9-ING-41 in Patients With Advanced Cancers

  • STATUS
    Recruiting
  • End date
    Nov 12, 2022
  • participants needed
    350
  • sponsor
    Actuate Therapeutics Inc.
Updated on 12 October 2020
anesthesia
ct scan
paclitaxel
renal function
cancer
corticosteroids
absolute neutrophil count
amylase
general anesthesia
measurable disease
lipase
growth factor
bone marrow procedure
doxorubicin
kidney function tests
metastasis
neutrophil count
carboplatin
liver metastasis
gemcitabine
irinotecan
human epidermal growth factor
solid tumors
solid tumour
solid tumor
epidermal growth factor
solid neoplasm
cytotoxic agents
serum amylase
lomustine
9-ing-41
renal function test
metastatic malignancy

Summary

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.

Description

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:

  • Part 1 (9-ING-41 as monotherapy): The standard 3+3 dose escalation design will be applied to all dose cohorts until the Maximum Tolerated Dose (MTD) or Recommended Phase 2 Dose (RP2D) is identified - COMPLETED
  • Part 2: 9-ING-41 combined with standard anticancer agents: The 3+3 dose escalation study design will be used for 8 chemotherapy combination regimens (9-ING-41 plus gemcitabine, doxorubicin, lomustine, carboplatin, irinotecan, nab-paclitaxel plus gemcitabine, paclitaxel plus carboplatin, pemetrexed plus carboplatin) to identify the MTD/RP2D of each regimen - COMPLETED
  • Part 3: Assessment of activity of 9-ING-41 based combination regimens: The primary objective for Study Part 3 is to assess the clinical benefit of selected 9-ING-41-based combination regimens. Secondary objectives will include the assessment of other efficacy variables, including progression-free survival (PFS), duration of tumor response, time to treatment failure, 1-year survival rate and overall survival (OS) as well as additional evaluation of toxicities. The Simon's 2-stage design will be employed for Study Part 3 for the 9-ING-41-based combination regimens. The initial Phase 2 study focused on the combination of 9-ING-41 with gemcitabine and nab-paclitaxel for patients with previously untreated metastatic or locally advanced pancreatic cancer is now open.

Details
Treatment Irinotecan, Lomustine, 9-ING-41, Gemcitabine - 21 day cycle, Doxorubicin., Carboplatin., Nab paclitaxel., Paclitaxel., Gemcitabine - 28 day cycle
Clinical Study IdentifierNCT03678883
SponsorActuate Therapeutics Inc.
Last Modified on12 October 2020

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