Indenoisoquinoline LMP744 in Adults With Relapsed Solid Tumors and Lymphomas

Summary

Participation Requirements

Description

Background: Indenoisoquinolines are non-camptothecin inhibitors of topoisomerase 1 (top1) withimproved characteristics over their predecessors. Indenoisoquinolines have better chemical stability, producing stable DNA-top1 cleavage complexes, and exhibit a preference for unique DNA cleavage sites, co...

Background: Indenoisoquinolines are non-camptothecin inhibitors of topoisomerase 1 (top1) withimproved characteristics over their predecessors. Indenoisoquinolines have better chemical stability, producing stable DNA-top1 cleavage complexes, and exhibit a preference for unique DNA cleavage sites, compared with their camptothecin counterparts. They have demonstrated activity against camptothecin-resistant cell lines and produce DNA-protein crosslinks, which are resistant to reversal. They also show less or no resistance to cells overexpressing the ATP-binding cassette (ABC) transporters, ABCG2, and multidrug resistance (MDR-1). Primary Objectives: -To establish the safety, tolerability and the maximum tolerated dose (MTD) of LMP744 (NSC 706744) administered intravenously (IV) daily for 5 days (QD x 5) schedule in patients with refractory solid tumors and lymphomas. Secondary Objectives: -Characterize the pharmacokinetic (PK) profile of LMP744. Exploratory Objectives: Evaluate the effect of LMP744 on markers of DNA damage ( >=H2AX, pNbs1, pATR, ERCC1, RAD51) and epithelial-mesenchymal transition (EMT) in circulating tumor cells (CTCs) and pre- and post- treatment tumor biopsies in patients at the expansion cohort. Assess preliminary antitumor activity of LMP744. Eligibility: -Adult patients must have histologically documented, relapsed solid tumors which have progressed after one line of therapy, or lymphoma which has progressed after initial therapy and without potentially curative options, or patient refuses potentially curative therapy. Study Design: Cycle 1 and subsequent cycles: Patients will receive LMP744 administered IV QD over 1 hour on days 1 5 followed by 23 days without drug (28-day cycle). PK and PD samples will be collected. Tumor biopsies will be optional during the escalation phase and mandatory during the expansion phase.

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