| Exclusion Criteria: | 1) Poorly controlled hypertension (SBP >/= 140 mmHg, or DBP >/= 90 mmHg). NOTE: Initiation or adjustment of BP medication is permitted prior to study entry provided that patient has two consecutive BP readings < 140/90 mmHg each separated by a minimum of 24 hrs. These readings need to be collected prior to enrolment.
2) Concurrent severe and/or uncontrolled medical disease (e.g. uncontrolled diabetes, congestive cardiac failure, poorly controlled hypertension, history of labile hypertension, history of poor compliance with antihypertensive regimen, chronic renal disease, or active uncontrolled infection) that could compromise participation in the study.
3) History of myocardial infarction, admission for unstable angina, cardiac angioplasty or stenting within three months of Day 1, Treatment Period 1.
4) Has Class III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system.
5) QTc prolongation defined as a QTc interval greater than or equal to 470 milliseconds.
6) History of venous or arterial thrombosis within 3 months of Day 1, Treatment Period 1.
7) Current use of therapeutic warfarin. NOTE: both low molecular weight heparin and prophylactic low-dose warfarin are permitted, however, PT/PTT must meet above inclusion criteria.
8) Excessive risk of bleeding as defined by stroke within the prior 6 months, history of CNS or intraocular bleed, or septic endocarditis.
9) Evidence of intratumor hemorrhage on pretreatment diagnostic imaging, except for stable post-operative Grade 1 hemorrhage.
10) Active systemic bleeding, such as gastrointestinal bleeding or gross hematuria. Hemoptysis within 6 weeks of Day 1, Treatment Period 1.
11) Female patients who are pregnant or breast feeding.
12) Acute or chronic liver disease (i.e., hepatitis, cirrhosis).
13) Patients who received investigational drugs < 21days prior to Day 1, Treatment Period 1, or who have not recovered from the toxic effects of such therapy.
14) Patients who received chemotherapy </= 21days prior (6 weeks for prior nitrosourea or mitomycin C) to Day 1, Treatment Period 1, or who have not recovered from the toxic effects of such therapy.
15) Patients who received radiation therapy </= 12 weeks prior to Day 1, Treatment Period 1, or who have not recovered from the toxic effects of such therapy. May consider allowing patients to be eligible at < 12 weeks if they develop PD that is characterized by new enhancement at a non-contiguous site outside of the previous radiation field, or if PD is determined to be biopsy-proven active GBM tumor.
16) Patients who received biologic, immunotherapeutic or cytostatic agents </= 14 days prior to Day 1, Treatment Period 1, or who have not recovered from the toxic effects of such therapy.
17) Patient is < 3 years free of another primary malignancy except: if the other primary malignancy is not currently clinically significant or requiring active intervention. Patients with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible.
18) Surgical resection of brain tumor or any other surgery </= 21 days prior to Day 1, Treatment Period 1, or who have not recovered from side effects of such a procedure. Patients who undergo stereotactic biopsy </= 14 days prior to Day 1 of Treatment Period 1, or who have not recovered from side effects of such a procedure.
19) Patients with any Grade of intraparenchymal CNS hemorrhage. Exceptions include Grade 1 intraparenchymal hemorrhage in the immediate post-operative period, or Grade 1 intraparenchymal hemorrhage that has been stable for >/= 3 months.
20) Patients unwilling to or unable to comply with the protocol.
21) Any serious and/or unstable pre-existing medical, psychiatric, or other condition (including lab abnormalities) that could interfere with patient safety or obtaining informed consent.
22) History of malabsorption syndrome, disease significantly affecting gastrointestinal function or major resection of the stomach or small bowel that could affect absorption, distribution, metabolism or excretion of study drugs. Has any unresolved bowel obstruction or diarrhea.
23) ( 22. continued) Other clinically significant gastrointestinal abnormalities that may increase the risk of GI bleeding or perforation including, but not limited to: • active peptic ulcer disease • inflammatory bowel disease such as ulcerative colitis, or other GI conditions with increased risk of perforation • history of abdominal fistula, GI perforation, or intra-abdominal abscess within 28 days prior to Day 1, Treatment Period 1.
24) Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.
25) Is on any specifically prohibited medication or requires any of these medications during treatment. |