CDK/histone deacetylase inhibition in acute leukemia

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DESCRIPTION (provided by applicant): The goal of this application is to conduct a Phase I trial and correlative laboratory studies in which the cyclin-dependent kinase (CDK) inhibitor flavopiridol (NSC 649890) is combined with the histone deacetylase inhibitor (HDACI) SAHA (NSC 701852) for the treatment of refractory acute leukemia. This concept is based on preclinical results from this and other laboratories indicating that flavopiridol, despite inducing cell cycle arrest, does not promote HDACI-mediated maturation in leukemic cells; instead, it results in a pronounced increase in mitochondrial injury and apoptosis. This phenomenon may stem from flavopiridol-mediated inhibition of the PTEF-b transcription complex and other kinases, leading to down-regulation/inactivation of various anti-apoptotic proteins, including p21CIP1, XIAP, Mcl-1, NF-kappa B, and diminished phosphorylation of RNA pol II carboxy-terminal domain (CTD). Furthermore, both flavopiridol and SAHA have shown promising evidence of activity in acute leukemia in early Phase I trials. These considerations have prompted the development of a CTEP-approved Phase I trial (NCI #P6637) of SAHA administered po TID x 14 d in conjunction with flavopiridol administered as a 1-hr infusion d 1-5 for patients with refractory leukemia. The goals of this application are 1) to establish the maximally tolerated dose (MTD) of SAHA and Flavopiridol administered in this manner; 2) define the recommended Phase II dose (RPTD) for this regimen; 3) characterize the dose-limiting toxicities (DLTs) of these agents; 4) obtain preliminary evidence of activity of the regimen; 5) characterize the pharmacokinetics of flavopiridol and SAHA. Correlative laboratory studies will also be carried out to test the hypotheses that 1) in vivo administration of flavopiridol and SAHA will result in down-regulation/inactivation of p21CIP1, XIAP, Mcl-1, NF-kappa B, and diminished phosphorylation of CTD RNA pol II in primary patient-derived blasts, as observed in preclinical studies; 2) similar events will occur in blasts exposed to these agents ex vivo; and 3) plasma flavopiridol levels will be achieved sufficient to block SAHA-mediated p21CIP1 induction in cultured leukemia cell lines. Information derived from this trial will lay the groundwork for subsequent rationally designed Phase II trials employing a novel strategy involving simultaneous CDK and HDAC inhibition in the treatment of refractory acute leukemia.