Phase 1 study of indenoisoquinoline LMP744 in adults with relapsed solid tumors and lymphomas.
Authors: Ko Brian , Chen Alice P. , Kummar Shivaani , Hogu Murielle , Rubinstein Larry V. , Takebe Naoko , Piekarz Richard , Sharon Elad , Beumer Jan Hendrik , Wilsker Deborah , Ketchum Donna , Ferry-Galow Katherine V. , Parchment Ralph E. , Holleran Julianne L. , Deppas Joshua J. , Collins Jerry M. , Johnson Barry C. , Ivy S. Percy , Doroshow James H. , O'Sullivan Coyne Geraldine Helen 
Published: June 2023

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Background: Indenoisoquinolines (IIQ) are non-camptothecin inhibitors of topoisomerase 1 (TOP1) that have improved characteristics over camptothecin TOP1 inhibitors. IIQs demonstrate better chemical stability, produce more persistent DNA breaks induced by trapping DNA-TOP1 cleavage complexes, induce DNA breaks at different sites than camptothecins, and are not substrates for cellular export proteins. We present data from a trial of LMP744 (NSC 706744), which was the most efficacious IIQ in a canine lymphoma trial, designed to establish the safety, efficacy, and maximum tolerated dose (MTD) of LMP744. Methods: We conducted a multicenter phase 1 trial in adult patients (pts) with dose escalations following design 3 of the Simon accelerated titration designs. LMP744 was administered intravenously daily on d1-5 in 28-day cycles (C), starting at dose level (DL) 1 (6 mg/m2/d). Responses and adverse events (AEs) were defined by RECIST 1.1 and CTCAE v4.0, respectively. Plasma concentrations were determined by LC-MS/MS with a validated assay over a range of 1-3,000 ng/mL. Paired biopsies (baseline and C1D2) were analyzed for DNA damage response markers (γH2AX, pNBS1, and Rad51) by IFA. Results: A total of 36 pts were enrolled, median age was 61 years (range 35-81), median prior lines of systemic treatment was 5 (range 2-10) and 26 pts (72%) had received prior TOP1 inhibitor therapy. One pt on DL6 (190 mg/m2/d) experienced a dose-limiting toxicity (DLT) of grade 3 hypokalemia during C1, reverting the study to a 3+3 design. MTD was established at DL6. Of 24 patients evaluable for response, 1 pt with small cell lung cancer on DL6 achieved a partial response (PR), remaining on treatment for 7C. 17 pts had stable disease (including 1 pt with an unconfirmed PR), and 6 had progressive disease. Median duration of response among pts with SD was 4.5C (range 1-28). A total of 6 pts on DL6 with colorectal cancer (n=4, all had received prior irinotecan), mesothelioma (n=1), and low-grade appendiceal mucinous neoplasm (n=1) remained on study for >6C. Treatment-related grade 3/4 AEs included leukopenia (n=9), anemia (n=4), dehydration (n=2), neutropenia (n=2) and nausea (n=2). Pharmacokinetic (PK) data for the first 17 patients suggests dose-linear PK, best fit to a 2-compartment model. Approximate half-life, clearance, central and peripheral volume values were 30 h, 90 L/h, 200 L, and 2500 L, respectively. Induction of γH2AX and Rad51 was measured in the pt with PR. Conclusions: The MTD of LMP744 was established at 190 mg/m2/d on d1-5 in a 28d C. The single agent activity of LMP744 in this heavily pretreated population was limited; however, 4 colorectal cancer pts had prolonged stabilization of disease with prior progression on irinotecan. Analyses of secondary and exploratory correlatives are ongoing. Clinical trial information: NCT03030417 .