LMP744 / Gibson Oncology, National Cancer Institute, Purdue University - LARVOL DELTA

Irreversible targeting of the C-MYC/TOPOISOMERASE I axis in glioblastoma: dual inhibition using a novel indenoisoquinoline inhibitor (SNO 2024) - "Human glioblastoma cells treated with LMP744 show a dose-dependent decrease in viability with LD50 ranging between 50 and 100 nM compared to 100-200µM following treatment with temozolomide in the same cell lines. Administration of 20 mg/kg of LMP744 via tail vein injection resulted in total eradication of tumor signal on bioluminescent imaging. These preliminary findings suggest that LMP744–and perhaps the class of non-camptothecin indenoisoquinolones–is a promising novel candidate for glioblastoma pharmacotherapy."

Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CHEK2 • MYC • TOP1

Treatment with novel topoisomerase inhibitors in Ewing sarcoma models reveals heterogeneity of tumor response. (PubMed, Front Cell Dev Biol) - "In this study, we evaluated the preclinical efficacy of three IIQs (LMP400, LMP744, and LMP776) in relevant models of EWS...LMP400 treatment induced ≥30% tumor regression in two of six PDX models, with more durable regression compared to irinotecan treatment in one of these models...These data, along with pharmacogenomic data on IIQs in sarcoma cell lines, are available at a new interactive public website: https://discover.nci.nih.gov/rsconnect/EwingSarcomaMinerCDB/. Our findings suggest that IIQs may be promising new agents for a subset of EWS patients."

Heterogeneity • Journal • Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor • TOP1

Amarex Achieves Orphan Drug Designation for Gibson Oncology’s Novel LMP744 Cancer Treatment (Businesswire) - "Amarex today announced its work on behalf of Gibson Oncology has resulted in an Orphan Drug Designation (ODD) by the United States Food and Drug Administration (FDA) for the drug LMP744. LMP744 treats gliomas, readily crossing the blood brain barrier (BBB) at 10 times the concentration required to kill cancer cells and sustains a high concentration for over 24 hours per dose....Obtaining ODD for LMP744 for all gliomas underscores the promising and novel treatment of the drug to inhibit two cancer targets: TOPO 1 and downregulate cMyc overexpression through the drug’s potent binding of the G4 quadruplex of cMyc."

Orphan drug • Glioma

Indenoisoquinoline LMP744 in Adults With Relapsed Solid Tumors and Lymphomas (clinicaltrials.gov) - P1 | N=36 | Completed | Sponsor: National Cancer Institute (NCI) | Recruiting ➔ Completed | N=53 ➔ 36

Enrollment change • Trial completion • Hematological Malignancies • Lymphoma • Oncology • Prostate Cancer • Solid Tumor • CD4

Phase 1 study of indenoisoquinoline LMP744 in adults with relapsed solid tumors and lymphomas. (ASCO 2023) - P1 | "The MTD of LMP744 was established at 190 mg/m2/d on d1-5 in a 28d C. The single agent activity of LMP744 in this heavily pretreated population was limited; however, 4 colorectal cancer pts had prolonged stabilization of disease with prior progression on irinotecan. Analyses of secondary and exploratory correlatives are ongoing. Clinical trial information: NCT03030417."

Clinical • P1 data • Anemia • Appendix Cancer • Colorectal Cancer • Gastrointestinal Cancer • Hematological Disorders • Hematological Malignancies • Leukopenia • Lung Cancer • Lymphoma • Mesothelioma • Neuroendocrine Tumor • Neutropenia • Oncology • Small Cell Lung Cancer • Solid Tumor • RAD51 • TOP1

Dual targeting MYC G-quadruplex and topoisomerase I by indenoisoquinolines for cancer therapy (AACR 2023) - "Three indenoisoquinolines, indotecan (LMP400), indimitecan (LMP776), and LMP744, have entered phase I clinical trials in adults with relapsed solid tumors and lymphomas. Therefore, these results indicate that targeting the MYC promoter G-quadruplex to downregulate MYC is a new mechanism of action for anticancer indenoisoquinolines. Moreover, our data reveals dual targeting of MycG4 and topoisomerase I as a novel strategy for cancer therapy."

Hematological Malignancies • Lymphoma • Oncology • Solid Tumor • TOP1

Indenoisoquinoline LMP744 in Adults With Relapsed Solid Tumors and Lymphomas (clinicaltrials.gov) - P1 | N=53 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Oct 2022 ➔ Oct 2023 | Trial primary completion date: Oct 2022 ➔ Oct 2023

Trial completion date • Trial primary completion date • Hematological Malignancies • Lymphoma • Oncology • Prostate Cancer • Solid Tumor • CD4

Development and validation of an LC-MS/MS generic assay platform for small molecule drug bioanalysis. (PubMed, J Pharm Biomed Anal) - "The generic approach has become a useful tool to further define the pharmacology of drugs studied in our laboratory and may be utilized as described, or as starting point to develop drug-specific assays with more extensive performance characterization."

Journal

Indenoisoquinoline LMP744 in Adults With Relapsed Solid Tumors and Lymphomas (clinicaltrials.gov) - P1; N=53; Recruiting; Sponsor: National Cancer Institute (NCI); Trial completion date: Oct 2020 ➔ Oct 2022; Trial primary completion date: Oct 2020 ➔ Oct 2022

Clinical • Trial completion date • Trial primary completion date • Hematological Malignancies • Lymphoma • Oncology • Solid Tumor

The indenoisoquinoline TOP1 inhibitors selectively target homologous recombination deficient- and Schlafen 11-positive cancer cells and synergize with olaparib. (PubMed, Clin Cancer Res) - "Our results provide a rationale for molecularly designed clinical trials with the indenoisoquinolines as single agents and in combination with PARP inhibitors in HRD cancers expressing SLFN11."

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

Targeting Topoisomerase I in the Era of Precision Medicine. (PubMed, Clin Cancer Res) - "Irinotecan and topotecan have been widely used as anticancer drugs for the past 20 years. We introduce new therapeutic strategies based on novel TOP1 inhibitor chemical scaffolds including the indenoisoquinolines LMP400 (indotecan), LMP776 (indimitecan) and LMP744, and on tumor-targeted delivery TOP1 inhibitors (TTTis) using liposome, PEGylation and antibody-drug conjugates. We also address how tumor-specific determinants such as homologous recombination defects (HRD and BRCAness) and Schlafen 11 (SLFN11) expression can be used to guide clinical application of TOP1 inhibitors in combination with DNA damage response inhibitors including PARP, ATR, CHEK1 and ATM inhibitors."

Journal • Oncology

[VIRTUAL] Dual targeting MYC G-quadruplex and topoisomerase I: Lead discovery indenoisoquinolines for cancer therapy (AACR-II 2020) - "Indenoisoquinolines are human topoisomerase I inhibitors with improved physicochemical and biological properties as compared to the clinically used camptothecin anticancer drugs. Three indenoisoquinolines, indotecan (LMP400), indimitecan (LMP776), and LMP744, have entered phase I clinical trials in adults with relapsed solid tumors and lymphomas...In conclusion, our result reveals MYC downregulation by MycG4 binding as a new mechanism of action for anticancer indenoisoquinolines. Moreover, we suggest dual targeting of MycG4 and topoisomerase I as a novel strategy for cancer therapy."

Hematological Malignancies • Oncology • Solid Tumor • PCR • TOP1

The indenoisoquinoline LMP517: a novel antitumor agent targeting both TOP1 and TOP2. (PubMed, Mol Cancer Ther) - "The camptothecin derivatives topoisomerase I (TOP1) inhibitors, irinotecan and topotecan are US-FDA approved for the treatment of colorectal, ovarian, lung and breast cancers. Because of the chemical instability of camptothecins, short plasma half-life, drug efflux by the multidrug-resistance ABC transporters and the severe diarrhea produced by irinotecan, indenoisoquinoline TOP1 inhibitors (LMP400, LMP776 and LMP744), which overcome these limitations, have been developed and are in clinical development...Histone γH2AX detection showed that, unlike classical TOP1 inhibitors, LMP517 targets cells independently of their position in the cell cycle. Our study establishes LMP517 as a dual TOP1 and TOP2 inhibitor with therapeutic potential."

Journal • Breast Cancer • Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • Thoracic Cancer • TOP1 • XRCC6

NCI Comparative Oncology Program Testing of Non-Camptothecin Indenoisoquinoline Topoisomerase I Inhibitors in Naturally Occurring Canine Lymphoma. (PubMed, Clin Cancer Res) - "These results demonstrate proof-of-mechanism for indenoisoquinoline TOP1 inhibitors supporting their further clinical development. They also highlight the value of the NCI Comparative Oncology Program (https://ccr.cancer.gov/Comparative-Oncology-Program) for evaluating novel therapies in immune-competent pets with cancers."

Journal

Novel fluoroindenoisoquinoline non-camptothecin topoisomerase I inhibitors. (PubMed, Mol Cancer Ther) - "Contrary to other anticancer targets, topoisomerase I (TOP1) is targeted by only one chemical class of FDA-approved drugs: topotecan and irinotecan, the derivatives of the plant alkaloid, camptothecin. The indenoisoquinolines LMP400, LMP744, and LMP776 are novel noncamptothecin TOP1 inhibitors in clinical trial, which overcome the limitations of camptothecins...Genomic analyses and activity assays in CCRF-CEM SLFN11-deleted cells showed that SLFN11 expression is a dominant determinant of response to LMP135. This study shows the potential value of the fluoroindenoisoquinolines for further development as novel anticancer agents targeting TOP1."

Journal

Indenoisoquinoline LMP744 in Adults With Relapsed Solid Tumors and Lymphomas (clinicaltrials.gov) - P1; N=50; Recruiting; Sponsor: National Cancer Institute (NCI); Suspended ➔ Recruiting

Clinical • Enrollment open

Indotecan (LMP400), indimitecan (LMP776) and LMP744, a new class of non-camptothecin topoisomerase I inhibitors selective for schlafen11-positive and BRCA-deficient cells that synergize with olaparib (AACR 2019) - "To overcome the limitations of topoisomerase inhibitors, irinotecan and topotecan (chemical instability, drug efflux substrates, short half-life, dose-limiting bone marrow and gastrointestinal toxicity), we have developed the indenoisoquinolines (LMP400, LMP776 and LMP744). Better efficacy was observed with the combination over single agent treatments of LMP400 or olaparib. Our results provide a rationale for Phase 2 indenoisoquinoline clinical trials with the indenoisoquinolines in HR-deficient cancers as single agents and in combination with PARP inhibitors, and for measuring Schlafen 11 (SLFN11) as a clinical response determinant."