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9-ING-41 in Patients With Advanced Cancers

Trial Status: Active

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.

Inclusion Criteria

  • Patient -
  • 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.
  • Is aged ≥ 18 years
  • Has pathologically confirmed advanced or metastatic malignancy characterized by one or more of the following:
  • Patient is intolerant of existing therapy(ies) known to provide clinical benefit for their condition
  • Malignancy is refractory to existing therapy(ies) known to potentially provide clinical benefit
  • Malignancy has relapsed after standard therapy
  • Malignancy for which there is no standard therapy that improves survival by at least 3 months
  • 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.
  • Has laboratory function within specified parameters (may be repeated):
  • Adequate bone marrow function: absolute neutrophil count (ANC) ≥ 500/mL; hemoglobin ≥ 8.5 g/dL, platelets ≥ 50,000/mL
  • 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
  • Adequate renal function: creatinine clearance ≥ 60 mL/min (Cockcroft and Gault)
  • Adequate blood coagulation: international normalized ratio (INR) ≤ 2.3
  • Serum amylase and lipase ≤ 1.5 x ULN
  • Has adequate performance status (PS): Eastern Co-operative Oncology Group (ECOG) PS 0-2
  • 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):
  • Chemotherapy, immunotherapy, or systemic radiation therapy - 14 days or ≥ 5 half-lives (whichever is shorter)
  • Focal radiation therapy - 7 days
  • Systemic and topical corticosteroids - 7 days
  • Surgery with general anesthesia - 7 days
  • Surgery with local anesthesia - 3 days
  • May continue endocrine therapies (e.g. for breast or prostate cancer) and/or anti-human epidermal growth factor (Her2) therapies while on this study
  • 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
  • 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
  • Must not be receiving any other investigational medicinal product

Exclusion Criteria

  • Patient -
  • Is pregnant or lactating
  • Is known to be hypersensitive to any of the components of 9-ING-41 or to the excipients used in its formulation
  • Has not recovered from clinically significant toxicities as a result of prior anticancer therapy, except alopecia and infertility. Recovery is defined as ≤ Grade 2 CTCAE Version 4.03
  • Has significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, or stroke within 6 months of the first dose of 9-ING-41, or cardiac arrhythmia requiring medical treatment detected at screening
  • Has had a myocardial infarction within 12 weeks of the first dose of 9-ING-41 or has electrocardiogram (ECG) abnormalities that are deemed medically relevant by the investigator or study medical coordinator
  • Has known symptomatic rapidly progressive brain metastases or leptomeningeal involvement as assessed by CT scan or MRI. Patients with stable asymptomatic brain metastases or leptomeningeal disease or slowly progressive disease are eligible provided that they have not required new treatments for this disease in a 28-day period before the first dose of study drug, and anticonvulsants and steroids are at a stable dose for a period of 14 days prior to the first dose of study drug
  • Has had major surgery (not including placement of central lines) within 7 days prior to study entry or is planned to have major surgery during the course of the study (major surgery may be defined as any invasive operative procedure in which an extensive resection is performed, e.g. a body cavity is entered, organs are removed, or normal anatomy is altered. In general, if a mesenchymal barrier is opened (pleural cavity, peritoneum, meninges), the surgery is considered major)
  • Has any medical and/or social condition which, in the opinion of the investigator or study medical coordinator would preclude study participation
  • Has received an investigational anti-cancer drug in the 14-day period before the first dose of study drug (or within 5 half-lives if longer) or is currently participating in another interventional clinical trial
  • Has a current active malignancy other than the target cancer
  • Is considered to be a member of a vulnerable population (for example, prisoners)

California

San Francisco
UCSF Medical Center-Mount Zion
Status: ACTIVE
Contact: UCSF Clinical Trials
Phone: 877-827-3222

Colorado

Aurora
University of Colorado Hospital
Status: WITHDRAWN

Florida

Tampa
Moffitt Cancer Center
Status: CLOSED_TO_ACCRUAL

Georgia

Atlanta
Emory University Hospital / Winship Cancer Institute
Status: ACTIVE

Illinois

Chicago
Northwestern University
Status: ACTIVE

Kansas

Kansas City
University of Kansas Cancer Center
Status: ACTIVE
Contact: Adam Hisham AlDouri
Phone: 913-945-7547

Michigan

Ann Arbor
University of Michigan Comprehensive Cancer Center
Status: ACTIVE

Minnesota

Rochester
Mayo Clinic in Rochester
Status: ACTIVE

North Carolina

Chapel Hill
UNC Lineberger Comprehensive Cancer Center
Status: IN_REVIEW

Tennessee

Nashville
Vanderbilt University / Ingram Cancer Center
Status: ACTIVE

Washington

Seattle
Fred Hutch / University of Washington Cancer Consortium
Status: ACTIVE

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 - 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.

Trial Phase Phase I/II

Trial Type Treatment

Lead Organization
Actuate Therapeutics Inc.

  • Primary ID 1801
  • Secondary IDs NCI-2018-03166
  • Clinicaltrials.gov ID NCT03678883