Tandutinib Plus Bevacizumab to Treat Recurrent Brain Tumors

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.