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.

Andrew P Mazar, PhD

Victor Moyo, MBChB

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.

Rhode Island Hospital

Clinical Trials Office All Mayo Clinic Locations

Mayo Clinic

Julie Klinker, RN

Arizona Oncology Associates

Brianna Denton

The University of Arizona Cancer Center

Jasime Balangue

University of California Irvine Health

UCSF Helen Diller Family Comprehensive Cancer Center

Denise Demaio

Christiana Care Health Services

Carol Goldener, RN

Sibley Memorial Hospital

Wendy White

Florida Cancer Specialists - South

Miami Cancer Institute

Florida Cancer Specialists - North

Devalingam Mahalingam, MD

Robert H. Lurie Comprehensive Cancer Center of Northwestern University

Missy Stravers, RN

Des Moines Oncology Research Association

Kansas University Cancer Center

Sarah Geiger

Ochsner Clinic Foundation

Vaibhav Sahai, MD

University of Michigan

Hannah Merrill

MetroMetro-Minnesota Community Oncology Research Consortium (MMCORC)

Clinical Trials Referral Office

Ann Lovelace

Comprehensive Cancer Centers of Nevada

Kathryn Radler

Morristown Medical Center

Patrick DeDeyne

Capital Health Medical Center/ Hopewell

Andrea Nicholson

MD Anderson Cancer Center at Cooper

Columbia University- Irving Medical Center

Benjamin Neter

Stony Brook University Hospital

Emily Bolch

Duke University Medical Center

Knight Clinical Trials Information

Oregon Health and Science University

Robin Rex

St. Luke's University Health Network

Samatha Cavolo

Allegheny Health Network

Benedito Carneiro, MD

Kim Williams

Prisma Health Cancer Institute

Steven Powell, MD

Sanford Research

Robin Patterson

West Cancer Center

Julie Ryder

Baptist Clinical Research Institute

Sarah Cannon Research Institute- Tennessee Oncology-Nashville

Elizabeth J Davis, MD

Vanderbilt-Ingram Cancer Center

Danielle Koetter, RN

Texas Oncology- Charles A. Sammons Cancer Center

Utah Cancer Specialists

Andrew Coveler, MD

Fred Hutchinson Cancer Research Center

Sabrina Martin

West Virginia University

UW Carbone Cancer Center

Timon Vandamme, MD

UZA- Antwerpen

Pieter-Jan Cuyle, MD

Imelda VZW

Karen Geboes, MD

UZ Gent

Jeroen Dekervel, MD

UZ Leuven Gasthuisberg

Cross Cancer Institute

QE II Health Sciences Centre

Melina Boutin

Centre Intégré de Santé et de Services Sociaux de la Montérégie-Centre

Petr Kavan, MD

Jewish General Hospital

Jamil Asselah, MD

McGill University Health Centre

Michelle Roy

Centre Hospitalier Universitaire de Sherbrooke

Angelique Vienot

Center Hospitalier Regional Universitaire de Besancon - Site Jean Minjoz

Jean-Phillipe Metges, MD

CHRU Brest Hopital Morvan

Anthony Turpin

Hopital Claude Huriez

Aurelien Lambert

Institute de Cancerologie de Lorraine

Simon Pernot

Institut Bergonie

Sandrine Hiret

Insitut de Cancerologie de l'Ouest

Laetitia Dahan, MD

Hopital de la Timone

Netherlands Cancer Institute

Tania Rodriguez, MD

Hospital Da Luz

Teresa Macarulla Mercade, MD

Vall d'Hebron Institute of Oncology

Laura Layos Romero

Institut Catala d'Oncologia

Javier Sastre Valera, MD

Hospital Clinico U San Carlos (HSC)

Emiliano Calvo, MD

START Madrid-HM CIOCC Hospital Universitario

Andrés Cervantes, MD

INCLIVA University of Valencia

9-ING-41 in Patients With Advanced Cancers

This phase IIa trial studies the side effects of abemaciclib monotherapy in treating patients age 70 years and older with hormone receptor positive, HER2 negative breast cancer that has spread to other places in the body.

PRIMARY OBJECTIVE:

I. To estimate the incidence of grade 3 or higher toxicities attributed to abemaciclib monotherapy in adults aged 70 or older with hormone receptor positive metastatic breast cancer.

SECONDARY OBJECTIVES:

I. To describe the full toxicity profile including all grade 2 and higher adverse events, and patient-reported adverse events (AEs) using Patients Reported Outcomes (PRO)-Common Terminology Criteria for Adverse Events (CTCAE) measures.

II. To describe rates of dose reductions, dose holds, treatment discontinuations due to factors other than progression, and hospitalizations.

III. To estimate median (and 95% confidence interval [CI]) failure-free survival, progression-free survival and overall survival.

IV. To describe the results of Was It Worth It (WIWI) and Overall Treatment Utility (OTU) questionnaires.

V. To describe the rate of adherence to abemaciclib. VI. To determine average plasma steady-state abemaciclib Ctrough concentrations.

VII. To evaluate the association of adherence rate with abemaciclib plasma t-rough concentrations.

VIII. To describe associations between cancer-specific, comprehensive Geriatric Assessment (cGA) scores and the incidence of toxicities and their grade.

EXPLORATORY OBJECTIVE:

I. To determine the association between biomarkers of aging and grades 3 or higher toxicity.

OUTLINE:

Patients receive abemaciclib orally (PO) twice daily (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, then every 6 months for 2 years.

Dana Farber Cancer Institute

City of Hope Medical Center

Roswell Park Comprehensive Cancer Center

Abemaciclib and Endocrine Therapy in Older Patients With Breast Cancer.

This research study is studying a drug called Abemaciclib as a possible treatment for have metastatic triple-negative type of breast cancer.

This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. "Investigational" means that the intervention is being studied.

The FDA (the U.S. Food and Drug Administration) has not approved abemaciclib as a treatment for any disease.

Some triple-negative breast cancers show expression of the Rb protein and are referred to as "Rb-positive." The Rb protein is important because it controls the way that cancer cells divide and grow. Drugs like abemaciclib work by changing the way that Rb functions. This can potentially stop cancer cells from dividing, and can also potentially lead to cancer cell death.

In this research study, the investigators are are looking to see how safe abemaciclib is and how well it will work to help people with triple-negative breast cancer that is Rb-positive.

EPSG:4326

Dana-Farber Cancer Institute

Abemaciclib for Patients With Retinoblastoma-Positive, Triple Negative Metastatic Breast Cancer

This study will evaluate the effect of adding abemaciclib to fulvestrant for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer that progressed or recurred after previous treatment with a type of drug known as a CDK4/6 inhibitor and endocrine therapy. Participation could last up to 5 years, depending on how you and your tumor respond.

Massachusetts General Hospital

Vernon Cancer Center Pharmacy, Massachusetts General Cancer Center at Newton-Wellesley

MGH Northshore Cancer Center

Dana-Farber Cancer Institute - Foxborough

Dana Farber Cancer Center Merrimack Valley

Dana Farber Cancer Center Institute - Milford

Reliant Medical Group

Lifespan Cancer Institute

Southcoast Centers for Cancer Care

New England Cancer Specialists

St. Joseph's Hospital and Medical Center

Providence Medical Foundation

Cancer and Blood Specialty Clinic

Keck School of Medicine of USC

TRIO-US (Translational Research in Oncology-US)

UCLA Hematology/Oncology - Parkside

Olive View-UCLA Medical Center

Torrance Memorial Physician Network / Cancer Care

PIH Health Hematology Medical Oncology

Millennium Oncology - Hollywood

University of Miami Hospital and Clinics, Sylvester Cancer Center

Winship Cancer Institute, Emory University

Northeast Georgia Medical Center

Central Georgia Cancer Care

Kapiolani Medical Center for Women and Children

Ingalls Memorial Hospital

Clinical Trials of SWLA

Central Maine Medical Center

Mfsmc-Hjwci

St. Vincent Frontier Cancer Center

University of New Mexico Comprehensive Cancer Center

Sarah Cannon Research Institute/SCRI

Texas Oncology - Bedford

Parkland Health and Hospital System

UT Southwestern Medical Center

Texas Oncology - McKinney

Texas Oncology-Plano West

Mays Cancer Center

US Oncology

Intermountain Medical Center

The University of Vermont Medical Center Inc.

Shenandoah Oncology, P.C.

Fundación Respirar

Centro de Investigaciones Metabólicas (CINME)

Fundación Cenit Para La Investigación En Neurociencias

Instituto Médico Río Cuarto

CER San Juan

Algemeen Ziekenhuis klina

Jessa Ziekenhuis

Multiscan

Fakultni nemocnice Hradec Kralove

Herlev and Gentofte Hospital

Regionshospitalet Herning

Centre Hospitalier Régional Universitaire de Brest - Hôpital Morvan

Hôpital privé du Confluent SAS

Institut Paoli-Calmettes

Onkoradiologiai Kozpont

Magyar Honvedseg Egeszsegugyi Kozpont

Országos Onkológiai Intézet

Soroka Medical Center

Humanitas Istituto Clinico Catanese

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori

Korea University Guro Hospital

Centro de Investigacion en Artritis y Osteoporosis SC

COI Tijuana - Centro Oncológico Internacional

Centro Oncológico Internacional (COI)

Centro Regiomontano de Investigación

Oncologico Potosino, S.C.

Europejskie Centrum Zdrowia - Oddzial Onkologii

Centrum Terapii Wspolczesnej J. M. Jasnorzewska Spolka Komandytowo-Akcyjna

Abemaciclib (LY2835219) Plus Fulvestrant Compared to Placebo Plus Fulvestrant in Previously Treated Breast Cancer

Oncology Clinical Trial Finder

Breast Cancer > Boston, MA, USA

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