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 (Veronica)

A Phase II, Multicenter, Randomized Study To Compare The Efficacy Of Venetoclax Plus Fulvestrant Versus 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

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.

Study Overview

• Status: Terminated
• Conditions: Estrogen Receptor-positive (ER+)/Human Epidermal Growth Factor Receptor (HER2)-Negative Locally Advanced or Metastatic Breast Cancer
• Intervention / Treatment: Drug: Venetoclax; Drug: Fulvestrant

• Study Type: Interventional
• Enrollment (Actual): 103
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • North Sydney, New South Wales, Australia, 2059
      • Mater Hospital; Patricia Ritchie Centre for Cancer Care and Research
  • Queensland
    • South Brisbane, Queensland, Australia, 4101
      • Mater Misericordiae Limited
  • Victoria
    • North Melbourne, Victoria, Australia, 3051
      • Peter MacCallum Cancer Center
• Canada
  • Ontario
    • Newmarket, Ontario, Canada, L3Y 2R2
      • Southlake Regional Health Center
    • Ottawa, Ontario, Canada, K1H 8L6
      • The Ottawa Hospital
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Health Sciences Centre
  • Quebec
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • Centre Hospitalier Universitaire de Sherbrooke - Hopital Fleurimont
• Germany
  • Aschaffenburg, Germany, 63739
    • Hämato-Onkologische Schwerpunktpraxis am Klinikum Aschaffenburg
  • Erlangen, Germany, 91054
    • Universitätsklinikum Erlangen; Frauenklinik
  • Frankfurt, Germany, 65929
    • Klinikum Frankfurt Höchst GmbH
  • Hamburg, Germany, 20249
    • Facharztzentrum Eppendorf, Studien GbR
  • Muenchen, Germany, 80637
    • Rotkreuzklinikum München; Frauenklinik
  • Ravensburg, Germany, 88212
    • Gemeinschaftspraxis für Hämatologie und Onkologie GbR; Dechow & Decker & Nonnenbroich
  • Rostock, Germany, 18059
    • Klinikum Südstadt Rostock
• United Kingdom
  • Bath, United Kingdom, BA1 3NG
    • Royal United Hospital Bath NHS Trust
  • Brighton, United Kingdom, BN2 5BE
    • Royal Sussex County Hospital
  • London, United Kingdom, EC1A 7BE
    • Barts Health NHS Trust - St Bartholomew's Hospital
  • Manchester, United Kingdom, M20 4BX
    • The Christie NHS Foundation Trust
  • Nottingham, United Kingdom, NG5 1PB
    • Nottingham University Hospitals NHS Trust - City Hospital
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Hospital
  • Arkansas
    • Springdale, Arkansas, United States, 72762
      • Highlands Oncology Group
  • California
    • La Jolla, California, United States, 92037
      • UC San Deigo Moores Cancer Center
    • Palm Springs, California, United States, 92262
      • Comprehensive Cancer Center at Desert Regional Medical Center
    • Santa Rosa, California, United States, 95403-1757
      • St. Joseph Health Medical Group - Annadel Medical Group
  • Florida
    • Miami, Florida, United States, 33136
      • Sylvester Comprehensive Cent.
  • Georgia
    • Marietta, Georgia, United States, 30060
      • Northwest Georgia Oncology Centers PC - Marietta
  • Hawaii
    • Honolulu, Hawaii, United States, 96819-1469
      • Kaiser Permanente - Moanalua Medical Center
  • Kentucky
    • Ashland, Kentucky, United States, 41101-7016
      • Ashland-Bellefonte Cancer Center
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital.
    • Peabody, Massachusetts, United States, 01960
      • Mass General/North Shore Cancer
  • Minnesota
    • Minneapolis, Minnesota, United States, 55407
      • Abbott Northwestern Hospital
  • Nebraska
    • Lincoln, Nebraska, United States, 68506
      • Nebraska Hematology Onco, PC
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • University of New Mexico Cancer Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57105
      • Sanford Health System
  • Texas
    • Dallas, Texas, United States, 75390
      • The University of Texas Southwestern Medical Center at Dallas
    • Fort Worth, Texas, United States, 76104
      • The Center for Cancer and Blood Disorders - Fort Worth
    • Houston, Texas, United States, 77090
      • Millennium Research & Clinical Development
  • Washington
    • Everett, Washington, United States, 98201
      • Providence Regional Cancer Partnership

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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).	Drug: Venetoclax; Venetoclax was administered orally, 800-mg tablet beginning on Cycle 1 Day 1 until the 9th October 2020.; 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
Active Comparator: 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).	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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS)	PFS was defined as the time from randomization to the first occurrence of disease progression (as determined by the investigator according to RECIST v1.1) or death from any cause, whichever occurs first.	Randomization through till 6 months after the last participant is enrolled into the study (up to approximately 23 months)
Objective Response (OR)	OR was defined as CR or PR, in participants with measurable disease at baseline as determined by the investigator according to RECIST v1.1.	Randomization through till 6 months after the last participant is enrolled into the study (up to approximately 23 months)
Duration of Response (DOR)	DOR was defined as the time from the first occurrence of a documented objective response to the time of the first documented disease progression (as determined by the investigator according to RECIST v1.1) or death from any cause, whichever occurs first.	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)	OS was defined as the time from randomization to death due to any cause.	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)	An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including abnormal laboratory values or abnormal clinical test results), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study were also considered as AEs.	Baseline up until 28 days after the last dose of study drug (venetoclax or fulvestrant, whichever is later) up to approximately 32 months
Plasma Concentrations of Venetoclax		Cycle 1 Day 1: 4 hours (hrs) post-dose; Cycle 2 Day 1: pre-dose (within 1 hr) and 2, 4, 6, 8 hrs post-dose; any time during visits up to study drug discontinuation/Early Termination (up to approximately 32 months)
Plasma Concentrations of Fulvestrant (in Presence of Venetoclax)		Cycle 2 Day 1: pre-dose (within 1 hr); Cycle 6 Day 1: pre-dose (within 1 hr); any time during visits up to study drug discontinuation/Early Termination (up to approximately 32 months)
Plasma Concentrations of Fulvestrant (in Absence of Venetoclax)		Cycle 2 Day 1: pre-dose (within 1 hr); any time during visits up to study drug discontinuation/Early Termination (up to approximately 32 months)

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start (Actual): September 6, 2018
• Primary Completion (Actual): August 5, 2020
• Study Completion (Actual): May 6, 2021

Study Registration Dates

• First Submitted: June 25, 2018
• First Submitted That Met QC Criteria: July 10, 2018
• First Posted (Actual): July 12, 2018

Study Record Updates

• Last Update Posted (Actual): June 28, 2022
• Last Update Submitted That Met QC Criteria: June 21, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Skin Diseases; Neoplasms; Neoplasms by Site; Disease Attributes; Breast Diseases; Breast Neoplasms; Recurrence; Physiological Effects of Drugs; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Hormone Antagonists; Estrogen Antagonists; Estrogen Receptor Antagonists; Fulvestrant; Venetoclax
• Other Study ID Numbers: WO40181; 2017-005118-74 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No