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A Pilot Study of Adjuvant Valproate for Patients With High Grade Sarcomas

Phase 1
18 Years
Open (Enrolling)
High Grade Sarcoma

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Trial Information

A Pilot Study of Adjuvant Valproate for Patients With High Grade Sarcomas

Adjuvant chemotherapy for high grade soft tissue sarcomas is controversial. Given the fact
that approximately 50% of patients receiving optimum treatment will recur in three years and
die of recurrence within five years, smarter adjuvant options are needed. One such treatment
option would be to "differentiate" the high grade sarcoma into a low grade sarcoma upon
recurrence. This differentiation effect will reduce the risk of subsequent death by 50% as
determined by the overall survival difference between high grade/poorly differentiated and
low grade/ well differentiated sarcomas. Given that differentiation takes place on a time
scale that is significantly longer than cytotoxic effects, the optimum time to initiate
differentiation therapy is in the adjuvant setting; when the time to disease recurrence is
measured in months to years.

The histone deacetylase inhibitor, Valproate, has been shown to promote differentiation in
myeloid malignancies when administered in standard dosing regiments. We have recently shown
that sarcomas are conceptually similar to hematopoietic malignancies, in that both represent
diseases of aberrant development in which developing cells along their respective lineages
arrest and transform at various points of differentiation. We have recently shown in vitro
that, as for acute promyelocytic leukemia, sarcomas can be reprogrammed to reenter normal
differentiation via epigenetic modulation using histone deacetylase inhibitors. It is
therefore appealing to study Valproate based differentiation therapy in the adjuvant setting
for sarcomas.

Inclusion Criteria:

- Patients must have histologically confirmed high-grade soft tissue sarcoma. Patients
may be entered based on local pathology.

- Surgical paraffin tissue (preferable) and/or 10-15 unstained slides must be available
for baseline analysis.

- No evidence of measurable disease.

- Primary surgery no longer than 12 weeks prior to starting treatment or within 4 weeks
of completing adjuvant cytotoxic chemotherapy, if administered.

- No more than four cycles of adjuvant based chemotherapy.

- No active liver disease.

- Are 18 years of age or older.

- Have a life expectancy greater than 3 months.

- Have an ECOG performance status of 0 or 1.

- Is capable of providing voluntary written informed consent in accordance with all
applicable regulations and follow the study procedures. Patients must be capable of
understanding the investigational nature, potential risks and benefits of the study.

Exclusion Criteria:

- Have inadequate organ function at the screening visit as defined by the following
laboratory values: platelet count less than 100 x 109/L; hemoglobin less than 9.0
g/dL; absolute neutrophil count (ANC) less than 1.5 x 109/L; international normalized
ratio (INR) greater or equal to 1.5 and a PTT greater than the upper limit of normal
(ULN) within 1 week prior to randomization; creatinine clearance (Cockroft Gault)
less than 50ml/min; urine protein: creatinine ratio greater or equal to 1.0 at
screening; aspartate transaminase (AST) greater than 1.5 x ULN; alanine transaminase
(ALT) greater than or equal to 1.5 x ULN; total bilirubin greater than 1.5 x ULN or
greater or equal to 5 x ULN in patients with liver metastases.

- Prior history of valproate use.

- History or active liver disease.

- Evidence of bleeding diathesis or coagulopathy.

- Has uncontrolled active systemic infection requiring therapy.

- Have had treatment for a cancer other than sarcoma within 5 years prior to
enrollment, with the exception of basal cell carcinoma or cervical cancer in-situ.

- Have known human immunodeficiency virus (HIV) positive or hepatitis B surface antigen
positive status or known active hepatitis C infection. Patients assessed by the
investigator to be at risk for HIV, hepatitis B or C infection should be tested in
accordance with local regulations.

- Are a pregnant or breast feeding female. Confirmation that the patient is not
pregnant must be established by a negative serum beta human chorionic gonadotropin
(beta hCG) pregnancy test result obtained during the Screening Period. Pregnancy
testing is not required for postmenopausal or surgically sterilized women.

- Are unwilling to employ adequate means of contraception (condoms, diaphragm, birth
control pills, injections, intrauterine device, or abstinence).

- Has a serious medical or psychiatric illness likely to interfere with participation
in this clinical study.

- Female subjects must either post-menopausal or surgically sterilized or willing to
use an acceptable method of birth control (i.e., a hormonal contraceptive,
intra-uterine device, diaphragm with spermicide, condom with spermicide, or
abstinence) for the duration of the study.

Type of Study:


Study Design:

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

Outcome Measure:

Recurrence rate of lower grade sarcoma

Outcome Description:

The primary end point will be evaluated by the 3-year recurrence rate of lower grade sarcoma histopathologically (or more well differentiated as compared to the primary tumor) amongst those who experience 3-year sarcoma recurrence.

Outcome Time Frame:

Up to 3 years

Safety Issue:


Principal Investigator

Kevin Kalinsky, MD, MS

Investigator Role:

Principal Investigator

Investigator Affiliation:

Columbia University


United States: Food and Drug Administration

Study ID:




Start Date:

October 2009

Completion Date:

October 2014

Related Keywords:

  • High Grade Sarcoma
  • Sarcoma



Columbia University Medical Center New York, New York  10032