Breast Cancer Clinical Trial

9-ING-41 in Patients With Advanced Cancers

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.

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Full 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.

View Eligibility Criteria

Eligibility Criteria

Inclusion Criteria:

Patient -

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.
Is aged ≥ 18 years

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

Patient is intolerant of existing therapy(ies) known to provide clinical benefit for their condition
Malignancy is refractory to existing therapy(ies) known to potentially provide clinical benefit
Malignancy has relapsed after standard therapy
Malignancy for which there is no standard therapy that improves survival by at least 3 months
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.

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

Adequate bone marrow function: absolute neutrophil count (ANC) ≥ 500/mL; hemoglobin ≥ 8.5 g/dL, platelets ≥ 50,000/mL
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
Adequate renal function: creatinine clearance ≥ 60 mL/min (Cockcroft and Gault)
Adequate blood coagulation: international normalized ratio (INR) ≤ 2.3
Serum amylase and lipase ≤ 1.5 x ULN
Has adequate performance status (PS): Eastern Co-operative Oncology Group (ECOG) PS 0-2

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
May continue endocrine therapies (e.g. for breast or prostate cancer) and/or anti-human epidermal growth factor (Her2) therapies while on this study
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
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
Must not be receiving any other investigational medicinal product

Exclusion Criteria:

Patient -

Is pregnant or lactating
Is known to be hypersensitive to any of the components of 9-ING-41 or to the excipients used in its formulation
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
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
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
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
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)
Has any medical and/or social condition which, in the opinion of the investigator or study medical coordinator would preclude study participation
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
Has a current active malignancy other than the target cancer
Is considered to be a member of a vulnerable population (for example, prisoners)

Part 3 ARMB Inclusion Criteria: Patient -

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
Is aged ≥ 18 years
Has pathologically confirmed metastatic pancreatic cancer AND is previously untreated with systemic agents in the recurrence/metastatic setting.
Must have at least 1 measurable lesion per RECIST v1.1, measured preferably by computed tomography (CT) scan or magnetic resonance image (MRI)

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)

Has Eastern Co-operative Oncology Group (ECOG) PS 0 or 1

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

Is pregnant or lactating
Is known to be hypersensitive to any of the components of 9-ING-41 or to the excipients used in its formulation
Has endocrine or acinar pancreatic carcinoma
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
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
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
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
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)
Has any medical and/or social condition which, in the opinion of the investigator or study medical coordinator would preclude study participation.
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.
Has a current active malignancy other than pancreatic cancer
Is considered to be a member of a vulnerable population (for example, prisoners).

Study is for people with:

Breast Cancer

Phase:

Phase 2

Estimated Enrollment:

350

Study ID:

NCT03678883

Recruitment Status:

Recruiting

Sponsor:

Actuate Therapeutics Inc.

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There are 16 Locations for this study

See Locations Near You

Mayo Clinic
Phoenix Arizona, 85054, United States More Info
Clinical Trials Office All Mayo Clinic Locations
Contact
401-606-5483
UCSF Helen Diller Family Comprehensive Cancer Center
San Francisco California, 94115, United States
Miami Cancer Institute
Miami Florida, 33176, United States
Robert H. Lurie Comprehensive Cancer Center of Northwestern University
Chicago Illinois, 60611, United States More Info
Devalingam Mahalingam, MD
Contact
[email protected]
Kansas University Cancer Center
Kansas City Kansas, 66160, United States
University of Michigan
Ann Arbor Michigan, 48109, United States More Info
Vaibhav Sahai, MD
Contact
[email protected]
MetroMetro-Minnesota Community Oncology Research Consortium (MMCORC)
Minneapolis Minnesota, 55416, United States More Info
Yan Ji, MD
Principal Investigator
Rhode Island Hospital
Providence Rhode Island, 02903, United States More Info
Benedito Carneiro, MD
Contact
[email protected]
Sanford Research
Sioux Falls South Dakota, 57105, United States More Info
Steven Powell, MD
Contact
[email protected]
Vanderbilt-Ingram Cancer Center
Nashville Tennessee, 37232, United States More Info
Elizabeth J Davis, MD
Contact
[email protected]
Fred Hutchinson Cancer Research Center
Seattle Washington, 98109, United States More Info
Andrew Coveler, MD
Contact
[email protected]
West Virginia University
Morgantown West Virginia, 26506, United States
Netherlands Cancer Institute
Amsterdam , 1066 , Netherlands
Institut Catala d'Oncologia
Barcelona , 8908, Spain More Info
Laura Layos Romero
Principal Investigator
Hospital Clinico U San Carlos (HSC)
Madrid , 28050, Spain More Info
Javier Sastre Valera, MD
Principal Investigator
START Madrid-HM CIOCC Hospital Universitario
Madrid , 28050, Spain More Info
Emiliano Calvo, MD
Contact
[email protected]
INCLIVA University of Valencia
Valencia , 46010, Spain More Info
Andrés Cervantes, MD
Contact
[email protected]

How clear is this clinincal trial information?

Study is for people with:

Breast Cancer

Phase:

Phase 2

Estimated Enrollment:

350

Study ID:

NCT03678883

Recruitment Status:

Recruiting

Sponsor:


Actuate Therapeutics Inc.

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