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Purpose <p>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.</p> Methods <p>Patients ≥ 18&#xa0;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&#xa0;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.</p> Results <p>The MTD of LMP776 was 12&#xa0;mg/m<sup>2</sup>/day and that of LMP744 was 190&#xa0;mg/m<sup>2</sup>/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).</p> Conclusion <p>MTDs and safety profiles are reported for LMP776 and LMP744. Target engagement by an indenoisoquinoline was measured for the first time in human samples.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月29日

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  • Geraldine O’Sullivan Coyne,
  • Shivaani Kummar,
  • Larry V. Rubinstein,
  • Deborah Wilsker,
  • Nancy Moore,
  • Murielle Hogu,
  • Richard Piekarz,
  • Joe Covey,
  • Jan H. Beumer,
  • Katherine V. Ferry-Galow,
  • Liza C. Villaruz,
  • Melinda G. Hollingshead,
  • Julianne L. Holleran,
  • Joshua J. Deppas,
  • Yves Pommier,
  • Brian Ko,
  • Barry C. Johnson,
  • Ralph E. Parchhment,
  • Percy Ivy,
  • James H. Doroshow,
  • Alice P. Chen

摘要

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.