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9-ING-41 in Patients With Advanced Cancers

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ClinicalTrials.gov Identifier: NCT03678883
Recruitment Status : Recruiting
First Posted : September 20, 2018
Last Update Posted : April 16, 2019
Sponsor:
Collaborator:
Developmental Therapeutics Consortium
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
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 Drug: 9-ING-41 Drug: Gemcitabine - 21 day cycle Drug: Doxorubicin. Drug: Lomustine Drug: Carboplatin. Drug: Nab paclitaxel. Drug: Paclitaxel. Drug: Gemcitabine - 28 day cycle Phase 1 Phase 2

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 6 chemotherapy combination regimens (9-ING-41 plus gemcitabine, doxorubicin, lomustine, carboplatin, 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 six combination regimens will be the 3rd 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 six 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 six 9-ING-41-based combination regimens.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 250 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : January 4, 2019
Estimated Primary Completion Date : November 2022
Estimated Study Completion Date : November 2022


Arm Intervention/treatment
Experimental: 9-ING-41
Drug: 9-ING-41
Drug: 9-ING-41
Starting dose of-9-ING-41 (1mg/kg) will be administered on Day 1 and 4 each week of a 21-day cycle. 9-ING-41 will be administered intravenously over 60 minutes.

Experimental: 9-ING-41 plus Gemcitabine
Drugs: Gemcitabine - 21 day cycle. 9-ING-41
Drug: 9-ING-41
Starting dose of-9-ING-41 (1mg/kg) will be administered on Day 1 and 4 each week of a 21-day cycle. 9-ING-41 will be administered intravenously over 60 minutes.

Drug: Gemcitabine - 21 day cycle
Gemcitabine 1250 mg/m2 as a 30-minute intravenous infusion on Days 1 and 8 of a 21-day cycle
Other Name: Gemzar

Experimental: 9-ING-41 plus Doxorubicin
Drugs: Doxorubicin. 9-ING-41
Drug: 9-ING-41
Starting dose of-9-ING-41 (1mg/kg) will be administered on Day 1 and 4 each week of a 21-day cycle. 9-ING-41 will be administered intravenously over 60 minutes.

Drug: Doxorubicin.
Doxorubicin 75 mg/m2, intravenous bolus on Day 1 of a 21-day cycle up to a maximum lifetime dose of 550 mg/m2.
Other Names:
  • Doxil
  • Adriamycin

Experimental: 9-ING-41 plus Lomustine
Drugs: Lomustine. 9-ING-41.
Drug: 9-ING-41
Starting dose of-9-ING-41 (1mg/kg) will be administered on Day 1 and 4 each week of a 21-day cycle. 9-ING-41 will be administered intravenously over 60 minutes.

Drug: Lomustine
Lomustine 30 mg/m² orally as a single dose, weekly for twelve weeks.
Other Names:
  • CCNU
  • Gleostine

Experimental: 9-ING-41 plus Carboplatin
Drugs: Carboplatin. 9-ING-41.
Drug: 9-ING-41
Starting dose of-9-ING-41 (1mg/kg) will be administered on Day 1 and 4 each week of a 21-day cycle. 9-ING-41 will be administered intravenously over 60 minutes.

Drug: Carboplatin.
Carboplatin AUC 6 IV over 1 hour on Day 1 of a 21-day cycle.
Other Name: Paraplatin

Experimental: 9-ING-41 plus nab paclitaxel Gemcitabine
Drugs: Nab-paclitaxel. Gemcitabine - 28 day cycle. 9-ING-41.
Drug: 9-ING-41
Starting dose of-9-ING-41 (1mg/kg) will be administered on Day 1 and 4 each week of a 21-day cycle. 9-ING-41 will be administered intravenously over 60 minutes.

Drug: Nab paclitaxel.
Nab-paclitaxel 125 mg/m2 intravenously on Days 1, 8 and 15 of a 28-day cycle
Other Names:
  • Abraxane
  • Protein-bound paclitaxel
  • Nanoparticle albumin-bound paclitaxel

Drug: Gemcitabine - 28 day cycle
Gemcitabine 1000 mg/m2 intravenously over 30-minutes on Days 1, 8 and 15 of a 28-day cycle
Other Name: Gemzar

Experimental: 9-ING-41 plus Paclitaxel/Carboplatin
Drugs: Paclitaxel. Carboplatin. 9-ING-41.
Drug: 9-ING-41
Starting dose of-9-ING-41 (1mg/kg) will be administered on Day 1 and 4 each week of a 21-day cycle. 9-ING-41 will be administered intravenously over 60 minutes.

Drug: Carboplatin.
Carboplatin AUC 6 IV over 1 hour on Day 1 of a 21-day cycle.
Other Name: Paraplatin

Drug: Paclitaxel.
Paclitaxel 175 mg/m2 intravenously over 3 hours on Day 1 of a 21-day cycle.
Other Name: Taxol




Primary Outcome Measures :
  1. Parts 1/2: Number of participants with treatment-related adverse events as assessed by CTCAE v4.03 [ Time Frame: 3 months to 3 years ]
    The standard assessments used to assign a score to any affected organ system as per the NCI CTCAE 4.03 will be conduced at each protocol-specified timepoint.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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) ≥ 1,000/mL; hemoglobin ≥ 8.5 g/dL, platelets ≥ 75,000/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 0-1
    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 - 21 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 21-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 had a previous (within 2 years) or has a current malignancy other than the target cancer with the exception of curatively treated local tumors including carcinoma in situ of the breast or cervix, basal or squamous cell carcinoma of the skin, or prostate cancer with Gleason Grade < 6 and prostate-specific antigen within normal range
    11. Is considered to be a member of a vulnerable population (for example, prisoners)
    12. For Study Parts 2 and 3, must not have developed persistent (>28 days) clinically significant Grade 3/4 toxicities attributable to same prior chemotherapy agent as that being considered for administration on this study in combination with 9-ING-41
    13. During Parts 1 and 2 of the study, patients taking strong inhibitors of CYP2C19, CYP3A4, and CYP1A2 or strong inducers of CYP3A4 should not be entered into the study protocol; this will be reviewed by the IDMC prior to Part 3 of the study opening to recruitment

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03678883


Contacts
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Contact: Francis J Giles, MD +12817961852 fgiles@actuatetherapeutics.com

Locations
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United States, California
UCSF Helen Diller Family Comprehensive Cancer Center Recruiting
San Francisco, California, United States, 94115
Contact: Pamela Munster, MD       Pmunster@medicine.ucsf.edu   
United States, Florida
Miami Cancer Institute Recruiting
Miami, Florida, United States, 33176
Contact: Ludimila Cavalcante, MD       LudimilaC@baptisthealth.net   
United States, Minnesota
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
Contact: Wen Wee Ma, M.B.B.S.       Ma.Wen@mayo.edu   
United States, Rhode Island
Rhode Island Hospital Recruiting
Providence, Rhode Island, United States, 02903
Contact: Benedito Carneiro, MD       Benedito.Carneiro@Lifespan.org   
United States, South Dakota
Sanford Research Recruiting
Sioux Falls, South Dakota, United States, 57105
Contact: Steven Powell, MD       Steven.Powell@SanfordHealth.org   
Sponsors and Collaborators
Actuate Therapeutics Inc.
Developmental Therapeutics Consortium
Investigators
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Principal Investigator: Francis J Giles, MD Actuate Therapeutics

Publications of Results:

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Responsible Party: Actuate Therapeutics Inc.
ClinicalTrials.gov Identifier: NCT03678883     History of Changes
Other Study ID Numbers: 1801
First Posted: September 20, 2018    Key Record Dates
Last Update Posted: April 16, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Actuate Therapeutics Inc.:
Refractory cancers
9-ING-41
Glycogen Synthase Kinase
GSK-3β
NF-κβ
Apoptosis
Chemoresistance
DNA damage response DDR
Ataxia telangiectasia mutated and Rad3 related ATR
Checkpoint kinase 1 CHK1

Additional relevant MeSH terms:
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Lymphoma
Neoplasms
Adenocarcinoma
Neoplasm Metastasis
Pancreatic Neoplasms
Lymphoma, Non-Hodgkin
Glioblastoma
Urinary Bladder Neoplasms
Breast Neoplasms
Glioma
Kidney Neoplasms
Carcinoma, Renal Cell
Bone Neoplasms
Osteosarcoma
Colorectal Neoplasms
Lung Neoplasms
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplastic Processes
Pathologic Processes
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases