Summary

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

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.

Eligibility

1. Patient -
2. Is able to understand and voluntarily sign a written informed consent and is willing and able to comply with the protocol requirements including scheduled visits, treatment plan, laboratory tests and other study procedures.
3. Is aged = 18 years
4. Has pathologically confirmed advanced or metastatic malignancy characterized by one or more of the following:
5. Patient is intolerant of existing therapy(ies) known to provide clinical benefit for their condition
6. Malignancy is refractory to existing therapy(ies) known to potentially provide clinical benefit
7. Malignancy has relapsed after standard therapy
8. Malignancy for which there is no standard therapy that improves survival by at least 3 months
9. Has evaluable tumor(s) by standard radiological and/or laboratory assessments as applicable to their malignancy - in Part 3, patients with solid tumors must have least 1 measurable lesion per response evaluation criteria in solid tumors (RECIST) v1.1 criteria, measured preferably by computed tomography (CT) scan or magnetic resonance image (MRI). In the case of patients with glioblastoma multiforme (GBM) or other central nervous system (CNS) tumors, the tumor must be measurable, defined as a clearly enhancing tumor with at two perpendicular diameters at entry equal or superior to 1cm.
10. Has laboratory function within specified parameters (may be repeated):
11. Adequate bone marrow function: absolute neutrophil count (ANC) = 500/mL; hemoglobin = 8.5 g/dL, platelets = 50,000/mL
12. Adequate liver function: transaminases (aspartate aminotransferase/ alanine aminotransferase, AST/ALT) and alkaline phosphatase = 3 (= 5 X the upper limit of normal (ULN) in the setting of liver metastasis or infiltration with malignant cells) x ULN; bilirubin = 1.5 x ULN
13. Adequate renal function: creatinine clearance = 60 mL/min (Cockcroft and Gault)
14. Adequate blood coagulation: international normalized ratio (INR) = 2.3
15. Serum amylase and lipase = 1.5 x ULN
16. Has adequate performance status (PS): Eastern Co-operative Oncology Group (ECOG) PS 0-2
17. Has received the final dose of any of the following treatments/ procedures with the specified minimum intervals before first dose of study drug (unless in the opinion of the investigator and the study medical coordinator the treatments/ procedures will not compromise patient safety or interfere with study conduct and with IDMC agreement):
18. Chemotherapy, immunotherapy, or systemic radiation therapy - 14 days or = 5 half-lives (whichever is shorter)
19. Focal radiation therapy - 7 days
20. Systemic and topical corticosteroids - 7 days
21. Surgery with general anesthesia - 7 days
22. Surgery with local anesthesia - 3 days
23. May continue endocrine therapies (e.g. for breast or prostate cancer) and/or anti-human epidermal growth factor (Her2) therapies while on this study
24. Women of childbearing potential must have a negative baseline blood or urine pregnancy test within 72 hours of first study therapy. Women may be neither breastfeeding nor intending to become pregnant during study participation and must agree to use effective contraceptive methods (hormonal or barrier method of birth control, or true abstinence) for the duration of study participation and in the following 90 days after discontinuation of study treatment
25. Male patients with partners of childbearing potential must take appropriate precautions to avoid fathering a child from screening until 90 days after discontinuation of study treatment and use appropriate barrier contraception or true abstinence
26. Must not be receiving any other investigational medicinal product

Treatment Sites in Georgia