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 62 Locations for this study

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Mayo Clinic
Phoenix Arizona, 85054, United States More Info
Clinical Trials Office All Mayo Clinic Locations
Contact
401-606-5483
Arizona Oncology Associates
Tucson Arizona, 85704, United States More Info
Julie Klinker, RN
Contact
520-269-3821
[email protected]
Suresh Mukkamala, MD
Principal Investigator
The University of Arizona Cancer Center
Tucson Arizona, 85719, United States More Info
Brianna Denton
Contact
[email protected]
Rachna Shroff, MD
Principal Investigator
University of California Irvine Health
Orange California, 92868, United States More Info
Jasime Balangue
Contact
[email protected]
Jennifer Valerin, MD
Principal Investigator
UCSF Helen Diller Family Comprehensive Cancer Center
San Francisco California, 94115, United States
Christiana Care Health Services
Newark Delaware, 19709, United States More Info
Denise Demaio
Contact
[email protected]
Jamal Misleh, MD
Principal Investigator
Sibley Memorial Hospital
Washington District of Columbia, 20016, United States More Info
Carol Goldener, RN
Contact
202-660-5629
[email protected]
Michael Pishvaian, MD
Principal Investigator
Florida Cancer Specialists - South
Fort Myers Florida, 33901, United States More Info
Wendy White
Contact
941-650-0441
[email protected]
Ivor Percent, MD
Principal Investigator
Miami Cancer Institute
Miami Florida, 33176, United States
Florida Cancer Specialists - North
Saint Petersburg Florida, 33705, United States More Info
Wendy White
Contact
941-650-0441
[email protected]
Sunil Gandhi, MD
Principal Investigator
Robert H. Lurie Comprehensive Cancer Center of Northwestern University
Chicago Illinois, 60611, United States More Info
Devalingam Mahalingam, MD
Contact
[email protected]
Des Moines Oncology Research Association
Des Moines Iowa, 50309, United States More Info
Missy Stravers, RN
Contact
515-241-3305
[email protected]
Joshua Lukenbill, MD
Principal Investigator
Kansas University Cancer Center
Kansas City Kansas, 66160, United States
Ochsner Clinic Foundation
New Orleans Louisiana, 70121, United States More Info
Sarah Geiger
Contact
504-894-2861
[email protected]
Jonathan Mizrahi, MD
Principal Investigator
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
Hannah Merrill
Contact
[email protected]
Yan Ji, MD
Principal Investigator
Mayo Clinic
Rochester Minnesota, 55905, United States More Info
Clinical Trials Referral Office
Contact
855-776-0015
Wen Wee Ma, MD
Principal Investigator
Comprehensive Cancer Centers of Nevada
Las Vegas Nevada, 89128, United States More Info
Ann Lovelace
Contact
[email protected]
Brian Vicuna, MD
Principal Investigator
Morristown Medical Center
Morristown New Jersey, 07960, United States More Info
Kathryn Radler
Contact
908-522-4899
[email protected]
Angela Alistar, MD
Principal Investigator
Capital Health Medical Center/ Hopewell
Pennington New Jersey, 08534, United States More Info
Patrick DeDeyne
Contact
609-303-4394
[email protected]
Arturo Loaiza-Bonilla, MD
Principal Investigator
MD Anderson Cancer Center at Cooper
Voorhees New Jersey, 08043, United States More Info
Andrea Nicholson
Contact
856-735-6249
[email protected]
Jamin Morrison, MD
Principal Investigator
Columbia University- Irving Medical Center
New York New York, 10032, United States
Stony Brook University Hospital
Stony Brook New York, 11794, United States More Info
Benjamin Neter
Contact
631-896-7990
[email protected]
Amna Sher, MD
Principal Investigator
Duke University Medical Center
Durham North Carolina, 27710, United States More Info
Emily Bolch
Contact
919-668-6359
[email protected]
Nikirika Mettu, MD
Principal Investigator
Oregon Health and Science University
Portland Oregon, 97239, United States More Info
Knight Clinical Trials Information
Contact
503-494-1080
Charles Lopez, MD
Principal Investigator
St. Luke's University Health Network
Bethlehem Pennsylvania, 18015, United States More Info
Robin Rex
Contact
484-658-1406
[email protected]
Yacoub Faroun, MD
Principal Investigator
Allegheny Health Network
Pittsburgh Pennsylvania, 15212, United States More Info
Samatha Cavolo
Contact
[email protected]
Nathan Bahary, MD
Principal Investigator
Rhode Island Hospital
Providence Rhode Island, 02903, United States More Info
Benedito Carneiro, MD
Contact
[email protected]
Prisma Health Cancer Institute
Greenville South Carolina, 26905, United States More Info
Kim Williams
Contact
864-241-6251
[email protected]
Ki Young Chung, MD
Principal Investigator
Sanford Research
Sioux Falls South Dakota, 57105, United States More Info
Steven Powell, MD
Contact
[email protected]
West Cancer Center
Germantown Tennessee, 38138, United States More Info
Robin Patterson
Contact
901-683-0055
[email protected]
Bradley Somer, MD
Principal Investigator
Baptist Clinical Research Institute
Memphis Tennessee, 38120, United States More Info
Julie Ryder
Contact
[email protected]
Donald Gravenor, MD
Principal Investigator
Sarah Cannon Research Institute- Tennessee Oncology-Nashville
Nashville Tennessee, 37203, United States More Info
Meredith Pelster, MD
Principal Investigator
Vanderbilt-Ingram Cancer Center
Nashville Tennessee, 37232, United States More Info
Elizabeth J Davis, MD
Contact
[email protected]
Texas Oncology- Charles A. Sammons Cancer Center
Dallas Texas, 75246, United States More Info
Danielle Koetter, RN
Contact
214-370-1000
[email protected]
Scott Paulson, MD
Principal Investigator
Utah Cancer Specialists
Salt Lake City Utah, 84124, United States More Info
Stephen Kendall, MD
Principal Investigator
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 More Info
Sabrina Martin
Contact
304-293-7374
[email protected]
Nour Daboul, MD
Principal Investigator
UW Carbone Cancer Center
Madison Wisconsin, 53792, United States More Info
UW Carbone Cancer Center
Contact
800-622-8922
[email protected]
Noelle LoConte, MD
Principal Investigator
UZA- Antwerpen
Edegem Antwerp, 2650, Belgium More Info
Timon Vandamme, MD
Principal Investigator
Imelda VZW
Bonheiden , 2820, Belgium More Info
Pieter-Jan Cuyle, MD
Principal Investigator
UZ Gent
Gent , 9000, Belgium More Info
Karen Geboes, MD
Principal Investigator
UZ Leuven Gasthuisberg
Leuven , 3000, Belgium More Info
Jeroen Dekervel, MD
Principal Investigator
Cross Cancer Institute
Edmonton Alberta, T6G 1, Canada More Info
Karen Mulder, MD
Principal Investigator
QE II Health Sciences Centre
Halifax Nova Scotia, B3H 2, Canada More Info
Ravi Ramjeesingh, MD
Principal Investigator
Centre Intégré de Santé et de Services Sociaux de la Montérégie-Centre
Greenfield Park Quebec, G4V 2, Canada More Info
Melina Boutin
Contact
1-450-466-5000
[email protected]
Melina Boutin, MD
Principal Investigator
Jewish General Hospital
Montréal Quebec, H3T 1, Canada More Info
Petr Kavan, MD
Principal Investigator
McGill University Health Centre
Montréal Quebec, H4A 3, Canada More Info
Jamil Asselah, MD
Contact
514-934-1934
[email protected]
Jamil Asselah, MD
Principal Investigator
Centre Hospitalier Universitaire de Sherbrooke
Sherbrooke Quebec, J1H 5, Canada More Info
Michelle Roy
Contact
1-819-346-1110
[email protected]
Frederic Lemay, MD
Principal Investigator
Center Hospitalier Regional Universitaire de Besancon - Site Jean Minjoz
Besançon Bourgogne-Franche-Comte, 25030, France More Info
Angelique Vienot
Principal Investigator
CHRU Brest Hopital Morvan
Brest Bretagne, 29200, France More Info
Jean-Phillipe Metges, MD
Principal Investigator
Hopital Claude Huriez
Lille Hauts De France, 59037, France More Info
Anthony Turpin
Principal Investigator
Institute de Cancerologie de Lorraine
Vandœuvre-lès-Nancy Meurthe-et-Moselle, 54500, France More Info
Aurelien Lambert
Principal Investigator
Institut Bergonie
Bordeaux Nouvelle Aquitaine, 33076, France More Info
Simon Pernot
Principal Investigator
Insitut de Cancerologie de l'Ouest
Saint-Herblain Pays-de-la-Loire, 44800, France More Info
Sandrine Hiret
Principal Investigator
Hopital de la Timone
Marseille , 13005, France More Info
Laetitia Dahan, MD
Principal Investigator
Netherlands Cancer Institute
Amsterdam , 1066 , Netherlands
Hospital Da Luz
Lisbon , 1500-, Portugal More Info
Tania Rodriguez, MD
Principal Investigator
Vall d'Hebron Institute of Oncology
Barcelona , 08035, Spain More Info
Teresa Macarulla Mercade, MD
Principal Investigator
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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