Clinical Trials /

9-ING-41 in Patients With Advanced Cancers

NCT03678883

Description:

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.

Related Conditions:
  • Hematopoietic and Lymphoid Malignancy
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 9-ING-41 in Patients With Advanced Cancers
  • 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

Clinical Trial IDs

  • ORG STUDY ID: 1801
  • NCT ID: NCT03678883

Conditions

  • 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

Interventions

DrugSynonymsArms
9-ING-419-ING-41
Gemcitabine - 21 day cycleGemzar9-ING-41 plus Gemcitabine
Doxorubicin.Doxil, Adriamycin9-ING-41 plus Doxorubicin
LomustineCCNU, Gleostine9-ING-41 plus Lomustine
Carboplatin.Paraplatin9-ING-41 plus Carboplatin
Nab paclitaxel.Abraxane, Protein-bound paclitaxel, Nanoparticle albumin-bound paclitaxel9-ING-41 plus nab paclitaxel Gemcitabine
Paclitaxel.Taxol9-ING-41 plus Paclitaxel/Carboplatin
Gemcitabine - 28 day cycleGemzar9-ING-41 plus nab paclitaxel Gemcitabine
IrinotecanCamptosar9-ING-41 plus Irinotecan

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
9-ING-41ExperimentalDrug: 9-ING-41
  • 9-ING-41
9-ING-41 plus GemcitabineExperimentalDrugs: Gemcitabine - 21 day cycle. 9-ING-41
  • 9-ING-41
  • Gemcitabine - 21 day cycle
9-ING-41 plus DoxorubicinExperimentalDrugs: Doxorubicin. 9-ING-41
  • 9-ING-41
  • Doxorubicin.
9-ING-41 plus LomustineExperimentalDrugs: Lomustine. 9-ING-41.
  • 9-ING-41
  • Lomustine
9-ING-41 plus CarboplatinExperimentalDrugs: Carboplatin. 9-ING-41.
  • 9-ING-41
  • Carboplatin.
9-ING-41 plus nab paclitaxel GemcitabineExperimentalDrugs: Nab-paclitaxel. Gemcitabine - 28 day cycle. 9-ING-41.
  • 9-ING-41
  • Nab paclitaxel.
  • Gemcitabine - 28 day cycle
9-ING-41 plus Paclitaxel/CarboplatinExperimentalDrugs: Paclitaxel. Carboplatin. 9-ING-41.
  • 9-ING-41
  • Carboplatin.
  • Paclitaxel.
9-ING-41 plus IrinotecanExperimentalDrugs: Irinotecan. 9-ING-41.
  • 9-ING-41
  • Irinotecan

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

        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)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Parts 1/2: Number of participants with treatment-related adverse events as assessed by CTCAE v4.03
Time Frame:3 months to 3 years
Safety Issue:
Description: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.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Actuate Therapeutics Inc.

Trial Keywords

  • 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

Last Updated

May 17, 2020