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BRIEF TITLE: Study of 9-ING-41, a Glycogen Synthase Kinase-3 Beta (GSK-3β) Inhibitor, as a Single Agent and Combined With Chemotherapy, in Patients With Refractory Hematologic Malignancies or Solid Tumors

Phase 1/2 Study of 9-ING-41, a Glycogen Synthase Kinase-3 Beta (GSK-3β) Inhibitor, as a Single Agent and Combined With Chemotherapy, in Patients With Refractory Hematologic Malignancies or Solid Tumors


  • Org Study ID: 1801
  • Secondary ID:
  • NCT ID: NCT03678883
  • NCT Alias:
  • Sponsor: Actuate Therapeutics Inc. - Industry
  • Source: 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.

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.

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

Primary Outcomes:

Primary Outcome 1 - Measure: Parts 1/2: Number of participants with treatment-related adverse events as assessed by CTCAE v4.03

Primary Outcome 1 - Time Frame: 3 months to 3 years

Condition:

  • Cancer
  • Lymphoma
  • Pancreatic Cancer
  • Glioblastoma Multiforme
  • Sarcoma
  • Breast Cancer
  • Bladder Cancer
  • Renal Cancer
  • Ovarian Cancer
  • Refractory Cancer
  • Refractory Neoplasm
  • Refractory Non-Hodgkin Lymphoma
  • Refractory Brain Tumor
  • Pancreatic Adenocarcinoma
  • Resistant Cancer
  • Neoplasm Metastasis
  • Neoplasm of Bone
  • Neoplasm, Breast
  • Neoplasm of Lung
  • Neoplasms,Colorectal
  • Neoplasms Pancreatic
  • Malignant Glioma
  • Malignancies
  • Malignancies Multiple
  • Bone Metastases
  • Bone Neoplasm
  • Bone Cancer
  • Pancreas Cancer
  • Pancreatic Neoplasms
  • Breast Neoplasms

Eligibility

Criteria:
Inclusion Criteria:

- Patient -

1. 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.

2. Is aged ≥ 18 years

3. Has pathologically confirmed advanced or metastatic malignancy characterized by
one or more of the following:

1. Patient is intolerant of existing therapy(ies) known to provide clinical
benefit for their condition

2. Malignancy is refractory to existing therapy(ies) known to potentially
provide clinical benefit

3. Malignancy has relapsed after standard therapy

4. Malignancy for which there is no standard therapy that improves survival by
at least 3 months

4. 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.

5. Has laboratory function within specified parameters (may be repeated):

1. Adequate bone marrow function: absolute neutrophil count (ANC) ≥ 500/mL;
hemoglobin ≥ 8.5 g/dL, platelets ≥ 50,000/mL

2. 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

3. Adequate renal function: creatinine clearance ≥ 60 mL/min (Cockcroft and
Gault)

4. Adequate blood coagulation: international normalized ratio (INR) ≤ 2.3

5. Serum amylase and lipase ≤ 1.5 x ULN

6. Has adequate performance status (PS): Eastern Co-operative Oncology Group (ECOG)
PS 0-2

7. 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

8. May continue endocrine therapies (e.g. for breast or prostate cancer) and/or
anti-human epidermal growth factor (Her2) therapies while on this study

9. 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

10. 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

11. Must not be receiving any other investigational medicinal product

12. For study Parts 2 and 3, must have received prior therapy for the same malignancy
including the same potential partner agent(s) as that/those being considered for
administration on study in combination with 9-ING-41

Exclusion Criteria:

- Patient -

1. Is pregnant or lactating

2. Is known to be hypersensitive to any of the components of 9-ING-41 or to the
excipients used in its formulation

3. Has not recovered from clinically significant toxicities as a result of prior
anticancer therapy, except alopecia and infertility. Recovery is defined as ≤
CTCAE) Version 4.03

4. 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

5. 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

6. 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

7. 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)

8. Has any medical and/or social condition which, in the opinion of the investigator
or study medical coordinator would preclude study participation

9. 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

10. Has a current active malignancy other than the target cancer

11. Is considered to be a member of a vulnerable population (for example, prisoners)
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Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

Official Information

Name: Francis J Giles, MD

Role: Study Chair

Affiliation: Actuate Therapeutics

Overall Contact

Name: Francis J Giles, MD

Phone: +12817961852

Email: fgiles@actuatetherapeutics.com

Locations

Facility Status Contact
UCSF Helen Diller Family Comprehensive Cancer Center
San Francisco, California 94115
United States
Recruiting Pamela Munster, MD

Pmunster@medicine.ucsf.edu
Miami Cancer Institute
Miami, Florida 33176
United States
Recruiting Bruno R Bastos, MD

BrunoBa@baptisthealth.net
Winship Cancer Institute
Atlanta, Georgia 30322
United States
Recruiting Donald Harvey, FCCP

rdharve@emory.edu
Mayo Clinic
Rochester, Minnesota 55905
United States
Recruiting Wen Wee Ma, M.B.B.S.

Ma.Wen@mayo.edu
Rhode Island Hospital
Providence, Rhode Island 02903
United States
Recruiting Benedito Carneiro, MD

Benedito.Carneiro@Lifespan.org
Sanford Research
Sioux Falls, South Dakota 57105
United States
Recruiting Steven Powell, MD

Steven.Powell@SanfordHealth.org