GSK-3 is a potentially important therapeutic target in human malignancies. The Actuate 1801 Phase 1/2 study is designed to evaluate the safety and efficacy of 9-ING-41, a potent GSK-3 inhibitor, as a single agent and in combination with cytotoxic agents, in patients with refractory cancers.
9-ING-41 is a first-in-class, intravenously administered, maleimide-based small molecule potent selective GSK-3 inhibitor with significant pre-clinical antitumor activity. GSK-3 is a serine/threonine kinase initially described as a key regulator of metabolism and has a role in diverse disease processes including cancer, immune disorders, pathologic fibrosis, metabolic disorders, and neurological disorders. GSK-3 has two ubiquitously expressed and highly conserved isoforms, GSK-3 and GSK-3, with both shared and distinct substrates and functional effects. GSK-3 is particularly important in tumor progression and modulation of oncogenes (including beta-catenin, cyclin D1 and c-Myc), cell cycle regulators (e.g. p27Kip1) and mediators of epithelial-mesenchymal transition (e.g. zinc finger protein SNAI1, Snail). Aberrant overexpression of GSK-3 has been shown to promote tumor growth and chemotherapy resistance in various solid tumors including colon, ovarian, and pancreatic cancers and glioblastoma through differential effects on the pro-survival nuclear factor kappa-light-chain-enhancer of activated B cells (NF-B) and c-Myc pathways as well on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and p53-mediated apoptotic mechanisms. GSK-3 helps maintain malignant cell survival and proliferation, particularly in terms of mediating resistance to standard anti-cancer therapies, through the NF-B pathway. GSK-3 has been established as a potential anticancer target in human bladder, breast, colorectal, glioblastoma, lung, neuroblastoma, ovarian, pancreatic, prostate, renal and thyroid cancers as well as chronic lymphocytic leukemia and lymphomas.
9-ING-41 is a small molecule potent selective GSK-3 inhibitor with broad spectrum pre-clinical antitumor activity. It's modes of action include downregulation of NF-B and decreasing the expression NF-B target genes including cyclin D1, Bcl-2, anti-apoptotic protein (XIAP) and B-cell lymphoma-extra large (Bcl-XL) leading to inhibition of tumor growth in multiple solid tumor cell and lymphoma lines and patient derived xenograft (PDX) models. NF-B is constitutively active in cancer cells and promotes anti-apoptotic molecule expression. NF-B activation is particularly important in cancer cells that have become chemo- and/or radio-resistant. 9-ING-41 also has significant activity in pre-clinical models of pathological pleural and pulmonary fibrosis. 9-ING-41 has significant in vitro and in vivo activity as a single agent and/or in combination with standard cytotoxic chemotherapies in a spectrum of solid tumors and hematological malignancies including bladder, breast, glioblastoma, neuroblastoma, pancreatic, sarcomas, and renal cancers as well as lymphomas.
The 1801 study will have three parts:
|Treatment||Irinotecan, Lomustine, 9-ING-41, Gemcitabine - 21 day cycle, Doxorubicin., Carboplatin., Nab paclitaxel., Paclitaxel., Gemcitabine - 28 day cycle|
|Clinical Study Identifier||NCT03678883|
|Sponsor||Actuate Therapeutics Inc.|
|Last Modified on||12 October 2020|
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