The objectives listed for project 1 in the last grant submission have been successfully addressed during the most recent funding period. The following major accomplishments may be cited as a consequence of the activities of Project 1: (1) DIFFERENTIATION: Since the last grant submission, MSKCC has been a leading center of the development and rational application of all trans-retinoic acid therapy for the treatment of acute promyelocytic leukemia. Studies supported by this program included studies of the pharmacokinetics and metabolism of all trans retinoic acid, its toxicity and its efficacy in the treatment of acute promyelocytic leukemia. (2) DRUG MODULATION AND RESISTANCE: Clinical trials of idarubicin, liposomal doxorubicin and intra hepatic verapamil have been completed. Combination studies of Edatrexate and established chemotherapy agents are continuing. (3) NEW AGENT DEVELOPMENT: A variety of new agents have been tested including edatrexate, lometrexol, deoxyspergualin, topotecan and chloroquinoloxalone sulfonamide. In the next funding period, we will continue our early drug development studies, focused on Phase I and Pharmacology studies of putative differentiation agents, modulation studies and new combination studies. The purpose of project 1 will be to provide Phase I toxicity and pharmacology data on promising new approaches to chemotherapy which can then be applied in a disease specific manner in both projects 2 and 3.
The Specific Aims will be 1) To determine the clinical toxicity and pharmacology of PUTATIVE DIFFERENTIATION INDUCING AGENTS, including a new retinoid LNG 1069, phenylbutyrate, and a new analog of hexamethylene bisacetamide. 2) To conduct a dose escalation study of lobaplatin, a chemotherapy agent which appears to be good candidate for HIGH DOSE THERAPY with growth factor and autologous stem cell support. 3) To determine the effect of RESISTANCE MODULATING AGENTS on the toxicity and pharmacology of established anticancer agents. The modulating agents to be studied include carboxypeptidase G2, and edatrexate leucovorin. 4) To conduct phase I / pharmacology studies of NEW AGENTS AND COMBINATIONS which appear to be synergistic in preclinical studies. These studies will include Phase I studies of the murine/human chimeric antibody HC225 with CDDP, desoxyspergualin and murine antibody cc49, and edatrexate with CDDP / taxol as well as an adaptive control study of 96 h taxol/cddp.
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