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A Pilot Study Targeting Angiogenesis Using Bevacizumab Combined With Chemotherapy and Histone Deacetylase Inhibitor (Valproic Acid) in Advanced Sarcomas

Phase 1/Phase 2
18 Years
Open (Enrolling)
Sarcoma, Soft Tissue Sarcoma, Locally Advanced Sarcoma, Unresectable Sarcoma, Metastatic Sarcoma

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Trial Information

A Pilot Study Targeting Angiogenesis Using Bevacizumab Combined With Chemotherapy and Histone Deacetylase Inhibitor (Valproic Acid) in Advanced Sarcomas

Soft tissue sarcomas (STS) are a heterogeneous group of benign and malignant tumors of
various supportive tissues arising from the mesoderm. There are 56 known subtypes classified
by the tissue of origin. Soft tissue sarcomas account for 1% of all human malignancies.
These tumors share a common mesenchymal origin with the vasculature. Many of the signaling
pathways involved in angiogenesis also drive sarcoma tumor cell growth. Autocrine and
paracrine vascular endothelial growth factor (VEGF) - and platelet-derived growth factor
(PDGF)-mediated growth plays a role in the pathogenesis of several sarcoma subtypes1.
Despite promising preclinical data supporting a role for angiogenesis inhibition in sarcoma,
relatively few clinical trials have evaluated antiangiogenic therapy in sarcoma.

Most of the studies for the use of anti-angiogenic drugs have been taken from phase I trials
of refractory solid tumors showing a lack of response in sarcomas. This may be due to an
inadequate dose, wrong sequence of the treatment or lack of studies with combination
treatments. Given the heterogeneity of sarcomas there may be a benefit in certain subgroups
that can easily be missed. A recent clinical trial has shown improved cytotoxic cell kill
and response rates by epigenetically modifying the tumor environment prior to chemotherapy.
It is believed that the efficacy of angiogenesis inhibitors has been shown to be greatly
improved when they are combined with other anticancer drugs.

Tumor metastasis is highly dependent on angiogenesis progressing through a metastatic
cascade that includes primary tumor growth, modification of tumor cell growth and behavior
and formation of new blood vessels. This angiogenic switch is believed to be the result of
changes in the balance of angiogenesis stimulators, inhibitors and modulators present at the
site of the tumor growth. These changes are due to both genetic alterations involving RAS,
RAF, MYC, SRC, EGFR and HER-2 and tumor suppressor genes and epigenetic circumstances such
as hypoxia, inflammation or hormonal stimulation. It is clear that vascular endothelial
growth factor (VEGF) has emerged as the key stimulatory molecule for promoting angiogenesis
in a variety of human malignancies. Other pro-angiogenic factors can be induced or amplified
in the presence of hypoxia hypoglycemia, inflammatory cytokines and altered cell-cell
contact. Thus it would be of interest to combine epigenetic modifiers like Valproic acid, a
histone deacetylase inhibitor, with Bevacizumab, an anti-angiogenic agent against VEGF and
standard chemotherapy (Gemcitabine /docetaxel) to better modulate the cytotoxic effects
against 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

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

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)

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Dose-limiting toxicities per CTCAE 4.0; grade 4 hematologic toxicity; grade 3 or 4 hepatotoxicity.

Outcome Time Frame:

After one cycle (3 weeks)

Safety Issue:


Principal Investigator

Mohammed Milhem, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Iowa


United States: Institutional Review Board

Study ID:




Start Date:

September 2010

Completion Date:

March 2014

Related Keywords:

  • Sarcoma
  • Soft Tissue Sarcoma
  • Locally Advanced Sarcoma
  • Unresectable Sarcoma
  • Metastatic Sarcoma
  • Sarcoma
  • Soft Tissue Sarcoma
  • Locally Advanced Sarcoma
  • Unresectable Sarcoma
  • Metastatic Sarcoma
  • Valproic Acid
  • Bevacizumab
  • Histone Deacetylase Inhibitor
  • Sarcoma



University of Iowa Hospitals and Clinics Iowa City, Iowa  52242