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

Background

- Glioblastoma (GBM) is the most common primary brain tumor. With optimal
treatment,consisting of focal radiotherapy with concurrent chemotherapy, followed by
adjuvant chemotherapy, median survival is 14.6 months. Most patients have evidence of
tumor progression within one year of diagnosis despite treatment. At progression,
treatment options are limited and mostly ineffective.

- Recently, bevacizumab was approved for recurrent GBM patients who fail bevacizumab
indicate a short survival, on the order of 10 weeks, an approximate PFS 3 and 6 months
of 0%.

- Pazopanib is an oral angiogenesis inhibitor targeting VEGFR, PDGFR, and c-Kit, and was
recently FDA approved for advanced renal cell carcinoma.

- Topotecan is an orally bioavailable topoisomerase I and HIF-1 alpha inhibitor with
reasonably high CNS/CSF penetration

- Recent pre-clinical reports have begun to argue for the clinical testing of metronomic
chemotherapy administration in various cancers. The theory of improved activity of
Pazopanib + Topotecan administered metronomically is based on targeting tumor
vasculature (both existing capillary endothelial cells and circulating bone marrow
derived endothelial cell precursors), immune modulation, as well as tumor cell HIF-1
alpha inhibition, and the induction of DNA damage. Further support for the combination
comes from recent data tying drug-induced VEGF inhibition to the induction of HIF-1
alpha activity in GBM suggesting possible synergy between Pazopanib and Topotecan

- The combination of Topotecan and Pazopanib has been directly demonstrated as active in

animal models

Objectives

- 6 month progression free survival rate for recurrent glioblastoma (rGBM) patients with
no prior bevacizumab exposure treated with pazopanib and topotecan (Group A).

- 3 month progression free survival rate for rGBM patients with prior bevacizumab exposure
treated with pazopanib and topotecan (Group B).

Eligibility

- Histologically proven intracranial glioblastoma multiforme (GBM) or gliosarcoma (GS)
with evidence of progression on MRI or 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 BEVincorporating
treatment (group B).

- Patients must be greater than 12 weeks following completion of chemoradiation.

- Archived tumor tissue must be available for confirmation of the diagnosis

- Patients must be > 18 years old.

- Patients must have a Karnofsky performance status of > 60.

- Patients must have adequate organ function.

- No pregnancy or lactation.

- 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 patient s ability to tolerate this therapy.

- No 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 eligible.

- No clinically significant gastrointestinal abnormalities that may increase the risk
for gastrointestinal bleeding including, or the absorption of the medications.

- No 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).

- No evidence of active bleeding or bleeding diathesis.

- No known endobronchial lesions and/or lesions infiltrating major pulmonary vessels.

- No serious and/or unstable pre-existing medical, psychiatric, or other condition
that could

interfere with subject s safety, provision of informed consent, or compliance to study
procedures.

.. No ongoing toxicity from prior anti-cancer therapy that is > Grade 1 and/or that is

progressing in severity, except alopecia.

- No ongoing use of enzyme-inducing anti-epileptic agents (EIAEDs), unless 2 week washout
has elapsed form last dose of EIAED.

- No known hypersensitivity to pazopanib or topotecan or to their excipients.

- No total daily dose of dexamethasone greater than 16 mg/day.

- No 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, PDGFR a, -b of cKIT could be allowed.

Design

This is a 2 arm phase II trial of the combination of topotecan and pazopanib in patients with
recurrent GBM or GS. Patients will be enrolled into one of the following groups: (A)
Glioblastoma or gliosarcoma with no prior bevacizumab exposure: (B) Glioblastoma or

gliosarcoma with prior bevacizumab exposure. Topotecan and pazopanib are administered orally
daily. The primary efficacy endpoint is progression free survival (PFS) at six months from
patient registration for bevacizumab na(SqrRoot) ve patients and PFS at 3 months for patients
with prior bevacizumab treatment.

- 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 MRI or 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 PI.

- Patients must have adequate organ function:

- Bone marrow function (WBC greater than or equal to 3,000/microl, ANC greater than
or equal to 1,500/mm3, platelet count of greater than or equal to 100,000/mm3,
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 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 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 investigator s
opinion cannot be adequately controlled with appropriate therapy or would compromise
the patient s 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 subject s safety, provision of informed consent, or compliance to
study procedures.

- Unable or unwilling to discontinue use of inducers and inhibitors of CYP450 listed in
Appendix 13.4 and BCRP and 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 investigator s
opinion cannot be adequately controlled with appropriate therapy or would compromise
the patient s 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, PDGFR a, -b of cKIT

could be allowed.

-Patients must not have any disease that will obscure toxicity or dangerously alter drug
metabolism.