Tandutinib Plus Bevacizumab to Treat Recurrent Brain Tumors

Background

Bevacizumab is a monoclonal antibody directed against vascular- endothelial growth factor
(VEGF), the major angiogenesis factor involved in high-grade glioma-mediated angiogenesis.
Preclinical studies in our laboratory and others have shown potent antiglioma activity in
vivo and early clinical trials of bevacizumab in combination with irinotecan and alone
(National Institutes of Health (NIH) study) have demonstrated significant anti-vascular
permeability and anti-glioma effects in patients with recurrent gliomas.

Tandutinib (MLN518) along with bevacizumab represents an attempt to further capitalize on
the concept of targeting the tumor vasculature. Tandutinib is a small molecule inhibitor of
fms-like tyrosine kinase receptor-3 (FLT3), platelet derived growth factor receptor (PDGFR),
and cKIT (type III receptor tyrosine kinases). It has demonstrated anti-leukemic activity in
patients with relapsed and refractory acute myeloid leukemia (AML) whose blasts contain an
activating internal tandem duplication mutation of FLT3. However, in this study tandutinib
is being added to bevacizumab primarily for its activity against the PDGFR and cKIT.
Hannahan and colleagues have demonstrated the additional anti-tumor activity that results in
vivo with combined inhibition of the vascular endothelial growth factor receptor (VEGFR) and
PDGFR. The activity of PDGFR inhibition is hypothesized to result from its effect on
pericytes, the cells that surround and support endothelial cells. These cells have abundant
expression of PDGFR and require platelet-derived growth factor (PDGF)-PDGFR interaction for
their normal function.

Objectives

To establish data regarding the anti-tumor activity of the combination of bevacizumab and
tandutinib in patients with recurrent high-grade gliomas, as determined by
progression-free-survival.

Eligibility

Patients with histologically proven recurrent malignant glioma are eligible for this study.

Design

Patients will receive tandutinib as a single agent at a daily dose of 500 mg PO bid for the
first 14 days of treatment. Radiology: Prior to the first dose of tandutinib patients will
undergo an MRI-perfusion scan and an FDG-PET scan. An MRI-perfusion scan will then be
repeated between days 12-14 of the first 14 days of tandutinib monotherapy. On day 15,
treatment with bevacizumab will be added to the ongoing treatment with tandutinib.
Bevacizumab will be given intravenously in a dose of 10 mg/kg, repeated once every 2 weeks.
After completion of the first 4 weeks of combined tandutinib and bevacizumab therapy (6
weeks after initiating treatment with tandutinib) considered the first cycle of therapy) the
MRI-perfusion and fludeoxyglucose 18F-positron emission tomography (FDG-PET) scans will be
repeated before the next dose of bevacizumab is given. Patients who are
clinically/neurologically stable, and who have radiographically stable or responding disease
at the end of that first cycle and every cycle thereafter (every 4 weeks), will continue
treatment with tandutinib and bevacizumab. Magnetic resonance imaging (MRI)-perfusion scans
will be repeated after the completion of every 4 weeks of therapy. A total of 80 patients
will be enrolled to this study (GBM (glioblastoma multiforme)=40, AG=40)

- 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.