9-ING-41 in Patients With Advanced Cancers

Summary

Objectives

9-ING-41 is a first-in-class, intravenously administered, maleimide-based small molecule
potent selective GSK-3ß 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-3a and GSK-3ß, with both shared and distinct
substrates and functional effects. GSK-3ß 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-3ß 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-3ß helps maintain malignant cell survival and
proliferation, particularly in terms of mediating resistance to standard anti-cancer
therapies, through the NF-?B pathway. GSK-3ß 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-3ß 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 had three parts:

- Completed: 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: 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.

- Part 3: A randomized Phase 2 study of 9-ING-41 either once or twice weekly with
gemcitabine and nab-paclitaxel (GA) versus GA alone for patients with previously
untreated metastatic or locally advanced pancreatic cancer is now open.