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.