This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This is a phase I study of suberoylanilide hydroxamic acid (SAHA) in children and adolescents with recurrent or refractory solid tumors or leukemia. SAHA is an inhibitor of histone deacetylase (HDAC) that causes the arrest of cell cycle transition at G1 and G2M phases. It has been reported to selectively induce expression of p21 waf/CIP1 cyclin-dependent kinase inhibitor, to effect cell cycle arrest1 and to induce p53 independent apoptosis. A possible model for the antitumor action of SAHA is the inhibition of HDAC activity causing the activation of transcription of genes whose expression force tumor differentiation, apoptosis or inhibit tumor growth. Retinoid acid receptors recruit co-regulatory complexes with HDAC activity in the absence of a ligand, which results in repression of gene transcription. This study will be done in 3 parts. In Part A, the SAHA maximum tolerated dose (MTD) will be determined for solid tumor patients by a standard Phase I dose escalation scheme. Pediatric and adolescent patients with recurrent or refractory solid tumors (including lymphomas) will be eligible for the single agent SAHA dose escalation part of the study if they have adequate hematologic, hepatic, renal, and pulmonary status. In Part B of the study, 6 patients with recurrent or refractory leukemia (in cohorts of 3) will be enrolled at the solid tumor MTD to assess the tolerability of the solid tumor MTD in patients with recurrent or refractory leukemia. If SAHA is not tolerated at the solid tumor MTD, SAHA will be studied in a separate phase I trial in patients with recurrent or refractory leukemia. In Part C of the study, a cohort of patients with neuroblastoma, medulloblastoma/ CNS neuroectodermal tumor (PNET) or atypical teratoid rhabdoid tumor (ATRT) will be enrolled to determine the MTD of SAHA when combined with 13-cis retinoic acid (13-cis RA) at the dose and schedule determined to improve event-free survival in neuroblastoma patients. Part C will start after the SAHA MTD has been determined in Part A. Participants will be given SAHA orally once daily, continuously. A course of therapy is considered to be 28 days. Enrollment to Parts B and C of the study will occur simultaneously after Part A is completed. Optional pharmacokinetic studies, pharmacogenetic studies and assessment of histone acetylation in peripheral blood mononuclear cells and tumor tissue will be performed concurrently.
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