9-ING-41 in Patients with Advanced Cancers

Phase 2

Active, not recruiting

• Conditions: Cancer; Pancreatic Cancer; Pancreatic Adenocarcinoma; Neoplasm, Breast; Neoplasms Pancreatic; Malignancies; Malignancies Multiple; Bone Cancer; Pancreatic Neoplasms; Neoplasm Metastasis
• Interventions: Drug: 9-ING-41; Drug: Gemcitabine - 21 day cycle; Drug: Nab paclitaxel.; Drug: Doxorubicin.; Drug: Carboplatin.; Drug: Lomustine; Drug: Irinotecan; Drug: Gemcitabine - 28 day cycle; Drug: Paclitaxel.

• Registration Number: NCT03678883
• Lead Sponsor: 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 had three parts:

* Completed: 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: 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.

* Part 3: A randomized Phase 2 study of 9-ING-41 either once or twice weekly with gemcitabine and nab-paclitaxel (GA) versus GA alone for patients with previously untreated metastatic or locally advanced pancreatic cancer is now open.

Study Timeline

• Study First Submitted: 2018-09-15
• Study First Submitted QC: 2018-09-18
• Study First Posted: 2018-09-20
• Study Start: 2019-01-04
• Status Verified: 2024-07
• Last Update Submitted: 2024-11-06
• Last Update Posted: 2024-11-07
• Primary Completion: 2025-01
• Study Completion: 2026-01

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 350

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

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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)

Part 3 ARMB 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 metastatic pancreatic cancer AND is previously untreated with systemic agents in the recurrence/metastatic setting.

4. Must have at least 1 measurable lesion per RECIST v1.1, measured preferably by computed tomography (CT) scan or magnetic resonance image (MRI)

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

   e. Adequate bone marrow function: absolute neutrophil count (ANC) ≥ 500/mL; hemoglobin ≥ 8.5 g/dL, platelets ≥ 75,000/mL f. Adequate liver function: transaminases (aspartate aminotransferase/ alanine aminotransferase, AST/ALT) and alkaline phosphatase ≤ 3 (≤ 10 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 ≥ 30 mL/min (Cockcroft and Gault)

6. Has Eastern Co-operative Oncology Group (ECOG) PS 0 or 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:

   • Focal radiation therapy - 7 days
   • Surgery with general anesthesia - 7 days
   • Surgery with local anesthesia - 3 days

8. May have received treatment with fluorouracil or gemcitabine as a radiation sensitizer in the adjuvant setting if the treatment was received at least 6 months before study enrollment

9. May have received neoadjuvant chemotherapy with FOLFIRINOX if last dose given at least 6 months before study enrollment

10. May have received prior cytotoxic doses of systemic chemotherapy in the adjuvant setting if last dose given at least 6 months before study enrollment

11. 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

12. 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

13. Must not be receiving any other investigational medicinal product

Patient who meets ANY of the following criteria is not eligible for this Part 3 study Arm B:

Exclusion Criteria:

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 endocrine or acinar pancreatic carcinoma
4. Has not recovered from clinically significant toxicities as a result of prior anticancer therapy, except alopecia and/or infertility. Recovery is defined as ≤ Grade 2 severity per CTCAE, v5.0
5. 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 study therapy, or uncontrolled cardiac arrhythmia
6. Has had a myocardial infarction within 12 weeks of the first dose of study therapy or has electrocardiogram (ECG) abnormalities that are deemed medically relevant by the investigator
7. Has symptomatic rapidly progressive brain metastases or leptomeningeal involvement as assessed by CT scan or MRI. Patients with stable 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
8. 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)
9. Has any medical and/or social condition which, in the opinion of the investigator or study medical coordinator would preclude study participation.
10. 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.
11. Has a current active malignancy other than pancreatic cancer
12. Is considered to be a member of a vulnerable population (for example, prisoners).

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
9-ING-41 plus nab paclitaxel Gemcitabine	Gemcitabine - 28 day cycle	Drugs: Nab-paclitaxel. Gemcitabine - 28 day cycle. 9-ING-41.
9-ING-41	9-ING-41	Drug: 9-ING-41
9-ING-41 plus Gemcitabine	Gemcitabine - 21 day cycle	Drugs: Gemcitabine - 21 day cycle. 9-ING-41
9-ING-41 plus Carboplatin	9-ING-41	Drugs: Carboplatin. 9-ING-41.
9-ING-41 plus nab paclitaxel Gemcitabine	Nab paclitaxel.	Drugs: Nab-paclitaxel. Gemcitabine - 28 day cycle. 9-ING-41.
9-ING-41 plus Doxorubicin	Doxorubicin.	Drugs: Doxorubicin. 9-ING-41
9-ING-41 plus Paclitaxel/Carboplatin	9-ING-41	Drugs: Paclitaxel. Carboplatin. 9-ING-41.
9-ING-41 plus Paclitaxel/Carboplatin	Carboplatin.	Drugs: Paclitaxel. Carboplatin. 9-ING-41.
9-ING-41 plus Doxorubicin	9-ING-41	Drugs: Doxorubicin. 9-ING-41
9-ING-41 plus Carboplatin	Carboplatin.	Drugs: Carboplatin. 9-ING-41.
9-ING-41 plus nab paclitaxel Gemcitabine	9-ING-41	Drugs: Nab-paclitaxel. Gemcitabine - 28 day cycle. 9-ING-41.
9-ING-41 plus Paclitaxel/Carboplatin	Paclitaxel.	Drugs: Paclitaxel. Carboplatin. 9-ING-41.
9-ING-41 plus Gemcitabine	9-ING-41	Drugs: Gemcitabine - 21 day cycle. 9-ING-41
9-ING-41 plus Irinotecan	9-ING-41	Drugs: Irinotecan. 9-ING-41.
9-ING-41 plus Lomustine	9-ING-41	Drugs: Lomustine. 9-ING-41.
9-ING-41 plus Lomustine	Lomustine	Drugs: Lomustine. 9-ING-41.
9-ING-41 plus Irinotecan	Irinotecan	Drugs: Irinotecan. 9-ING-41.

Primary Outcome Measures

Name	Time	Method
Parts 1/2: Number of participants with treatment-related adverse events as assessed by CTCAE v4.03	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.
Part 3 Arm B	3 months to 3 years	To determine the 1-year survival rate of patients treated on the 9-ING-41 schedule chosen from the run-in stage of the study compared to the control arm

Trial Locations

Locations (65)

Institut Catala d'Oncologia; 🇪🇸 Barcelona, Spain

Hospital Clinico U San Carlos (HSC); 🇪🇸 Madrid, Spain

START Madrid-HM CIOCC Hospital Universitario; 🇪🇸 Madrid, Spain

INCLIVA University of Valencia; 🇪🇸 Valencia, Spain

Mayo Clinic; 🇺🇸 Rochester, Minnesota, United States

Arizona Oncology Associates; 🇺🇸 Tucson, Arizona, United States

The University of Arizona Cancer Center; 🇺🇸 Tucson, Arizona, United States

University of California Irvine Health; 🇺🇸 Orange, California, United States

UCSF Helen Diller Family Comprehensive Cancer Center; 🇺🇸 San Francisco, California, United States

Christiana Care Health Services; 🇺🇸 Newark, Delaware, United States

Sibley Memorial Hospital; 🇺🇸 Washington, District of Columbia, United States

Florida Cancer Specialists - South; 🇺🇸 Fort Myers, Florida, United States

Miami Cancer Institute; 🇺🇸 Miami, Florida, United States

Florida Cancer Specialists - North; 🇺🇸 Saint Petersburg, Florida, United States

Robert H. Lurie Comprehensive Cancer Center of Northwestern University; 🇺🇸 Chicago, Illinois, United States

Des Moines Oncology Research Association; 🇺🇸 Des Moines, Iowa, United States

Kansas University Cancer Center; 🇺🇸 Kansas City, Kansas, United States

Ochsner Clinic Foundation; 🇺🇸 New Orleans, Louisiana, United States

University of Michigan; 🇺🇸 Ann Arbor, Michigan, United States

MetroMetro-Minnesota Community Oncology Research Consortium (MMCORC); 🇺🇸 Minneapolis, Minnesota, United States

Comprehensive Cancer Centers of Nevada; 🇺🇸 Las Vegas, Nevada, United States

Morristown Medical Center; 🇺🇸 Morristown, New Jersey, United States

Capital Health Medical Center/ Hopewell; 🇺🇸 Pennington, New Jersey, United States

MD Anderson Cancer Center at Cooper; 🇺🇸 Voorhees, New Jersey, United States

Columbia University- Irving Medical Center; 🇺🇸 New York, New York, United States

Stony Brook University Hospital; 🇺🇸 Stony Brook, New York, United States

Duke University Medical Center; 🇺🇸 Durham, North Carolina, United States

Oregon Health and Science University; 🇺🇸 Portland, Oregon, United States

St. Luke's University Health Network; 🇺🇸 Bethlehem, Pennsylvania, United States

Allegheny Health Network; 🇺🇸 Pittsburgh, Pennsylvania, United States

Rhode Island Hospital; 🇺🇸 Providence, Rhode Island, United States

Prisma Health Cancer Institute; 🇺🇸 Greenville, South Carolina, United States

Sanford Research; 🇺🇸 Sioux Falls, South Dakota, United States

West Cancer Center; 🇺🇸 Germantown, Tennessee, United States

Baptist Clinical Research Institute; 🇺🇸 Memphis, Tennessee, United States

Sarah Cannon Research Institute- Tennessee Oncology-Nashville; 🇺🇸 Nashville, Tennessee, United States

Vanderbilt-Ingram Cancer Center; 🇺🇸 Nashville, Tennessee, United States

Vall d'Hebron Institute of Oncology; 🇪🇸 Barcelona, Spain

Texas Oncology- Charles A. Sammons Cancer Center; 🇺🇸 Dallas, Texas, United States

UT Southwestern Medical Center; 🇺🇸 Dallas, Texas, United States

Utah Cancer Specialists; 🇺🇸 Salt Lake City, Utah, United States

Fred Hutchinson Cancer Research Center; 🇺🇸 Seattle, Washington, United States

West Virginia University; 🇺🇸 Morgantown, West Virginia, United States

UW Carbone Cancer Center; 🇺🇸 Madison, Wisconsin, United States

UZA- Antwerpen; 🇧🇪 Edegem, Antwerp, Belgium

Imelda VZW; 🇧🇪 Bonheiden, Belgium

UZ Gent; 🇧🇪 Gent, Belgium

UZ Leuven Gasthuisberg; 🇧🇪 Leuven, Belgium

Cross Cancer Institute; 🇨🇦 Edmonton, Alberta, Canada

QE II Health Sciences Centre; 🇨🇦 Halifax, Nova Scotia, Canada

Centre Intégré de Santé et de Services Sociaux de la Montérégie-Centre; 🇨🇦 Greenfield Park, Quebec, Canada

Jewish General Hospital; 🇨🇦 Montréal, Quebec, Canada

McGill University Health Centre; 🇨🇦 Montréal, Quebec, Canada

Centre Hospitalier Universitaire de Sherbrooke; 🇨🇦 Sherbrooke, Quebec, Canada

Center Hospitalier Regional Universitaire de Besancon - Site Jean Minjoz; 🇫🇷 Besançon, Bourgogne-Franche-Comte, France

CHRU Brest Hopital Morvan; 🇫🇷 Brest, Bretagne, France

Hopital Claude Huriez; 🇫🇷 Lille, Hauts de France, France

Institute de Cancerologie de Lorraine; 🇫🇷 Vandœuvre-lès-Nancy, Meurthe-et-Moselle, France

Institut Bergonie; 🇫🇷 Bordeaux, Nouvelle Aquitaine, France

Insitut de Cancerologie de l'Ouest; 🇫🇷 Saint-Herblain, Pays-de-la-Loire, France

Hopital de la Timone; 🇫🇷 Marseille, France

Netherlands Cancer Institute; 🇳🇱 Amsterdam, Netherlands

Fundacao Champalimaud; 🇵🇹 Lisbon, Portugal

Hospital Da Luz; 🇵🇹 Lisbon, Portugal

Centro Hospitalar Universitario Sao Joao; 🇵🇹 Porto, Portugal