. (CYP3A4 substrates can be administered, but investigators will need to be aware of possible increased or decreased effectiveness of the non-study drug and this should be recorded in concomitant medications. Dexamethasone is acceptable although listed as a CYP3A4 inducers/inhibitors as long as the dose is 16 mg/day or lesser.
* Any ongoing toxicity from prior anti-cancer therapy that is \> Grade 1 and/or that is progressing in severity, except alopecia.
* Ongoing use of enzyme-inducing anti-epileptic agents (EIAEDs), unless 2 week washout has elapsed form last dose of EIAED.
* Patients must not have any significant medical illnesses that in the investigators opinion cannot be adequately controlled with appropriate therapy or would compromise the patients ability to tolerate this therapy.
* Patients with a known hypersensitivity to pazopanib or topotecan or to their excipients.
* Patients on total daily dose of dexamethasone greater than 16 mg/day.
* Patients must not have received prior therapy with topotecan, pazopanib, or related drugs such as tyrosine kinase inhibitors, VEGF inhibitors (except bevacizumab). Prior treatment with TKIs that do not impact VEGFR -1, -2, or -3, Platelet Derived Growth Factor Receptor Alpha (PDGFRa) Platelet Derived Growth Factor Receptor Beta (-b) of cKIT could be allowed.
* Patients must not have any disease that will obscure toxicity or dangerously alter drug metabolism.