Adjuvant Valproate for High Grade Sarcomas
For patients initially presenting with localized sarcoma the standard of care is surgery followed by with radiation therapy (if feasible). Subsequent or adjuvant cytotoxic based chemotherapy even for aggressive sarcoma histopathologies (as commonly done for colorectal cancer or breast cancer) is controversial since over 20 individual adjuvant randomized clinical trials have not been able to consistently demonstrate a statistically significant improvement in overall survival. Maturation or differentiation therapy provides an opportunity to fundamentally change the biology of the underlying cancer (and thus its overall prognosis) by promoting cellular maturation within that cancer. A change from a poorly 'differentiated/high grade' tumor to a well 'differentiated/low grade' tumor is attainable and can change an individual's median time of survival from months to decades. The investigators have significant preclinical data that differentiation therapy using a group of drugs referred to as histone deacetylase inhibitors (such as Valproate, also a commonly used and safe anti seizure medication) is feasible for sarcomas. This approach has not been clinically addressed in solid tumors. Since adjuvant therapy is controversial for sarcomas, and building on the investigators' preclinical data, adjuvant based differentiation therapy using valproate would be predicted to be both safe and potentially extremely beneficial in terms of a) increasing the time to disease recurrence, b) improving the histology upon recurrence; and c) improving overall survival in patients with sarcomas.
Patients with high grade sarcomas will receive Valproate in the adjuvant setting daily and clinically/radiologically followed until recurrence. Relapse free survival, time to local failure, time to distant failure, overall survival, and comparative histopathology of primary and recurrence will be assessed.
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Pilot Study of Adjuvant Valproate for Patients With High Grade Sarcomas|
- Recurrence rate of lower grade sarcoma [ Time Frame: Up to 3 years ] [ Designated as safety issue: Yes ]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.
- Relapse free survival rate [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
- Time to local failure [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
- Time to distant failure [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
|Study Start Date:||October 2009|
|Estimated Study Completion Date:||October 2014|
|Estimated Primary Completion Date:||October 2013 (Final data collection date for primary outcome measure)|
Taken orally, daily to reach serum levels between 50 to 100 µg/mL.
Drug: Valproic Acid
Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 - 100 µg/mL).
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01010958
|Contact: Herbert Irving Comprehensive Cancer Center Clinical Research Management Office||212-305-8615|
|United States, New York|
|Columbia University Medical Center||Recruiting|
|New York, New York, United States, 10032|
|Principal Investigator: Kevin Kalinsky, MD|
|Sub-Investigator: Fabrizio Remotti, MD|
|Sub-Investigator: Francis Lee, MD|
|Sub-Investigator: Bret Taback, MD|
|Principal Investigator:||Kevin Kalinsky, MD, MS||Columbia University|