Estrogen receptor-positive (ER+)/human epidermal growth factor receptor (HER2)-negative locally advanced or metastatic breast cancer (MBC) MedDRA version: 23.0 Level: LLT Classification code 10070575 Term: Estrogen receptor positive breast cancer System Organ Class: 100000004864
Conditions
Interventions
Product Name: Venetoclax
Product Code: RO5537382
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: VENETOCLAX
CAS Number: 1257044-40-8
Current Sponsor code: RO5537382
Other descriptive name
Sponsors
F. Hoffmann-La Roche Ltd
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: - Female and >= 18 years of age - Histological or cytological confirmation of ER+ invasive carcinoma of the breast with documented HER2-negative as per ASCO/CAP criteria status. 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 B-cell lymphoma 2 (BCL-2) immunohistochemistry value at time of screening - Evidence of metastatic or locally advanced disease not amenable to surgical or local therapy with curative intent - Be either postmenopausal - OR pre- or perimenopausal and amenable to being treated with the luteinizing hormone-releasing hormone (LHRH) agonist goserelin - 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 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 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 or use non-hormonal contraceptive methods with a failure rate of 3 months Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 105 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range 0
Exclusion criteria
Exclusion criteria: - Prior treatment with fulvestrant or other selective estrogen receptor degraders, venetoclax, or any investigational 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 metastases - 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 (except palliative intent in non-target lesion), hormonal therapy, immunotherapy, antineoplastic vaccines, or other investigational therapy - Concurrent radiotherapy to any site or prior radiotherapy within 21 days of Cycle 1 Day 1 or previous radiotherapy to the target lesion sites or prior radiotherapy to > 25% of bone marrow - Current severe, uncontrolled, systemic 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, - Strong CYP3A inhibitors or moderate CYP3A inhibitors, - Strong CYP3A inducers or moderate CYP3A inducers - 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 - Known infection with HIV or human T-cell leukemia virus 1 - Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection at study enrollment, or any major episode of infection requiring treatment with IV antibiotics or hospitalization 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 - Active HCV infection, defined as having a positive HCV antibody test at screening - 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 patient’s participation in the study - Inability or unwillingness to swallow pills or receive intra muscular injections - History of malabsorption syndrome or other condition that would interfere with enteral absorption - History of inflammatory bowel disease or active bowel inflammation - Concurrent hormone replacement therapy - Inability to comply with study and follow-up procedures - Known hypersensitivity to any of the study medications or to any of the excipients
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the efficacy of venetoclax in combination with fulvestrant compared with fulvestrant alone based on Clinical Benefit defined as complete response (CR), partial response (PR) or stable disease (SD)lasting =24 weeks from randomization in patients with measurable disease at baseline according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1);Secondary Objective: To evaluate - the efficacy of venetoclax in combination with fulvestrant compared with fulvestrant alone based on progression-free survival , objective response, duration of response, overall survival according to RECIST v1.1 - Safety and tolerability of venetoclax in combination with fulvestrant compared with fulvestrant alone - PK of venetoclax and fulvestrant following administration of venetoclax in combination with fulvestrant - Predictive, prognostic, and PD biomarkers in tumor tissue and plasma associated with disease activity, response to treatment, or resistance to venetoclax in combination with fulvestrant - Patient-reported outcome (PRO)s of function, disease/treatment-related symptoms, GHS/overall HRQoL associated with venetoclax in combination with fulvestrant compared with fulvestrant alone - Compare PROs of disease-related pain in venetoclax in combination with fulvestrant compared with fulvestrant alone ;Primary end point(s): 1. Clinical benefit defined as CR, PR or SD lasting =24 weeks;Timepoint(s) of evaluation of this end point: 1. Up to 2 years after the last patient is enrolled or all patients in the study have withdrawn consent or died, or if the study is prematurely terminated by the Sponsor, whichever occurs first (approximately 43 months) | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Progression-free survival 2. Objective response 3. Duration of response 4. Overall survival 5. Frequency and severity of adverse events, focusing on serious adverse events (SAEs), adverse events of special interest (AESI), and AEs leading to drug and/or study discontinuation 6. Plasma concentrations of venetoclax and fulvestrant and fulvestrant at specified timepoints 7. Plasma concentrations or PK parameters of venetoclax and fulvestrant given in combination compared with these agents given alone 8. Baseline BCL 2 protein levels as measured by IHC correlating with clinical response measures 9. Expanded biomarkers measured at baseline, on-treatment, and at end of treatment relative to clinical response measures 10. Mean and mean changes from baseline scores in functional (i.e., role, physical, emotional, and social), disease/treatment-related symptoms, and GHS/HRQoL by cycle as assessed by the scales of the EORTC (European Organisation for Research and Treatment of Cancer) QLQ-C 30 11. Change in baseline pain score as assessed by the pain scale of EORTC QLQ-C30;Timepoint(s) of evaluation of this end point: 1-5. Up to 2 years after the last patient is enrolled or all patients in the study have withdrawn consent or died, or if the study is prematurely terminated by the Sponsor, whichever occurs first (approximately 43 months) 6-7. Day 1 of Cycle 1, 2, 6 and at study drug discontinuation/early termination 8-9. Mandatory: at baseline (day-28—1), Optional at: Day 1 of Cycle 3 and at study drug discontinuation visit 10-11. At baseline, Day 1 of each cycle and at study drug discontinuation visit | — |
Countries
Australia, Canada, France, Germany, United Kingdom, United States
Contacts
Public ContactTrial Information Support Line-TISL
F. Hoffmann-La Roche Ltd
Outcome results
None listed