Clinical trial NCT03584009: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Estrogen Receptor-positive (ER+)/Human Epidermal Growth Factor Receptor (HER2)-Negative Locally Advanced or Metastatic Breast Cancer
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2018-07-12
Enrollment: 103
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: 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
timeFrame: Randomization through till 6 months after the last participant is enrolled into the study (up to approximately 23 months)
Secondary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: Randomization through till 6 months after the last participant is enrolled into the study (up to approximately 23 months)
measure: Objective Response (OR)
timeFrame: Randomization through till 6 months after the last participant is enrolled into the study (up to approximately 23 months)
measure: Duration of Response (DOR)
timeFrame: 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)
measure: Overall Survival (OS)
timeFrame: Randomization to death from any cause, through till the end of the study (up to approximately 32 months)
measure: Percentage of Participants With Adverse Events (AEs)
timeFrame: Baseline up until 28 days after the last dose of study drug (venetoclax or fulvestrant, whichever is later) up to approximately 32 months
measure: Plasma Concentrations of Venetoclax
timeFrame: 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)
measure: Plasma Concentrations of Fulvestrant (in Presence of Venetoclax)
timeFrame: 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)
measure: Plasma Concentrations of Fulvestrant (in Absence of Venetoclax)
timeFrame: 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)
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic Hospital
state: Arizona
city: Springdale
country: United States
facility: Highlands Oncology Group
state: Arkansas
city: La Jolla
country: United States
facility: UC San Deigo Moores Cancer Center
state: California
city: Palm Springs
country: United States
facility: Comprehensive Cancer Center at Desert Regional Medical Center
state: California
city: Santa Rosa
country: United States
facility: St. Joseph Health Medical Group - Annadel Medical Group
state: California
city: Miami
country: United States
facility: Sylvester Comprehensive Cent.
state: Florida
city: Marietta
country: United States
facility: Northwest Georgia Oncology Centers PC - Marietta
state: Georgia
city: Honolulu
country: United States
facility: Kaiser Permanente - Moanalua Medical Center
state: Hawaii
city: Ashland
country: United States
facility: Ashland-Bellefonte Cancer Center
state: Kentucky
city: Baltimore
country: United States
facility: University of Maryland Medical Center
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital.
state: Massachusetts
city: Peabody
country: United States
facility: Mass General/North Shore Cancer
state: Massachusetts
city: Minneapolis
country: United States
facility: Abbott Northwestern Hospital
state: Minnesota
city: Lincoln
country: United States
facility: Nebraska Hematology Onco, PC
state: Nebraska
city: Albuquerque
country: United States
facility: University of New Mexico Cancer Center
state: New Mexico
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Sioux Falls
country: United States
facility: Sanford Health System
state: South Dakota
city: Dallas
country: United States
facility: The University of Texas Southwestern Medical Center at Dallas
state: Texas
city: Fort Worth
country: United States
facility: The Center for Cancer and Blood Disorders - Fort Worth
state: Texas
city: Houston
country: United States
facility: Millennium Research & Clinical Development
state: Texas
city: Everett
country: United States
facility: Providence Regional Cancer Partnership
state: Washington
city: North Sydney
country: Australia
facility: Mater Hospital; Patricia Ritchie Centre for Cancer Care and Research
state: New South Wales
city: South Brisbane
country: Australia
facility: Mater Misericordiae Limited
state: Queensland
city: North Melbourne
country: Australia
facility: Peter MacCallum Cancer Center
state: Victoria
city: Newmarket
country: Canada
facility: Southlake Regional Health Center
state: Ontario
city: Ottawa
country: Canada
facility: The Ottawa Hospital
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
city: Sherbrooke
country: Canada
facility: Centre Hospitalier Universitaire de Sherbrooke - Hopital Fleurimont
state: Quebec
city: Aschaffenburg
country: Germany
facility: Hämato-Onkologische Schwerpunktpraxis am Klinikum Aschaffenburg
city: Erlangen
country: Germany
facility: Universitätsklinikum Erlangen; Frauenklinik
city: Frankfurt
country: Germany
facility: Klinikum Frankfurt Höchst GmbH
city: Hamburg
country: Germany
facility: Facharztzentrum Eppendorf, Studien GbR
city: Muenchen
country: Germany
facility: Rotkreuzklinikum München; Frauenklinik
city: Ravensburg
country: Germany
facility: Gemeinschaftspraxis für Hämatologie und Onkologie GbR; Dechow & Decker & Nonnenbroich
city: Rostock
country: Germany
facility: Klinikum Südstadt Rostock
city: Bath
country: United Kingdom
facility: Royal United Hospital Bath NHS Trust
city: Brighton
country: United Kingdom
facility: Royal Sussex County Hospital
city: London
country: United Kingdom
facility: Barts Health NHS Trust - St Bartholomew's Hospital
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust - City Hospital
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: