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
Condition: Estrogen Receptor-positive (ER+)/Human Epidermal Growth Factor Receptor (HER2)-Negative Locally Advanced or Metastatic Breast Cancer
MeSH terms: Breast Neoplasms; Recurrence
Intervention: Venetoclax; Fulvestrant
Intervention description: Venetoclax was administered orally, 800-mg tablet beginning on Cycle 1 Day 1 until the 9th October 2020.; 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
Intervention MeSH terms: Venetoclax; Fulvestrant
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 103.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No

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.