9-ING-41 in Patients With Advanced Cancers

  • End date
    Nov 8, 2022
  • participants needed
  • sponsor
    Actuate Therapeutics Inc.
Updated on 28 July 2021
ct scan
renal function
local anesthesia
absolute neutrophil count
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measurable disease
growth factor
bone marrow procedure
cytotoxic chemotherapy
kidney function tests
neutrophil count
liver metastasis
chemotherapy regimen
human epidermal growth factor
solid tumors
primary cancer
cancer chemotherapy
glioblastoma multiforme
solid tumour
solid tumor
epidermal growth factor
solid neoplasm
cytotoxic agents
serum amylase
renal function test
metastatic malignancy


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:

  • 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.

Condition Pancreatic Cancer, Bone Cancer, urinary tract neoplasm, Ovarian disorder, Colorectal Cancer, Connective and Soft Tissue Neoplasm, Malignant neoplasm of kidney, Nephropathy, Lymphoma, Metastasis, Cancer, Pancreatic disorder, bladder cancer, bladder disorder, Glioma, Breast Cancer, Ovarian Cancer, Glioblastoma Multiforme, Lung Neoplasm, Lymphoproliferative Disorder, Lymphoma, Neoplasm of unspecified nature of digestive system, Sarcoma, Pancreatic Disorders, Non-Hodgkin's Lymphoma, All Solid Tumors, Liver Metastases, Bone Metastases, Kidney Disease (Pediatric), Colon Cancer Screening, Cancer/Tumors, Solid Tumors, Colon cancer; rectal cancer, Ovarian Function, Pancreatic Adenocarcinoma, Refractory Non Hodgkin Lymphoma, High Grade Glioma, Brain Metastases, Ewing's Family Tumors, Bone Metastasis, Urothelial Cancer, Refractory Cancer, Recurrent Ovarian Cancer, Malignancies Multiple, Cancer Refractory, Pain; Bone Neoplasms; Neoplasm Metastasis, Cancer (Pediatric), Sarcoma (Pediatric), Islet Ce417ll Cancer, Refractory Brain Tumor, Kidney Cancer, Lung Cancer, Refractory Neoplasm, Resistant Cancer, Kidney Disease, Metastatic Cancer, Gliomas, Neoplasms, Bladder Disorders, Renal Cancer, Digestive System Neoplasms, Soft Tissue Sarcoma, Neoplasm Metastasis, Bone Neoplasm, Lymphoproliferative disorders, Bladder Carcinoma, Urologic Cancer, malignant glioma, primary cancer, primary malignant neoplasm, malignancy, cancers, malignancies, malignant tumor, malignant tumors, sarcomas, soft tissue sarcomas, breast tumors, tumor of the breast, breast tumor, bone tumor, bone tumors, cancer of the pancreas, pancreatic neoplasm, cancer, renal, pancreatic cancers, cancer, pancreatic, lung tumor, metastases, metastatic disease, secondary cancer, secondaries, metastatic tumor, metastasized
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 on28 July 2021


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