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
{"title":"吲哚异喹啉类药物LMP776和LMP744在实体瘤和淋巴瘤患者中的一期研究。","authors":"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","doi":"10.1007/s00280-025-04778-5","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>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><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>The MTD of LMP776 was 12 mg/m<sup>2</sup>/day and that of LMP744 was 190 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><p><strong>Conclusion: </strong>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>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"58"},"PeriodicalIF":2.7000,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12122562/pdf/","citationCount":"0","resultStr":"{\"title\":\"Phase 1 studies of the indenoisoquinolines LMP776 and LMP744 in patients with solid tumors and lymphomas.\",\"authors\":\"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\",\"doi\":\"10.1007/s00280-025-04778-5\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose: </strong>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><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>The MTD of LMP776 was 12 mg/m<sup>2</sup>/day and that of LMP744 was 190 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><p><strong>Conclusion: </strong>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>\",\"PeriodicalId\":9556,\"journal\":{\"name\":\"Cancer Chemotherapy and Pharmacology\",\"volume\":\"95 1\",\"pages\":\"58\"},\"PeriodicalIF\":2.7000,\"publicationDate\":\"2025-05-29\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12122562/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cancer Chemotherapy and Pharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s00280-025-04778-5\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Chemotherapy and Pharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00280-025-04778-5","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"ONCOLOGY","Score":null,"Total":0}
Phase 1 studies of the indenoisoquinolines LMP776 and LMP744 in patients with solid tumors and lymphomas.
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.
期刊介绍：
Addressing a wide range of pharmacologic and oncologic concerns on both experimental and clinical levels, Cancer Chemotherapy and Pharmacology is an eminent journal in the field. The primary focus in this rapid publication medium is on new anticancer agents, their experimental screening, preclinical toxicology and pharmacology, single and combined drug administration modalities, and clinical phase I, II and III trials. It is essential reading for pharmacologists and oncologists giving results recorded in the following areas: clinical toxicology, pharmacokinetics, pharmacodynamics, drug interactions, and indications for chemotherapy in cancer treatment strategy.
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