Clinical Trials

Inclusion Criteria:

• Female and  ≥ 18 years of age at time of signing Informed Consent Form.
• Signed Informed Consent Form.
• Histological or cytological confirmation of ER+ invasive carcinoma of the breast with the following tumor molecular characteristics:
  • Documented ER+ defined by using IHC per ASCO/CAP criteria (Hammond et al. 2010).
• Documented HER2-negative per ASCO/CAP criteria (Wolff et al. 2013). Patients who were originally diagnosed with HER2-positive breast cancer that converted to HER2-negative MBC are NOT eligible to take part in this study.
• Evaluable sample for BCL-2 IHC value at the time of screening.
• Evidence of metastatic or locally advanced disease not amenable to surgical or local therapy with curative intent.
• Be either:
  • Postmenopausal, defined as:
    • Age ≥ 60 years; OR
    • Age < 60 years AND have undergone bilateral oophorectomy, medically confirmed ovarian failure; OR
    • Age < 60 years AND have had cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause and have serum levels of estradiol and follicle-stimulating timulating hormone within the laboratory’s reference range for postmenopausal females.
  • Or pre- or perimenopausal and amenable to being treated with the luteinizing hormone-releasing hormone (LHRH) agonist goserelin.
    • Patients must have commenced treatment with goserelin or an alternative LHRH agonist at least 28 days prior to first dose of treatment. If patients have received an alternative LHRH agonist prior to study entry, they must switch to goserelin for the duration of the trial.
  • Patients 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 patients 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.
  • Patients 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.
    • A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus);
    • Examples of non-hormonal contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, and copper intrauterine devices;
    • The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
• Willing to provide tumor biopsy sample:
  • A tumor biopsy sample (either archival or fresh) must be collected from all patients from either the primary tumor or a metastatic site (if clinically feasible) for determination of expression of BCL-2 by central laboratory testing for patient eligibility purposes and for exploratory research on biomarkers. The tumor specimen must contain adequate evaluable tumor cells (≥ 20% tumor cells) to enable BCL-2 IHC and other relevant biomarker analysis. Samples can be in a tissue block (preferred) or prepared as 20 unstained serial slides, and should be accompanied by an associated pathology report. If a tumor sample is not available, a fresh biopsy must be collected. The specimen must be a formalin-fixed, paraffin-embedded (FFPE) tumor specimen, or another appropriate fixative must be used (notation of the type of fixative should be included). Cytological or fine-needle aspiration samples are not acceptable.
• Have at least one measurable lesion via RECIST v1.1.
  • Bone lesions that have been irradiated are not evaluable. Previously irradiated lesions can be considered as measurable disease only if progressive disease has been unequivocally documented at that site since radiation.
• Have an Eastern Cooperative Oncology Group (ECOG) Performance Score of 0−1.
• Have adequate organ and marrow function as defined below:
  • Hemoglobin ≥ 9 g/dL;
  • Absolute neutrophil count ≥ 1.5 × 109/L;
  • Platelet count ≥ 100 × 109/L;
  • ALT and AST ≤ 2.5 × upper limit of normal (ULN), with the following exception:
    • Patients with documented liver metastases: AST and/or ALT ≤ 5.0 × ULN.
  • Total serum bilirubin ≤1.5 × ULN, with the following exception:
    • Patients with previously documented Gilbert syndrome who may have a bilirubin <5 × ULN.
  • Creatinine clearance ≥ 50 mL/min calculated with the use of the 24-hour creatinine clearance or modified Cockcroft-Gault equation (i.e., estimation of creatinine clearance rate [eCCr]) with the use of ideal body mass (IBM) instead of mass):
    • eCCr = (140 − Age) × IBM (kg) × [0.85 for female]
    •                        72 × serum creatinine (mg/dL)
    • Or, if serum creatinine is in μmol/L:
    • eCCr = (140 − Age) × IBM (kg) × [1.04 for female]
    •                         serum creatinine (μmol/L)

• Meet the following coagulation requirements:
  • For patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 1.5 × ULN within 14 days prior to initiation of study treatment
  • For patients receiving therapeutic anticoagulation:
    • INR or aPTT within therapeutic limits for at least 1 week immediately prior to initiation of study treatment;
    • Stable anticoagulant regimen and stable INR during the 14 days immediately preceding initiation of study treatment.
• Have a life expectancy > 3 months.

Exclusion Criteria:

• Prior treatment with fulvestrant or other SERDs, venetoclax, or any investigatoinal agent whose mechanism of action is to inhibit BCL-2.
• Pregnant, lactating, or intending to become pregnant during the study.
• Known untreated or active CNS metastases (progressing or requiring anticonvulsants or corticosteroids for symptomatic control).
  Patients who have had previous treatment of brain metastases with surgery or radiotherapy may be eligible provided they meet all of the following criteria:
  • Evaluable or measurable disease per inclusion criteria outside the CNS is present;
  • Radiographic demonstration of improvement upon the completion of CNS-directed therapy and no evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic study;
  • No history of intracranial or spinal cord hemorrhage;
  • Administration of treatment ≥ 4 weeks prior to Cycle 1 Day 1 of the study;
  • Asymptomatic from CNS metastases;
  • Recovered from significant (Grade ≥ 3) acute toxicity with no ongoing requirement for ≥10 mg of prednisone per day or an equivalent dose of other corticosteroids and no change in dose of corticosteroid for at least 2 weeks prior to Cycle 1 Day 1 of treatment.
• 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, with the following exception:
  • 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:
  • Prior radiation therapy is allowed if it was completed > 21 days before the Cycle 1 Day 1 treatment AND the patient has recovered from all toxicities to CTCAE Grade ≤ 1 AND disease evaluable for response outside of the radiation fields or evidence of post-radiation progression of previously irradiated sites of disease.
• 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.
• Administration of the following agents within 7 days prior to the first dose of study drug:
  • Steroid therapy for anti-neoplastic intent (stable steroid medication not more than 10 mg prednisolone per day or an equivalent dose of other corticosteroids for controlling CNS metastases is acceptable);
  • Strong CYP3A inhibitors (e.g., ketoconazole, clarithromycin) or moderate CYP3A inhibitors (e.g., fluconazole, ciprofloxacin, verapamil);
  • Strong CYP3A inducers (e.g., carbamazepine, phenytoin) or moderate CYP3A inducers (e.g., efavirenz, modafinil).
• 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).
• Need for current chronic corticosteroid therapy (≥10 mg of prednisone per day or an equivalent dose of other anti-inflammatory corticosteroids).
• Known infection with 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 1.
• Positive test results for hepatitis B core antibody (HBcAb) or hepatitis C virus (HCV) antibody at screening:
  • Patients who are positive for HCV antibody must be negative for HCV by PCR to be eligible for study participation.
  • Patients 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 patients must be willing to undergo monthly DNA testing.
• Active HCV infection, defined as having a positive HCV antibody test at screening:
  • Patients 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:
  • Patients must agree not to receive live, attenuated influenza vaccine (e.g., FluMist®) within 4 weeks prior to randomization, during treatment, or within 2 months following the last dose of venetoclax.
• Cardiopulmonary dysfunction as defined by any of the following prior to randomization:
  • History of NCI CTCAE v4.0 Grade ≥ 3 symptomatic congestive heart failure or New York Heart Association criteria Class ≥ II;
  • Angina pectoris requiring anti-anginal medication, serious cardiac arrhythmia not controlled by adequate medication, severe conduction abnormality, or clinically significant valvular disease;
  • High-risk uncontrolled arrhythmias (i.e., atrial tachycardia with a heart rate ≥ 100/min at rest, significant ventricular arrhythmia [ventricular tachycardia], or higher-grade atrioventricular [AV]-block [second-degree AV-block Type 2 {Mobitz 2} or third degree AV-block]);
  • Significant symptoms (Grade ≥ 2) relating to left ventricular dysfunction, cardiac arrhythmia, or cardiac ischemia;
  • Myocardial infarction within 12 months prior to randomization;
  • Uncontrolled hypertension (systolic blood pressure > 180 mmHg and/or diastolic blood pressure > 100 mmHg);
  • Evidence of transmural infarction on ECG;
  • Requirement for oxygen therapy.
• Other medical or psychiatric conditions that, in the opinion of the investigatory, may interfere with the patient’s participation in the study.
• Inability or unwillingness to swallow pills or receive 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.