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.
- 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 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.
- Have at least one measurable lesion via RECIST v1.1.
- Have an Eastern Cooperative Oncology Group (ECOG) Performance Score of 0-1.
- Have adequate organ and marrow function.
- Have a life expectancy > 3 months.
- To full fill the coagulation requirements for patient with or without therapeutic
- 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
- 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
- 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
- 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 are positive for HCV antibody must be 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 must be willing to undergo monthly DNA testing.
- Participants who have 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
- 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.