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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 : February 2, 2021
Sponsor:
Collaborator:
Developmental Therapeutics Consortium
Information provided by (Responsible Party):
Actuate Therapeutics Inc.

Tracking Information
First Submitted Date  ICMJE September 15, 2018
First Posted Date  ICMJE September 20, 2018
Last Update Posted Date February 2, 2021
Actual Study Start Date  ICMJE January 4, 2019
Estimated Primary Completion Date November 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 2, 2018)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: September 18, 2018)
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.
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 9-ING-41 in Patients With Advanced Cancers
Official Title  ICMJE 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
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 - 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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Cancer
  • Pancreatic Cancer
  • Sarcoma
  • Renal Cancer
  • Refractory Cancer
  • Refractory Neoplasm
  • Refractory Non-Hodgkin Lymphoma
  • 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
Intervention  ICMJE
  • Drug: 9-ING-41
    Starting dose of-9-ING-41 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
  • 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
  • Drug: Lomustine
    Lomustine 30 mg/m² orally as a single dose, weekly for twelve weeks.
    Other Names:
    • CCNU
    • Gleostine
  • Drug: Carboplatin.
    Carboplatin AUC 6 IV over 1 hour on Day 1 of a 21-day cycle.
    Other Name: Paraplatin
  • 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: Paclitaxel.
    Paclitaxel 175 mg/m2 intravenously over 3 hours on Day 1 of a 21-day cycle.
    Other Name: Taxol
  • 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
  • Drug: Irinotecan
    Irinotecan 350 mg/m2 intravenously over 90-minutes on Day 1 of a 21-day cycle
    Other Name: Camptosar
Study Arms  ICMJE
  • Experimental: 9-ING-41
    Drug: 9-ING-41
    Intervention: Drug: 9-ING-41
  • Experimental: 9-ING-41 plus Gemcitabine
    Drugs: Gemcitabine - 21 day cycle. 9-ING-41
    Interventions:
    • Drug: 9-ING-41
    • Drug: Gemcitabine - 21 day cycle
  • Experimental: 9-ING-41 plus Doxorubicin
    Drugs: Doxorubicin. 9-ING-41
    Interventions:
    • Drug: 9-ING-41
    • Drug: Doxorubicin.
  • Experimental: 9-ING-41 plus Lomustine
    Drugs: Lomustine. 9-ING-41.
    Interventions:
    • Drug: 9-ING-41
    • Drug: Lomustine
  • Experimental: 9-ING-41 plus Carboplatin
    Drugs: Carboplatin. 9-ING-41.
    Interventions:
    • Drug: 9-ING-41
    • Drug: Carboplatin.
  • Experimental: 9-ING-41 plus nab paclitaxel Gemcitabine
    Drugs: Nab-paclitaxel. Gemcitabine - 28 day cycle. 9-ING-41.
    Interventions:
    • Drug: 9-ING-41
    • Drug: Nab paclitaxel.
    • Drug: Gemcitabine - 28 day cycle
  • Experimental: 9-ING-41 plus Paclitaxel/Carboplatin
    Drugs: Paclitaxel. Carboplatin. 9-ING-41.
    Interventions:
    • Drug: 9-ING-41
    • Drug: Carboplatin.
    • Drug: Paclitaxel.
  • Experimental: 9-ING-41 plus Irinotecan
    Drugs: Irinotecan. 9-ING-41.
    Interventions:
    • Drug: 9-ING-41
    • Drug: Irinotecan
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 20, 2019)
350
Original Estimated Enrollment  ICMJE
 (submitted: September 18, 2018)
250
Estimated Study Completion Date  ICMJE November 2022
Estimated Primary Completion Date November 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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

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 ≤ Grade 2 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)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Francis J Giles, MD +12817961852 fgiles@actuatetherapeutics.com
Listed Location Countries  ICMJE Netherlands,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03678883
Other Study ID Numbers  ICMJE 1801
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Actuate Therapeutics Inc.
Study Sponsor  ICMJE Actuate Therapeutics Inc.
Collaborators  ICMJE Developmental Therapeutics Consortium
Investigators  ICMJE
Study Director: Ludimila Cavalcante, MD DTC
PRS Account Actuate Therapeutics Inc.
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP