Bevacizumab, Chemotherapy and Valproic Acid in Advanced Sarcomas

Inclusion Criteria:

1. Male or female patients aged ≥ 18 years old.

2. ECOG Performance Status of ≤ 2.

3. Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed.

4. Patients must meet the following laboratory criteria:

Hematology: Neutrophil count of > 1500/mm3; Platelet count of >100,000/mm3L; Hemoglobin ≥ 9 g/dL Biochemistry:AST/SGOT and ALT/SGPT ≤ 2.5 x upper limit of normal (ULN) or ≤ 5.0 x ULN if the transaminase elevation is due to disease involvement; Serum bilirubin ≤ 1.5 x ULN; Serum creatinine ≤ 1.5 x ULN or 24-hour creatinine clearance ≥ 50 ml/min; Total serum calcium (corrected for serum albumin) or ionized calcium ≥ LLN; Serum potassium ≥ LLN; Serum sodium ≥ LLN; Serum albumin ≥ LLN or 3g/dl; Patients with any elevated alkaline phosphatase due to bone metastasis can be enrolled

5. Screening EKG with a QTc less than 450 msec confirmed by central laboratory prior to enrollment to the study.

6. Baseline MUGA or ECHO done only in subjects with prior doxorubicin exposure. The test must demonstrate LVEF ≥ the lower limit of the institutional normal.

7. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 7 days of the first administration of study treatment and must be willing to use two methods of contraception one of them being a barrier method during the study and for 3 months after last study drug administration

8. Any patient with the diagnosis of locally advanced, unresectable or metastatic sarcoma from any site. These include untreated patients or those treated with chemotherapy 1st line, 2nd line and 3rd line. Patients must have measurable disease defined as at least 1 lesion ≥ 1cm in the greatest dimension.

9. Previous exposure to Gemcitabine and Taxotere will only be allowed if there is no residual toxicity from previous treatments. Toxicity must be graded as 0 or 1 prior to study.

10. Patients must have had disease progression on or following their most recent treatment regimen or on presentation for the first time with locally advanced unresectable or metastatic disease.

1.All subtypes of sarcoma are eligible for the trial.

Exclusion Criteria:

1. Prior use of Bevacizumab for the treatment of cancer.

2. Prior HDAC, DAC, HSP90 inhibitors or valproic acid for the treatment of cancer.

3. Patients who will need valproic acid for any medical condition .

4. Inadequately controlled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure > 100 mmHg).

5. Prior history of hypertensive crisis or hypertensive encephalopathy.

6. New York Heart Association (NYHA) Grade II or greater congestive heart failure.

7. History of myocardial infarction or unstable angina within 6 months prior to Day 1.

8. History of stroke or transient ischemic attack within 6 months prior to Day 1.

9. Known CNS disease, except for treated brain metastasis: Treated brain metastases are defined as having no evidence of progression or hemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period. Anticonvulsants (stable dose) are allowed. Treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS; Gamma Knife, LINAC, or equivalent) or a combination as deemed appropriate by the treating physician. Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to Day 1 will be excluded.

10. Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1

11. History of hemoptysis (>/= 1/2 teaspoon of bright red blood per episode) wit hin 1 month prior to Day 1

12. Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)

13. Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to Day 1

14. History of abdominal fistula or gastrointestinal perforation within 6 months prior to Day 1

15. Serious, non-healing wound, active ulcer, or untreated bone fracture

16. Proteinuria as demonstrated by a UPC ratio >/= 1.0 at screening

17. Pregnancy (positive pregnancy test) or lactation. Use of effective means of contraception (men and women) in subjects of child-bearing potential

18. Concomitant use of drugs with a risk of causing torsades de pointes

19. Concomitant use of CYP3A4 inhibitors

20. Other concurrent severe and/or uncontrolled medical conditions

21. Patients who have received chemotherapy or any investigational drug < 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy.

22. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1 or anticipation of need for major surgical procedure during the course of the study.

23. Concomitant use of any anti-cancer therapy or radiation therapy.

24. Male patients whose sexual partners are WOCBP not using a double method of contraception during the study and 3 months after the end of treatment. One of these methods must be a condom.

25. Patients with a history of another primary malignancy within 2 years other than curatively treated CIS of the cervix, or basal or squamous cell carcinoma of the skin

26. Patients with known positivity for human immunodeficiency virus (HIV); baseline testing for HIV is not required

27. Patients with any significant history of non-compliance to medical regimens or with inability to grant a reliable informed consent

28. Bone sarcoma is excluded

29. Patients who are on drugs that prolong QT-interval on EKG (many antiarrhythmics, tricyclics, phenothiazines, and others)