This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.This is a two arm, dose escalating Phase 1 study to determine the effects of UCN-01 and perifosine in combination in relapsed and refractory acute leukemias. UCN-01 will be dose escalated to a maximum tolerated dose/recommended phase 2 dose in the presence of the recommended phase 2 dose of perifosine. The sequence of administration of the two drugs will also be studied. The current proposed protocol will examine in a focused way whether in patients with circulating or marrow-accessible tumor cells each agent alone and in combination will affect akt phosphorylation status, the possible target of perifosine. Owing to the tight binding of UCN-01 to alpha1-acid glycoprotein, a Phase I escalation of UCN-01 is proposed initially in the presence of the recommended Phase 2 concentrations of perifosine to confirm the absence of unexpected toxicities of the combination. Neither agent was myelotoxic in initial Phase I studies conducted by a co-investigator of this proposed protocol. UCN-01 caused dose limiting hyperglycemia and nausea, while gastrointestinal side effects dominated in the case of perifosine. Note that the perifosine schedule proposed for use here utilizes a style of loading and maintenance perifosine doses that achieves similar perifosine concentrations with potentially continuous rather than interrupted dosing with manageable gastrointestinal toxicity, as compared to the interrupted schedule in the NCI phase 1 experience. Antiemetic prophylaxis will be routinely used prior to perifosine loading, and with UCN-01 as needed. In prior perifosine and UCN-01 phase 1 investigations, drug concentrations as single agents expected to modulate akt were achieved. UCN-01 will be administered as a three hour infusion, a schedule with which University of Maryland has experience and has already developed supportive care algorithms owing to a previous combined UCN-01 and carboplatin phase I experience.
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