Phase 1 studies of the indenoisoquinolines LMP776 and LMP744 in patients with solid tumors and lymphomas

Abstract

Purpose: Indenoisoquinolines are a class of topoisomerase I (TOP1) inhibitors designed to overcome clinical limitations of camptothecins. Three indenoisoquinolines (LMP400, LMP776, and LMP744) demonstrated activity in murine models and a comparative canine lymphoma study. Clinical data for LMP400 were previously reported (NCT01051635). The maximum tolerated dose (MTD), safety, and clinical data from phase 1 studies of LMP776 (NCT01051635) and LMP744 (NCT03030417) are reported herein. Methods: Patients ≥ 18 years of age with advanced, refractory solid tumors or lymphomas received either LMP776 (n = 34) or LMP744 (n = 35) intravenously following a Simon accelerated titration design. Both LMP776 and LMP744 were administered daily for 5 days (QDx5) in 28-day cycles. Adverse events and clinical responses were evaluated according to CTCAE and RECIST v1.1 criteria, respectively. Pharmacokinetic and pharmacodynamic changes were evaluated. Results: The MTD of LMP776 was 12 mg/m2/day and that of LMP744 was 190 mg/m2/day. Dose-limiting toxicities (DLTs) for LMP776 included hypercalcemia, anemia, and hyponatremia; DLTs for LMP744 included hypokalemia, anemia, and weight loss. There was 1 confirmed partial response (cPR) among 35 patients receiving LMP744 (overall response rate 3%) and no objective responses in patients receiving LMP776. Tumor biopsies from the patient with cPR demonstrated high baseline expression of SLFN11 and a unique pattern of pharmacodynamic responses, including increased RAD51, phosphorylated KAP1 (pKAP1), γH2AX, and cleaved caspase-3 (cCasp3). Conclusion: MTDs and safety profiles are reported for LMP776 and LMP744. Target engagement by an indenoisoquinoline was measured for the first time in human samples.