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

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

  2. Author Address

    Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, 31 Center Drive, Building 31, Room 3A44, Bethesda, MD, 20892, USA., Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA., Biometric Research Program, NCI, NIH, Bethesda, MD, USA., Clinical Pharmacodynamics Biomarker Program, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Cancer Therapeutics Evaluation Program, NCI, NIH, Bethesda, MD, USA., UPMC Hillman Cancer Center, Pittsburgh, PA, USA., Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA., Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Biological Testing Branch, NCI, NIH, Frederick, MD, USA., Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, NIH, Bethesda, MD, USA., Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, 31 Center Drive, Building 31, Room 3A44, Bethesda, MD, 20892, USA. chenali@mail.nih.gov.,
    1. Year: 2025
    2. Date: May 29
    3. Epub Date: 2025 05 29
  2. Journal: Cancer Chemotherapy and Pharmacology
    1. 95
    2. 1
    3. Pages: 58
  4. Type of Article: Article
  5. Article Number: 58
  1. Abstract:

    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. 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. 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), ?H2AX, and cleaved caspase-3 (cCasp3). MTDs and safety profiles are reported for LMP776 and LMP744. Target engagement by an indenoisoquinoline was measured for the first time in human samples. © 2025. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

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External Sources

  1. View Full Text
  2. DOI: 10.1007/s00280-025-04778-5
  3. PMID: 40439882
  4. PII : 10.1007/s00280-025-04778-5

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