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<p>LP-184 is a novel acylfulvene pro-drug that alkylates DNA after bioactivation by the intracellular oxidoreductase prostaglandin reductase 1 (PTGR1). In preclinical studies, potent growth inhibition has been observed against a wide variety of solid tumor models, particularly those carrying DNA damage repair deficiency. Here, we report results of the first-in-human dose escalation trial of LP-184 in advanced solid tumors. A dose escalation Bayesian optimal interval design was used with a starting dose of 0.01&#xa0;mg/kg. Eligible patients with advanced refractory solid tumors were enrolled to receive LP-184 intravenously on days 1 and 8 of each 21-day cycle. Sixty-three patients were enrolled, with a median age of 62&#xa0;years. Twelve dose levels (DLs) were evaluated with one dose-limiting toxicity (DLT) at DL11 (0.49&#xa0;mg/kg; grade 4 platelet count decreased) and two DLTs at DL12 (0.61&#xa0;mg/kg; grade 3 alanine aminotransferase increased and acute liver injury). The most common (≥ 20%) treatment-related adverse events of any grade included nausea, vomiting, fatigue, and platelet count decreased. No treatment-related deaths occurred during the study. Best response to monotherapy LP-184 was stable disease (SD), which was observed in 22 (40%) of the evaluable patients. Three patients experienced SD that lasted more than 12&#xa0;months. LP-184 was safe and tolerable in the Phase 1a trial in patients with advanced refractory solid tumors. The maximum tolerated dose (MTD) of LP-184 is 0.49&#xa0;mg/kg. Registry: ClinicalTrials.gov, TRN: NCT05933265, Registration date: June 23, 2023.</p>

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A first-in-human phase 1a study of LP-184, a tumor-site activated novel alkylating agent, in patients with advanced solid tumors

  • 期刊论文

  • 发表日期：

    2026年7月7日

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  • Daruka Mahadevan,
  • Jay Parekh,
  • Joseph T. Beck,
  • Willam B. McKean Jr.,
  • Karisa C. Schreck,
  • Anthony J. Olszanski,
  • Misty D. Shields,
  • Vu Phan,
  • John T. Hamm,
  • Bruce B. Bank,
  • Jianli Zhou,
  • Marc Chamberlain,
  • Kishor Bhatia,
  • Reginald Ewesuedo

摘要

LP-184 is a novel acylfulvene pro-drug that alkylates DNA after bioactivation by the intracellular oxidoreductase prostaglandin reductase 1 (PTGR1). In preclinical studies, potent growth inhibition has been observed against a wide variety of solid tumor models, particularly those carrying DNA damage repair deficiency. Here, we report results of the first-in-human dose escalation trial of LP-184 in advanced solid tumors. A dose escalation Bayesian optimal interval design was used with a starting dose of 0.01 mg/kg. Eligible patients with advanced refractory solid tumors were enrolled to receive LP-184 intravenously on days 1 and 8 of each 21-day cycle. Sixty-three patients were enrolled, with a median age of 62 years. Twelve dose levels (DLs) were evaluated with one dose-limiting toxicity (DLT) at DL11 (0.49 mg/kg; grade 4 platelet count decreased) and two DLTs at DL12 (0.61 mg/kg; grade 3 alanine aminotransferase increased and acute liver injury). The most common (≥ 20%) treatment-related adverse events of any grade included nausea, vomiting, fatigue, and platelet count decreased. No treatment-related deaths occurred during the study. Best response to monotherapy LP-184 was stable disease (SD), which was observed in 22 (40%) of the evaluable patients. Three patients experienced SD that lasted more than 12 months. LP-184 was safe and tolerable in the Phase 1a trial in patients with advanced refractory solid tumors. The maximum tolerated dose (MTD) of LP-184 is 0.49 mg/kg. Registry: ClinicalTrials.gov, TRN: NCT05933265, Registration date: June 23, 2023.