Proof of mechanism (POM) in the first-in-human trial of two novel indenoisoquinoline, non-camptothecin topoisomerase I (TOP1) inhibitors.

3031 Background: Indenoisoquinolines LMP 400 and LMP 776 form stable DNA-top1 cleavage complexes, have a preference for unique DNA cleavage sites, and are not substrates for ABC transporters compared to camptothecins. We conducted a randomized phase I trial of LMP 400 and LMP 776 in patients (pts) with refractory tumors to establish safety and MTD of LMP 400 and LMP 776 administered IV daily x 5 d, q 28d; determine PK; evaluate TOP1 and γH2AX levels in tumor biopsies (bx); and compare pharmacodynamic responses of LMP400 and LMP776. Methods: Pts had refractory malignancies; ≥ 18 yrs old; KPS > 70%; adequate organ function. DLT: drug-related gr ≥ 3 non-hem or gr 4 hem toxicities during C1. Pts assigned to receive either LMP 400 or LMP 776. Dose level (DL) in mg/m2/day for LMP 776: 1, 2, 3, 4.5 mg; LMP 400: 2.5, 5, 10, 20, 40, 80. Accelerated titration design with one pt per dose level (DL), 100% dose escalation until one DLT or 2 gr 2 toxicities, then 3+3 design. Tumor bx and circulating tumor cells (CTCs) ...