A Phase II Study Comparing The Efficacy Of Venetoclax + Fulvestrant Vs. Fulvestrant In Women With Estrogen Receptor-Positive, Her2-Negative Locally Advanced Or Metastatic Breast Cancer Who Experienced Disease Recurrence Or Progression During Or After CDK4/6 Inhibitor Therapy

NCT ID: NCT03584009

Last Updated: 2022-06-28

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 103 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-09-06
• Study Completion Date: 2021-05-06

Brief Summary

This is a Phase II, multicenter, open-label, randomized study to compare the efficacy of venetoclax in combination with fulvestrant compared with fulvestrant alone in women with ER+, HER2-negative, locally advanced or Metastatic Breast Cancer (MBC) who experienced disease recurrence or progression during or after treatment with CDK4/6i therapy for at least 8 weeks. As of 9th October 2020, participants in the Venetoclax + Fulvestrant arm, have all discontinued Venetoclax treatment and have continued on Fulvestrant treatment alone.

Conditions

Estrogen Receptor-positive (ER+)/Human Epidermal Growth Factor Receptor (HER2)-Negative Locally Advanced or Metastatic Breast Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Venetoclax + Fulvestrant

Participants were administered Venetoclax 800mg orally once daily (QD) and Fulvestrant 500mg intramuscularly (IM) on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).

Group Type: EXPERIMENTAL

Venetoclax

Intervention Type: DRUG

Venetoclax was administered orally, 800-mg tablet beginning on Cycle 1 Day 1 until the 9th October 2020.

Fulvestrant

Intervention Type: DRUG

Fulvestrant was administered orally, 500 mg administered as two 250-mg IM injections on Cycle 1 Days 1 and 15 and on Day 1 of each subsequent 28-day cycle

Fulvestrant

Participants were administered Fulvestrant 500mg only IM on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).

Group Type: ACTIVE_COMPARATOR

Fulvestrant

Intervention Type: DRUG

Fulvestrant was administered orally, 500 mg administered as two 250-mg IM injections on Cycle 1 Days 1 and 15 and on Day 1 of each subsequent 28-day cycle

Interventions

Venetoclax

Venetoclax was administered orally, 800-mg tablet beginning on Cycle 1 Day 1 until the 9th October 2020.

Intervention Type: DRUG

Fulvestrant

Fulvestrant was administered orally, 500 mg administered as two 250-mg IM injections on Cycle 1 Days 1 and 15 and on Day 1 of each subsequent 28-day cycle

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Histological or cytological confirmation of estrogen receptor-positive (ER+) invasive carcinoma of the breast. ER+, HER2- negative invasive carcinoma of the breast with evaluable sample for BCL-2 IHC value at the time of screening. Participants who were originally diagnosed with HER2-positive breast cancer that converted to HER2-negative MBC are not eligible.
• Evidence of metastatic or locally advanced disease not amenable to surgical or local therapy with curative intent.
• Be postmenopausal or pre- or perimenopausal women amenable to being treated with the luteinizing hormone-releasing hormone (LHRH) agonist goserelin.
• Participants must not have received more than two prior lines of hormonal therapy in the locally advanced or metastatic setting. In addition, at least one line of treatment must be a CDK4/6i AND participants must have experienced disease recurrence or progression during or after CDK4/6i therapy, which must have been administered for a minimum of 8 weeks prior to progression.
• Participants for whom endocrine therapy (e.g., fulvestrant) is recommended and treatment with cytotoxic chemotherapy is not indicated at the time of entry into the study, as per national or local treatment guidelines.
• Women of childbearing potential (i.e., not postmenopausal for at least 12 months or surgically sterile) must have had a negative serum pregnancy test result at screening, within 14 days prior to the first study drug administration.
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use non-hormonal contraceptive methods with a failure rate of <1% per year during the treatment period and for up to 2 years after the last dose of study drug (or based on the local prescribing information for fulvestrant). Women must refrain from donating eggs during this same period.
• Willing to provide tumor biopsy sample.
• Had at least one measurable lesion via RECIST v1.1.
• Had an Eastern Cooperative Oncology Group (ECOG) Performance Score of 0-1.
• Had adequate organ and marrow function.
• Had a life expectancy > 3 months.
• To full fill the coagulation requirements for patient with or without therapeutic anticoagulation.

Exclusion Criteria

• Prior treatment with fulvestrant or other selective estrogen receptor degraders (SERDs), venetoclax, or any agent whose mechanism of action is to inhibit BCL-2.
• Pregnant, lactating, or intending to become pregnant during the study.
• Known untreated or active Central Nervous System (CNS) metastases (progressing or requiring anticonvulsants or corticosteroids for symptomatic control.
• Prior chemotherapy in the locally advanced or metastatic setting regardless of the duration of the treatment.
• Any anti-cancer therapy received within 21 days of the first dose of study drug, including chemotherapy, radiotherapy, hormonal therapy, immunotherapy, antineoplastic vaccines, or other investigational therapy. (Radiotherapy with palliative intent to non-target sites is allowed).
• Concurrent radiotherapy to any site or prior radiotherapy within 21 days of Cycle 1 Day 1 or previous radiotherapy to the target lesion sites (the sites that are to be followed for determination of a response) or prior radiotherapy to > 25% of bone marrow.
• Current severe, uncontrolled, systemic disease (e.g., clinically significant cardiovascular, pulmonary, metabolic or infectious disease.
• Any major surgery within 28 days of the first dose of study drug or anticipation of the need for major surgery during the course of study treatment.
• Consumption of one or more of the following within 3 days prior to the first dose of study drug: Grapefruit or grapefruit products; Seville oranges including marmalade containing Seville oranges; Star fruit (carambola).
• Administration within 7 days prior first dose of study treatment of Steroid therapy for anti-neoplastic intent, Strong or moderate CYP3A inhibitors or Strong or moderate CYP3A inducers.
• Need for current chronic corticosteroid therapy (> 10 mg of prednisone per day or an equivalent dose of other anti-inflammatory corticosteroids).
• Known infection with (human immunodeficiency virus) HIV or human T-cell leukemia virus 1.
• Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment, or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics) within 4 weeks prior to Cycle 1 Day).
• Positive test results for hepatitis B core antibody (HBcAb) or hepatitis C virus (HCV) antibody at screening. Participants who were positive for HCV antibody should have been negative for HCV by PCR to be eligible for study participation. Participants with a past or resolved hepatitis B virus (HBV) infection (defined as having a positive total HBcAb and negative hepatitis B surface antigen [HbsAg]) may be included if HBV DNA is undetectable. These participants should have been willing to undergo monthly DNA testing.
• Participants who had a positive HCV antibody test are eligible for the study if a PCR assay is negative for HCV RNA.
• History of other malignancies within the past 5 years except for treated skin basal cell carcinoma, squamous cell carcinoma, non-malignant melanoma <= 1.0 mm without ulceration, localized thyroid cancer, or cervical carcinoma in-situ.
• Administration of a live, attenuated vaccine within 4 weeks prior to initiation of study treatment or anticipation of need for such a vaccine during the study.
• Cardiopulmonary dysfunction.
• Other medical or psychiatric conditions that, in the opinion of the investigatory, may interfere with the participant's participation in the study.
• Inability or unwillingness to swallow pills or receive intramuscular (IM) injections.
• History of malabsorption syndrome or other condition that would interfere with enteral absorption.
• History of inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis) or active bowel inflammation (e.g., diverticulitis).
• Concurrent hormone replacement therapy.
• Inability to comply with study and follow-up procedures.
• History or active cardiopulmonary dysfunction.
• Known hypersensitivity to any of the study medications (fulvestrant, venetoclax) or to any of the excipients.

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Hoffmann-La Roche

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Trials

Role: STUDY_DIRECTOR

Hoffmann-La Roche

Locations

Mayo Clinic Hospital

Phoenix, Arizona, United States

Highlands Oncology Group

Springdale, Arkansas, United States

UC San Deigo Moores Cancer Center

La Jolla, California, United States

Comprehensive Cancer Center at Desert Regional Medical Center

Palm Springs, California, United States

St. Joseph Health Medical Group - Annadel Medical Group

Santa Rosa, California, United States

Sylvester Comprehensive Cent.

Miami, Florida, United States

Northwest Georgia Oncology Centers PC - Marietta

Marietta, Georgia, United States

Kaiser Permanente - Moanalua Medical Center

Honolulu, Hawaii, United States

Ashland-Bellefonte Cancer Center

Ashland, Kentucky, United States

University of Maryland Medical Center

Baltimore, Maryland, United States

Massachusetts General Hospital.

Boston, Massachusetts, United States

Mass General/North Shore Cancer

Peabody, Massachusetts, United States

Abbott Northwestern Hospital

Minneapolis, Minnesota, United States

Nebraska Hematology Onco, PC

Lincoln, Nebraska, United States

University of New Mexico Cancer Center

Albuquerque, New Mexico, United States

Cleveland Clinic

Cleveland, Ohio, United States

Sanford Health System

Sioux Falls, South Dakota, United States

The University of Texas Southwestern Medical Center at Dallas

Dallas, Texas, United States

The Center for Cancer and Blood Disorders - Fort Worth

Fort Worth, Texas, United States

Millennium Research & Clinical Development

Houston, Texas, United States

Providence Regional Cancer Partnership

Everett, Washington, United States

Mater Hospital; Patricia Ritchie Centre for Cancer Care and Research

North Sydney, New South Wales, Australia

Mater Misericordiae Limited

South Brisbane, Queensland, Australia

Peter MacCallum Cancer Center

North Melbourne, Victoria, Australia

Southlake Regional Health Center

Newmarket, Ontario, Canada

The Ottawa Hospital

Ottawa, Ontario, Canada

Sunnybrook Health Sciences Centre

Toronto, Ontario, Canada

Centre Hospitalier Universitaire de Sherbrooke - Hopital Fleurimont

Sherbrooke, Quebec, Canada

Hämato-Onkologische Schwerpunktpraxis am Klinikum Aschaffenburg

Aschaffenburg, , Germany

Universitätsklinikum Erlangen; Frauenklinik

Erlangen, , Germany

Klinikum Frankfurt Höchst GmbH

Frankfurt, , Germany

Facharztzentrum Eppendorf, Studien GbR

Hamburg, , Germany

Rotkreuzklinikum München; Frauenklinik

München, , Germany

Gemeinschaftspraxis für Hämatologie und Onkologie GbR; Dechow & Decker & Nonnenbroich

Ravensburg, , Germany

Klinikum Südstadt Rostock

Rostock, , Germany

Royal United Hospital Bath NHS Trust

Bath, , United Kingdom

Royal Sussex County Hospital

Brighton, , United Kingdom

Barts Health NHS Trust - St Bartholomew's Hospital

London, , United Kingdom

The Christie NHS Foundation Trust

Manchester, , United Kingdom

Nottingham University Hospitals NHS Trust - City Hospital

Nottingham, , United Kingdom

Countries

United States; Australia; Canada; Germany; United Kingdom

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

2017-005118-74

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

WO40181

Identifier Type: -

Identifier Source: org_study_id