CLINICAL TRIAL: A PHASE I STUDY OF VORINOSTAT AND TEMOZOLOMIDE

Baylor College Of Medicine, Houston TX

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. This is a phase I study of suberoylanilide hydroxamic acid (SAHA) plus temozolomide for children and adolescents with recurrent or refractory central nervous system tumors. SAHA is an inhibitor of histone deacetylase (HDAC) that causes the arrest of cell cycle transition at G1 and G2M phases. SAHA binds to HDAC by inserting a hydroxamic group, most of the aliphatic chain and part of the phenyl amino group in the active site of the enzyme. The insertion of SAHA into the active site prevents the binding of the natural substrate and blocks enzymatic deacetylation. Temozolomide is an oral imidazotetrazine prodrug that undergoes spontaneous hydrolysis to the active metabolite MTIC, which methylates DNA at O6-guanine and other sites. Since we theorize that pretreatment with SAHA may potentiate the activity of temozolomide by relaxing DNA and increasing susceptibility to methylating agents, we will first escalate the dose of SAHA while holding the temozolomide dose constant at 150 mg/m2/day x 5. Previous studies suggest this temozolomide dose is well tolerated and has potential for antitumor activity. If the highest dose of SAHA appears tolerable, then temozolomide dosing will be increased to the standard single-agent dose of 200 mg/m2/day.