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

NCT03584009 | Terminated Phase 2 Results FDA Drug

• 2 other identifiers: WO401812017-005118-74
• Study Type: interventional
• Target: 103
• Locations: 5 countries
• Sites: 40

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

Outcome Measures

Primary Outcomes (1)

• Clinical Benefit Defined as Complete Response (CR), Partial Response (PR) or Stable Disease (SD) Lasting >= 24 Weeks, as Determined by the Investigator According to RECIST v1.1

  Clinical Benefit was defined as CR, PR, or SD lasting more than equal to 24 weeks from randomization in participants with measurable disease at baseline, as determined by the investigator according to Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.1. Per RECIST v1.1 for target lesions assessed by CT or MRI: CR, Disappearance of all target lesions; PR, PR \>= 30% decrease in the sum of diameters of target lesions (TL) taking as reference the baseline sum of diameters; SD, neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Disease Progression (PD), PD\>= 20% increase in the sum of diameters of TL taking as reference the smallest sum on study(Nadir). In addition to the relative increase of 20% sum must have demonstrate an absolute increase of at least 5mm.

  Randomization through till 6 months after the last participant is enrolled into the study (up to approximately 23 months)

Secondary Outcomes (8)

• Progression Free Survival (PFS)

  Randomization through till 6 months after the last participant is enrolled into the study (up to approximately 23 months)

• Objective Response (OR)

  Randomization through till 6 months after the last participant is enrolled into the study (up to approximately 23 months)

• Duration of Response (DOR)

  Time from first occurrence of a documented objective response to the first documented disease progression or death from any cause, whichever occurs first, until 6 months after the last participant is enrolled in the study (up to approximately 23 months)

• Overall Survival (OS)

  Randomization to death from any cause, through till the end of the study (up to approximately 32 months)

• Percentage of Participants With Adverse Events (AEs)

  Baseline up until 28 days after the last dose of study drug (venetoclax or fulvestrant, whichever is later) up to approximately 32 months

Study Arms (2)

Venetoclax + Fulvestrant

EXPERIMENTAL

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).

Drug: Venetoclax; Drug: Fulvestrant

Fulvestrant

ACTIVE COMPARATOR

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).

Drug: Fulvestrant

Interventions

Venetoclax DRUG

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

Venetoclax + Fulvestrant

Fulvestrant 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; Venetoclax + Fulvestrant

Eligibility Criteria

• Age: 18 Years+
• Gender Eligibility Details: Female and \>= 18 years of age at time of signing Informed Consent Form
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (40)

Mayo Clinic Hospital

Phoenix, Arizona, 85054, United States

Location

Highlands Oncology Group

Springdale, Arkansas, 72762, United States

Location

UC San Deigo Moores Cancer Center

La Jolla, California, 92037, United States

Location

Comprehensive Cancer Center at Desert Regional Medical Center

Palm Springs, California, 92262, United States

Location

St. Joseph Health Medical Group - Annadel Medical Group

Santa Rosa, California, 95403-1757, United States

Location

Sylvester Comprehensive Cent.

Miami, Florida, 33136, United States

Location

Northwest Georgia Oncology Centers PC - Marietta

Marietta, Georgia, 30060, United States

Location

Kaiser Permanente - Moanalua Medical Center

Honolulu, Hawaii, 96819-1469, United States

Location

Ashland-Bellefonte Cancer Center

Ashland, Kentucky, 41101-7016, United States

Location

University of Maryland Medical Center

Baltimore, Maryland, 21201, United States

Location

Massachusetts General Hospital.

Boston, Massachusetts, 02114, United States

Location

Mass General/North Shore Cancer

Peabody, Massachusetts, 01960, United States

Location

Abbott Northwestern Hospital

Minneapolis, Minnesota, 55407, United States

Location

Nebraska Hematology Onco, PC

Lincoln, Nebraska, 68506, United States

Location

University of New Mexico Cancer Center

Albuquerque, New Mexico, 87131, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

Sanford Health System

Sioux Falls, South Dakota, 57105, United States

Location

The University of Texas Southwestern Medical Center at Dallas

Dallas, Texas, 75390, United States

Location

The Center for Cancer and Blood Disorders - Fort Worth

Fort Worth, Texas, 76104, United States

Location

Millennium Research & Clinical Development

Houston, Texas, 77090, United States

Location

Providence Regional Cancer Partnership

Everett, Washington, 98201, United States

Location

Mater Hospital; Patricia Ritchie Centre for Cancer Care and Research

North Sydney, New South Wales, 2059, Australia

Location

Mater Misericordiae Limited

South Brisbane, Queensland, 4101, Australia

Location

Peter MacCallum Cancer Center

North Melbourne, Victoria, 3051, Australia

Location

Southlake Regional Health Center

Newmarket, Ontario, L3Y 2R2, Canada

Location

The Ottawa Hospital

Ottawa, Ontario, K1H 8L6, Canada

Location

Sunnybrook Health Sciences Centre

Toronto, Ontario, M4N 3M5, Canada

Location

Centre Hospitalier Universitaire de Sherbrooke - Hopital Fleurimont

Sherbrooke, Quebec, J1H 5N4, Canada

Location

Hämato-Onkologische Schwerpunktpraxis am Klinikum Aschaffenburg

Aschaffenburg, 63739, Germany

Location

Universitätsklinikum Erlangen; Frauenklinik

Erlangen, 91054, Germany

Location

Klinikum Frankfurt Höchst GmbH

Frankfurt, 65929, Germany

Location

Facharztzentrum Eppendorf, Studien GbR

Hamburg, 20249, Germany

Location

Rotkreuzklinikum München; Frauenklinik

München, 80637, Germany

Location

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

Ravensburg, 88212, Germany

Location

Klinikum Südstadt Rostock

Rostock, 18059, Germany

Location

Royal United Hospital Bath NHS Trust

Bath, BA1 3NG, United Kingdom

Location

Royal Sussex County Hospital

Brighton, BN2 5BE, United Kingdom

Location

Barts Health NHS Trust - St Bartholomew's Hospital

London, EC1A 7BE, United Kingdom

Location

The Christie NHS Foundation Trust

Manchester, M20 4BX, United Kingdom

Location

Nottingham University Hospitals NHS Trust - City Hospital

Nottingham, NG5 1PB, United Kingdom

Location

MeSH Terms

Conditions

Breast Neoplasms

Interventions

venetoclax; Fulvestrant

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Limitations and Caveats

The study was terminated due to Sponsor's decision and there were no safety concerns. Primary and secondary efficacy endpoints have been updated to report 95% confidence interval (CI) for Clinical Benefit estimate and 95% CI for the Cox proportional hazards model for PFS, following reporting conventions.

Results Point of Contact

• Title: Medical Communications
• Organization: Hoffmann-La Roche

genentech@druginfo.com

800 821-8590

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 25, 2018
• First Posted: July 12, 2018
• Study Start: September 6, 2018
• Primary Completion: August 5, 2020
• Study Completion: May 6, 2021
• Last Updated: June 28, 2022
• Results First Posted: September 27, 2021

Record last verified: 2022-06

Locations

US (21); DE (7); GB (5); CA (4); AU (3)