Inclusion Criteria:
Estimated life expectancy \>+3 months Recovery from toxic effects of prior therapy to NCI CTCAE v5.0 Grade 1 (non-hematologic toxicities) or Grade \<=2(hematologic toxicities, except deep vein thrombosis) KPS \>=70%
Adequate organ function as determined by:
* Absolute Neutrophil ≥1500/microliter (may not use G-CSF or GM CSF)
* Platelet ≥100 × 103/microliter
* Hemoglobin ≥9 g/dL (may not transfuse or use erythropoietin to obtain this Hgb level)
* Creatinine Clearance ≥ 40ml/min (Cockcroft-Gault)
* Total bilirubin ≤1.5 times ULN (or ≤ 2 times ULN for patients with known Gilbert's syndrome)
* AST ≤ 3 times ULN
* ALT ≤ 3 times ULN
* INR, PT, PTT, or aPTT ≤1.5 x ULN Note: The use of anticoagulants is permitted as long as the PT/(a)PTT is within therapeutic limits (according to the local institution standard) and the patient has been on a stable anticoagulant regimen for at least 2 weeks prior to study Day 1.
If on antiepileptic drug; dose must be stable and no seizures 14 days prior to study Day 1 If on corticosteroids at baseline, dose must be stable or decreasing for at least 5 days prior to study Day 1. For the dose expansion part of the study, the dose must be ≤ 4 mg dexamethasone per day (or equivalent dose if other corticosteroids are used). A higher stable dose of corticosteroids, if used as HRT, may be allowed upon discussion with the Medical Monitor.
Females of childbearing potential must have a negative serum or urine pregnancy test Male or female patients of child-producing potential must agree to use contraception or use prevention of pregnancy measures or agreement to refrain completely from heterosexual intercourse during the study and for 6 months (females \& males) after the last dose of study drug
Exclusion Criteria:
Prior therapy with bevacizumab or other anti-vascular endothelial growth factor (VEGF) treatments within 3 months prior to study Day 1, Multifocal disease, leptomeningeal metastasis, or extracranial metastasis Abnormal ECGs that are clinically significant, including those where QT prolongation (QTcF\>450 msec for males and \>470 msec for females); and/or history of Torsade de Pointes Left ventricular ejection fraction \<40% as determined by ECHO or MUGA Known dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally Know active Crohn's or other inflammatory bowel disease History of another primary cancer within the 2 years prior to study Day 1, except for the following: non-melamona skin cancer, cervical carcinoma in situ, superficial bladder cancer that has been removed or curatively treated.
Have a known detectable viral load for HIV or HVC, or evidence of a HBV surface antigen, all being indicative of active infection. \[Note: Female breastfeeding patients may be enrolled if they interrupt breastfeeding. Breastfeeding should not be resumed for at least 6 months after the last dose of study drug.\]
The presence of any active retinal abnormality determined by screening tests using visual acuity, visual field, fundoscopy, and OCT
Significant cardiovascular disease, including NYHA Class III or IV congestive heart failure, myocardial infarction, unstable angina, poorly controlled cardiac arrhythmias, or stroke in the preceding 6 months prior to study Day 1
Uncontrolled intercurrent illness including, but not limited to, psychiatric illness/social situations that would limit compliance with study requirements, or disorders associated with significant immunocompromised state
Major surgical procedure, surgical resection, open biopsy, or significant traumatic injury within 4 weeks prior to study Day 1 or anticipation of need for major surgical procedure during the course of the study
Minor surgical procedures, fine needle aspirations, or core biopsies within 7 days prior to study Day 1
Evidence of CNS hemorrhage on baseline MRI or CT scan (except for postsurgical, asymptomatic, Gr 1 hemorrhage that has been stable at least 4 weeks for enrolled patients) Chemotherapy or investigational anticancer therapy administered within 4 weeks (except 6 weeks for nitrosoureas and immunotherapy, or 8 weeks for an implanted nitrosoureas wafer) prior to study Day 1
Radiotherapy within 12 weeks prior to study Day 1, unless relapse is confirmed by tumor biopsy or new lesion outside of radiation field, or if there are 2 MRIs (performed 8 weeks apart) confirming progressive disease
Concurrent use of prohibited medications: carbamazepine, phenytoin, phenobarbital, and other strong or moderate CYP3A4 inhibitors or inducers, and strong CYP2D6 inhibitors. These should be discontinued 1 week or 5 half-lives (whichever is greater) prior to study Day 1
Concurrent treatment with Tumor Treatment Field (Optune) is not allowed. Patients must stop Optune 1 day prior to the first dose of study drug. Any wounds from Optune must be healed adequately prior to study Day 1
History of, within 6 months of study Day 1:
1. Pneumonitis or interstitial lung disease
2. Any other lung condition that in the investigators' judgement may put the patient at an increased risk for lung toxicity (including, but not limited to, suspected interstitial lung disease or radiation-induced lung injury)
