High Grade Sarcoma Clinical Trial
Official title:
A Pilot Study of Adjuvant Valproate for Patients With 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.
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.
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Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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