gimatecan (CPT-184) / Lee's Pharm - LARVOL DELTA

The Topoisomerase-I Inhibitor Gimatecan Exhibits Potent and Selective Activities Against B-Cell Precursor Acute Lymphoblastic Leukemia with a Favorable Cardiotoxicity Profile (ASH 2023) - "In contrast, the four standard chemotherapeutics (cytarabine, daunorubicin, dexamethasone and vincristine) exhibited much higher median IC50s against BCP-ALL (18-2,201 nM). In short, gimatecan possesses remarkable anti-leukemia activities and tolerable toxicity profiles compared to counterpart topoisomerase-II inhibitor. This study, therefore, puts forward a new agent for BCP-ALL and points towards randomized clinical trials to realize its potential on acute leukemias."

IO biomarker • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • AFF1 • CHEK1 • ETV6 • KMT2A • PARP1 • PBX1 • RUNX1 • TCF3

Increasing the therapeutic vulnerability of heterogenous cell phenotypes within prostate cancer (AACR 2024) - "Tested compounds with differential sensitivity between aggressive and non-aggressive cells were those inhibiting histone deacetylase (vorinostat, fimepinostat, and pracinostat), proteasomes (bortezomib, delanzomib, ixazomib), topoisomerases (gimatecan and daunorubicin), and other compounds identified independently by us targeting nicotinamide phosphoribosyl transferase (FK866) and DNA (bleomycin). Funding was provided by the University of Arizona Cancer Center (NCI-P30 CA23074 and NCI-R01 CA159406) and by the Partnership in Native American Cancer Prevention at the University of Arizona (U54CA143924) and Northern Arizona University (U54CA143925). Collaborators at NCATS were supported by the intramural research program."

Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CDH1 • CLDN4 • CLDN7 • KRT6A • ZEB1

Phenotype plasticity and altered sensitivity to chemotherapeutic agents in aggressive prostate cancer cells. (PubMed, Front Cell Dev Biol) - "Eleven compounds were selected for additional testing, which revealed that vorinostat, 5-azacitidine, and fimepinostat (epigenetic inhibitors) showed 2.6-to-7.5-fold increases in lethality for the aggressive prostate cancer cell population as compared to the parent, as judged by the concentration of drug to inhibit 50% cell growth (IC). On the other hand, the DU145 cells were 2.2-to-4.0-fold resistant to mitoxantrone, daunorubicin, and gimatecan (topoisomerase inhibitors) as compared to DU145. No differences in sensitivities between cell populations were found for docetaxel or pirarubicin. The increased sensitivity of DU145 prostate cancer cells to chromatin modifying agents suggests a therapeutic vulnerability occurs after tumor cells invade into and through muscle. Future work will determine which epigenetic modifiers and what combinations will be most effective to eradicate early aggressive tumor populations."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

A Study of Oral Gimatecan in Platinum-Resistant Epithelial Ovarian, Fallopian Tube or Peritoneal Cancer (clinicaltrials.gov) - P2; N=46; Not yet recruiting; Sponsor: Lee's Pharmaceutical Limited

New P2 trial • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Solid Tumor

Overexpression of Efflux Pumps, Mutations in the Pumps' Regulators, Chromosomal Mutations, and AAC(6')-Ib-cr Are Associated With Fluoroquinolone Resistance in Diverse Sequence Types of Neonatal Septicaemic Acinetobacter baumannii: A 7-Year Single Center Study. (PubMed, Front Microbiol) - "This study investigates susceptibility toward three fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin), multiple fluoroquinolone-resistance mechanisms, and epidemiological relationship of neonatal septicaemic Acinetobacter baumannii...baumannii were highly diverse as 24 sequence-types with seven novel STs (ST-1440/ST-1441/ST-1481/ST-1482/ST-1483/ST-1484/ST-1486) were identified among 47 A. baumannii...The high variability of FQ susceptibility among FQRAB, possessing the same set of mutations in gyrA, parC, and efflux pump regulators, was also noted. This reveals the complexity of interpreting the interplay of multiple resistance mechanisms in A. baumannii."

Clinical • Journal • Infectious Disease • Septic Shock

A Phase II Study of Gimatecan (ST1481) in Locally Advanced or Metastatic Pancreatic Cancer (clinicaltrials.gov) - P2; N=60; Not yet recruiting; Sponsor: Lee's Pharmaceutical Limited

Clinical • New P2 trial • Alzheimer's Disease • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor

A Study of Gimatecan (ST1481) in Small Cell Lung Cancer (clinicaltrials.gov) - P2; N=70; Not yet recruiting; Sponsor: Lee's Pharmaceutical Limited

Clinical • New P2 trial • Esophageal Cancer • Gastrointestinal Cancer • Lung Cancer • Oncology • Prostate Cancer • Small Cell Lung Cancer • Solid Tumor

A novel oral camptothecin analog, gimatecan, exhibits superior antitumor efficacy than irinotecan toward esophageal squamous cell carcinoma in vitro and in vivo. (PubMed, Cell Death Dis) - "In ESCC, gimatecan suppressed the expression and function of topoisomerase I, induced DNA damage and intra-S phase cell cycle arrest, and resulted in apoptosis. And the results suggest that gimatecan has higher potency in inhibiting ESCC tumor growth than irinotecan, providing a rational novel therapeutic strategy for future clinical evaluation."

IO Biomarker • Journal • Preclinical

A Clinical Study of Gimatecan in Advanced Ovarian Epithelial Cancer, Fallopian Tube Cancer or Primary Peritoneal Cancer (clinicaltrials.gov) - P1; N=12; Recruiting; Sponsor: Lee's Pharmaceutical Limited

Clinical • New P1 trial

Growth inhibition of human ovarian carcinoma by a novel AvidinOX-anchored biotinylated camptothecin derivative. (PubMed, Bioorg Med Chem Lett) - "A novel biotinylated gimatecan-derived camptothecin, coded ST8161AA1, was injected at suboptimal doses into human tumors xenografted in mice alone or pre-complexed to AvidinOX. Significantly higher growth inhibition was observed when the drug was anchored to AvidinOX suggesting the potential utility of this delivery modality for the local treatment of inoperable tumors."

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