Brief Title: 9-ING-41 in Patients With Advanced Cancers

INTRODUCTION

• Org Study ID: 1801
• Secondary ID: N/A
• NCT ID: NCT03678883
• Sponsor: Actuate Therapeutics Inc.

BRIEF SUMMARY

GSK-3β 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-3β
inhibitor, as a single agent and in combination with cytotoxic agents, in patients with
refractory cancers.

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DETAILED DESCRIPTION

9-ING-41 is a first-in-class, intravenously administered, maleimide-based small molecule
potent selective GSK-3β 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-3α and GSK-3β, with both shared and distinct substrates and
functional effects. GSK-3β 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-3β 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-κB) and c-Myc pathways as well on tumor
necrosis factor-related apoptosis-inducing ligand (TRAIL) and p53-mediated apoptotic
mechanisms. GSK-3β helps maintain malignant cell survival and proliferation, particularly in
terms of mediating resistance to standard anti-cancer therapies, through the NF-κB pathway.
GSK-3β 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-3β inhibitor with broad spectrum
pre-clinical antitumor activity. It's modes of action include downregulation of NF-κB and
decreasing the expression NF-κB 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-κB is constitutively active in cancer cells and promotes anti-apoptotic molecule
expression. NF-κB 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

- Part 2: 9-ING-41 combined with standard anticancer agents: The 3+3 dose escalation study
design will be used for 7 chemotherapy combination regimens (9-ING-41 plus gemcitabine,
doxorubicin, lomustine, carboplatin, irinotecan, nab-paclitaxel plus gemcitabine,
paclitaxel plus carboplatin) to identify the MTD/RP2D of each regimen. Part 2 will be
started after a maximum of 3 dose escalations of 9-ING-41 as a single agent in Part 1.
The starting dose level in Part 2 of 9-ING-41 within the seven combination regimens will
be the 4th dose level of single agent 9-ING-41 (or lower if the IDMC so recommends).
Dose escalations of 9-ING-41 as a single agent in Part 1 will continue in parallel with
dose escalations of 9-ING-41 in combination treatments in Part 2.

- 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 each of the seven
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 seven 9-ING-41-based combination regimens.

• Overall Status
  Recruiting
• Start Date
  January 4, 2019
• Phase
  Phase 1/Phase 2
• Study Type
  Interventional