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
Overview
- Phase
- Phase 2
- Status
- Terminated
- Sponsor
- Hoffmann-La Roche
- Enrollment
- 103
- Locations
- 40
- Primary Endpoint
- 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
Overview
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- Female
- Accepts Healthy Volunteers
- No
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.
- •Had an Eastern Cooperative Oncology Group (ECOG) Performance Score of 0-
Exclusion Criteria
- Not provided
Arms & Interventions
Venetoclax + Fulvestrant
Participants were administered Venetoclax 800mg orally once daily (QD) and Fulvestrant 500mg intramuscularly (IM) on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).
Intervention: Venetoclax (Drug)
Venetoclax + Fulvestrant
Participants were administered Venetoclax 800mg orally once daily (QD) and Fulvestrant 500mg intramuscularly (IM) on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).
Intervention: Fulvestrant (Drug)
Fulvestrant
Participants were administered Fulvestrant 500mg only IM on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).
Intervention: Fulvestrant (Drug)
Outcomes
Primary Outcomes
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
Time Frame: Randomization through till 6 months after the last participant is enrolled into the study (up to approximately 23 months)
Clinical Benefit was defined as CR, PR, or SD lasting more than equal to 24 weeks from randomization in participants with measurable disease at baseline, as determined by the investigator according to Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.1. Per RECIST v1.1 for target lesions assessed by CT or MRI: CR, Disappearance of all target lesions; PR, PR \>= 30% decrease in the sum of diameters of target lesions (TL) taking as reference the baseline sum of diameters; SD, neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Disease Progression (PD), PD\>= 20% increase in the sum of diameters of TL taking as reference the smallest sum on study(Nadir). In addition to the relative increase of 20% sum must have demonstrate an absolute increase of at least 5mm.
Secondary Outcomes
- Objective Response (OR)(Randomization through till 6 months after the last participant is enrolled into the study (up to approximately 23 months))
- Plasma Concentrations of Fulvestrant (in Absence of Venetoclax)(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))
- Progression Free Survival (PFS)(Randomization through till 6 months after the last participant is enrolled into the study (up to approximately 23 months))
- Duration of Response (DOR)(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))
- Overall Survival (OS)(Randomization to death from any cause, through till the end of the study (up to approximately 32 months))
- Percentage of Participants With Adverse Events (AEs)(Baseline up until 28 days after the last dose of study drug (venetoclax or fulvestrant, whichever is later) up to approximately 32 months)
- Plasma Concentrations of Venetoclax(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))
- Plasma Concentrations of Fulvestrant (in Presence of Venetoclax)(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))