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.

Keywords: Clinical trial; Indenoisoquinoline; Pharmacodynamic; Topoisomerase.

Fig. 1

Cycles of treatment completed for each patient. Bars are color-coded based on best responses as indicated for LMP400 (left panel, [17]), LMP776 (middle panel), or LMP744 (right panel). White ovals indicate the times of initial partial response, the yellow oval indicates the time of confirmed partial response

Fig. 2

Pharmacokinetics of LMP776 and LMP744. A left: Plasma concentrations of LMP776 over the first 24 h after EOI on day 1 increase with dose level up to DL7; DL8 concentrations overlap with DL7 values. right: Representative concentration–time curve (patient 55) during cycle 1 at the MTD (DL7) of LMP776. B left: Plasma concentrations of LMP744 over the first 24 h after EOI on day 1 increase with dose level up to DL6; DL7 concentrations overlap with DL6 values. right: Representative concentration–time curve (patient 14) during cycle 1 at the MTD (DL6) of LMP744

Fig. 3

Immunohistochemical analysis of SLFN11 expression in baseline (pre-treatment) tumor biopsies. Sections of pre-treatment tumor biopsies from 6 patients in the expansion cohort of LMP744 at MTD (DL6; 190 mg/m²/day) were stained either with (left) hematoxylin and eosin or (right) anti-SLFN11 monoclonal antibody. Expression was low in patients with colorectal cancer (patients 28 and 36) and ovarian cancer (patients 31 and 33). Expression of SLFN11 in patients with ampullary cancer (patient 35) has not been reported. SLFN11 expression was high in the biopsy from patient 29, who exhibited the only cPR

Fig. 4

Pharmacodynamic responses to LMP744 in paired biopsies. Biomarkers of drug engagement of the TOP1 target and consequent DNA damage responses were measured in sections of pre-treatment (C1D1 pre-dose) and post-treatment (C1D2 post-dose) tumor biopsy pairs from 6 patients in the expansion cohort of LMP744 at MTD (DL6; 190 mg/m2/day), using validated quantitative immunofluorescence microscopy (qIF) assays and validated image analysis pipelines. A Nuclear TOP1, pNBS1, γH2AX, and pKAP1 were quantified as percent nuclear area positive (% NAP); nuclear RAD51 was quantified as % of nuclei with ≥ 5 foci; TOP1cc was quantified as the percent of nuclei with ≥ 19 foci. Intra-patient changes are shown as indicated in the legend. Mean values (± standard deviation) are shown as gray bars. In some cases, significant intra-patient changes occurred without the group mean values being significantly different (e.g., group mean values of γH2AX did not change significantly, but a γH2AX response was measured in one patient (patient 29, SCLC, cPR). B Representative qIF images of paired tumor biopsies with statistically significant responses in TOP1 and TOP1cc (left panels, patient 31), RAD51 (center panels, patient 35), and γH2AX (right panels, patient 29). Reflex testing of the biopsies from patient 29 for cCasp3 revealed a pharmacodynamic response to LMP744 (cells positive for both γH2AX and cCasp3) indicative of apoptosis as indicated by yellow arrows [29]