Veronica: 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

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03584009
• Collaborator: (none)
• Enrollment: 103
• Locations: 40
• Arms: 2
• Actual Duration (Months): 32
• Patients Per Site: 2.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Estrogen Receptor-positive (ER+)/Human Epidermal Growth Factor Receptor (HER2)-Negative Locally Advanced or Metastatic Breast Cancer	Drug: Venetoclax; Drug: Fulvestrant	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 103 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Sep 6, 2018
• Actual Primary Completion Date: Aug 5, 2020
• Actual Study Completion Date: May 6, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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).	Drug: Venetoclax; Venetoclax was administered orally, 800-mg tablet beginning on Cycle 1 Day 1 until the 9th October 2020.; Drug: Fulvestrant; 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
Active Comparator: 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).	Drug: Fulvestrant; 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

Outcome Measures

Primary Outcome Measures

1. 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 [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 Outcome Measures

1. Progression Free Survival (PFS) [Randomization through till 6 months after the last participant is enrolled into the study (up to approximately 23 months)]

   PFS was defined as the time from randomization to the first occurrence of disease progression (as determined by the investigator according to RECIST v1.1) or death from any cause, whichever occurs first.

2. Objective Response (OR) [Randomization through till 6 months after the last participant is enrolled into the study (up to approximately 23 months)]

   OR was defined as CR or PR, in participants with measurable disease at baseline as determined by the investigator according to RECIST v1.1.

3. 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)]

   DOR was defined as the time from the first occurrence of a documented objective response to the time of the first documented disease progression (as determined by the investigator according to RECIST v1.1) or death from any cause, whichever occurs first.

4. Overall Survival (OS) [Randomization to death from any cause, through till the end of the study (up to approximately 32 months)]

   OS was defined as the time from randomization to death due to any cause.

5. 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]

   An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including abnormal laboratory values or abnormal clinical test results), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study were also considered as AEs.

6. 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)]

7. 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)]

8. 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)]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: 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 v1.1.

• 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

• 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic Hospital	Phoenix	Arizona	United States	85054
2	Highlands Oncology Group	Springdale	Arkansas	United States	72762
3	UC San Deigo Moores Cancer Center	La Jolla	California	United States	92037
4	Comprehensive Cancer Center at Desert Regional Medical Center	Palm Springs	California	United States	92262
5	St. Joseph Health Medical Group - Annadel Medical Group	Santa Rosa	California	United States	95403-1757
6	Sylvester Comprehensive Cent.	Miami	Florida	United States	33136
7	Northwest Georgia Oncology Centers PC - Marietta	Marietta	Georgia	United States	30060
8	Kaiser Permanente - Moanalua Medical Center	Honolulu	Hawaii	United States	96819-1469
9	Ashland-Bellefonte Cancer Center	Ashland	Kentucky	United States	41101-7016
10	University of Maryland Medical Center	Baltimore	Maryland	United States	21201
11	Massachusetts General Hospital.	Boston	Massachusetts	United States	02114
12	Mass General/North Shore Cancer	Peabody	Massachusetts	United States	01960
13	Abbott Northwestern Hospital	Minneapolis	Minnesota	United States	55407
14	Nebraska Hematology Onco, PC	Lincoln	Nebraska	United States	68506
15	University of New Mexico Cancer Center	Albuquerque	New Mexico	United States	87131
16	Cleveland Clinic	Cleveland	Ohio	United States	44195
17	Sanford Health System	Sioux Falls	South Dakota	United States	57105
18	The University of Texas Southwestern Medical Center at Dallas	Dallas	Texas	United States	75390
19	The Center for Cancer and Blood Disorders - Fort Worth	Fort Worth	Texas	United States	76104
20	Millennium Research & Clinical Development	Houston	Texas	United States	77090
21	Providence Regional Cancer Partnership	Everett	Washington	United States	98201
22	Mater Hospital; Patricia Ritchie Centre for Cancer Care and Research	North Sydney	New South Wales	Australia	2059
23	Mater Misericordiae Limited	South Brisbane	Queensland	Australia	4101
24	Peter MacCallum Cancer Center	North Melbourne	Victoria	Australia	3051
25	Southlake Regional Health Center	Newmarket	Ontario	Canada	L3Y 2R2
26	The Ottawa Hospital	Ottawa	Ontario	Canada	K1H 8L6
27	Sunnybrook Health Sciences Centre	Toronto	Ontario	Canada	M4N 3M5
28	Centre Hospitalier Universitaire de Sherbrooke - Hopital Fleurimont	Sherbrooke	Quebec	Canada	J1H 5N4
29	Hämato-Onkologische Schwerpunktpraxis am Klinikum Aschaffenburg	Aschaffenburg		Germany	63739
30	Universitätsklinikum Erlangen; Frauenklinik	Erlangen		Germany	91054
31	Klinikum Frankfurt Höchst GmbH	Frankfurt		Germany	65929
32	Facharztzentrum Eppendorf, Studien GbR	Hamburg		Germany	20249
33	Rotkreuzklinikum München; Frauenklinik	Muenchen		Germany	80637
34	Gemeinschaftspraxis für Hämatologie und Onkologie GbR; Dechow & Decker & Nonnenbroich	Ravensburg		Germany	88212
35	Klinikum Südstadt Rostock	Rostock		Germany	18059
36	Royal United Hospital Bath NHS Trust	Bath		United Kingdom	BA1 3NG
37	Royal Sussex County Hospital	Brighton		United Kingdom	BN2 5BE
38	Barts Health NHS Trust - St Bartholomew's Hospital	London		United Kingdom	EC1A 7BE
39	The Christie NHS Foundation Trust	Manchester		United Kingdom	M20 4BX
40	Nottingham University Hospitals NHS Trust - City Hospital	Nottingham		United Kingdom	NG5 1PB

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 16, 2020

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT03584009
• Other Study ID Numbers: WO40181; 2017-005118-74
• First Posted: Jul 12, 2018
• Last Update Posted: Jun 28, 2022
• Last Verified: Jun 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Breast Neoplasms; Recurrence; Venetoclax; Fulvestrant

Study Results

Participant Flow

Recruitment Details	The study was conducted at 38 centers in 5 countries.
Pre-assignment Detail	A total of 103 participants were randomized in this study. Of these, 101 participants received at least one dose of any study drug.

Arm/Group Title	Venetoclax + Fulvestrant	Fulvestrant
Arm/Group Description	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).	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).
Period Title: Overall Study
STARTED	51	52
COMPLETED	0	0
NOT COMPLETED	51	52

Baseline Characteristics

Arm/Group Title	Venetoclax + Fulvestrant	Fulvestrant	Total
Arm/Group Description	Participants were administered Venetoclax 800mg orally QD and Fulvestrant 500mg IM on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).	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).	Total of all reporting groups
Overall Participants	51	52	103
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.4 (10.6)	58.8 (11.7)	58.1 (11.1)
Sex: Female, Male (Count of Participants)
Female	51 100%	52 100%	103 100%
Male	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 2%	3 5.8%	4 3.9%
Not Hispanic or Latino	47 92.2%	46 88.5%	93 90.3%
Unknown or Not Reported	3 5.9%	3 5.8%	6 5.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	6 11.8%	3 5.8%	9 8.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	3 5.9%	2 3.8%	5 4.9%
White	40 78.4%	46 88.5%	86 83.5%
More than one race	1 2%	0 0%	1 1%
Unknown or Not Reported	1 2%	1 1.9%	2 1.9%

Outcome Measures

1. Primary Outcome

Title	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
Description	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.
Time Frame	Randomization through till 6 months after the last participant is enrolled into the study (up to approximately 23 months)

Outcome Measure Data

Analysis Population Description

The Baseline Measurable Disease Population represented all randomized participants with measurable disease at baseline.

Arm/Group Title	Venetoclax + Fulvestrant	Fulvestrant
Arm/Group Description	Participants were administered Venetoclax 800mg orally QD and Fulvestrant 500mg IM on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).	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).
Measure Participants	51	51
Number (95% Confidence Interval) [Percentage of Participants]	11.8 23.1%	13.7 26.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Venetoclax + Fulvestrant, Fulvestrant
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7286
	Comments	P-value is based on Stratified Analysis (Stratified by BCL2 status (High vs Low) and Lines of Therapy (2 vs 1)).
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-1.96
	Confidence Interval	(2-Sided) 95%; -16.86 to 12.94
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	PFS was defined as the time from randomization to the first occurrence of disease progression (as determined by the investigator according to RECIST v1.1) or death from any cause, whichever occurs first.
Time Frame	Randomization through till 6 months after the last participant is enrolled into the study (up to approximately 23 months)

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants whether or not they were assigned to the arm where the study treatment was administered.

Arm/Group Title	Venetoclax + Fulvestrant	Fulvestrant
Arm/Group Description	Participants were administered Venetoclax 800mg orally QD and Fulvestrant 500mg IM on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).	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).
Measure Participants	51	52
Median (95% Confidence Interval) [Months]	2.69	1.94

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Venetoclax + Fulvestrant, Fulvestrant
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7853
	Comments	P-value is based on Stratified Analysis (Stratified by BCL2 status (High vs Low) and Lines of Therapy (2 vs 1)).
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 95%; 0.61 to 1.45
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Objective Response (OR)
Description	OR was defined as CR or PR, in participants with measurable disease at baseline 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)

Outcome Measure Data

Analysis Population Description

The Baseline Measurable Disease Population represented all randomized participants with measurable disease at baseline.

Arm/Group Title	Venetoclax + Fulvestrant	Fulvestrant
Arm/Group Description	Participants were administered Venetoclax 800mg orally QD and Fulvestrant 500mg IM on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).	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).
Measure Participants	51	51
Number (95% Confidence Interval) [Percentage of Participants]	3.9 7.6%	5.9 11.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Venetoclax + Fulvestrant, Fulvestrant
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5978
	Comments	P-value is based on Stratified Analysis (Stratified by BCL2 status (High vs Low) and Lines of Therapy (2 vs 1)).
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-1.96
	Confidence Interval	(2-Sided) 95%; -12.29 to 8.37
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Duration of Response (DOR)
Description	DOR was defined as the time from the first occurrence of a documented objective response to the time of the first documented disease progression (as determined by the investigator according to RECIST v1.1) or death from any cause, whichever occurs first.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

Only participants with a documented objective response were analysed for this Outcome Measure.

Arm/Group Title	Venetoclax + Fulvestrant	Fulvestrant
Arm/Group Description	Participants were administered Venetoclax 800mg orally QD and Fulvestrant 500mg IM on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).	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).
Measure Participants	2	3
Median (95% Confidence Interval) [Months]	NA	3.61

5. Secondary Outcome

Title	Overall Survival (OS)
Description	OS was defined as the time from randomization to death due to any cause.
Time Frame	Randomization to death from any cause, through till the end of the study (up to approximately 32 months)

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants whether or not they were assigned to the arm where the study treatment was administered.

Arm/Group Title	Venetoclax + Fulvestrant	Fulvestrant
Arm/Group Description	Participants were administered Venetoclax 800mg orally QD and Fulvestrant 500mg IM on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).	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).
Measure Participants	51	52
Median (95% Confidence Interval) [Months]	19.71	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Venetoclax + Fulvestrant, Fulvestrant
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0403
	Comments	P-value is based on Stratified Analysis (Stratified by BCL2 status (High vs Low) and Lines of Therapy (2 vs 1)).
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.87
	Confidence Interval	(2-Sided) 95%; 1.02 to 3.43
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratios were estimated by Cox regression.

6. Secondary Outcome

Title	Percentage of Participants With Adverse Events (AEs)
Description	An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including abnormal laboratory values or abnormal clinical test results), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study were also considered as AEs.
Time Frame	Baseline up until 28 days after the last dose of study drug (venetoclax or fulvestrant, whichever is later) up to approximately 32 months

Outcome Measure Data

Analysis Population Description

Safety-evaluable population which included all participants who received any amount of any component of the investigational or non-investigational study treatments.

Arm/Group Title	Venetoclax + Fulvestrant	Fulvestrant
Arm/Group Description	Participants were administered Venetoclax 800mg orally QD and Fulvestrant 500mg IM on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).	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).
Measure Participants	50	51
Number [Percentage of Participants]	94.0 184.3%	76.5 147.1%

7. Secondary Outcome

Title	Plasma Concentrations of Venetoclax
Time Frame	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)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) evaluable population included all participants who received at least one dose of the study drugs (either venetoclax or fulvestrant) and had evaluable PK data. Number analyzed is the number of participants with data available for analyses at the given time-point.

Arm/Group Title	Venetoclax
Arm/Group Description	Participants were administered Venetoclax 800mg orally QD and Fulvestrant 500mg IM on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).
Measure Participants	47
Cycle 1 Day 1: 4 hrs post-dose	1.78 (61.8)
Cycle 2 Day 1: pre-dose	1.04 (85.4)
Cycle 2 Day 1: 2 hrs post-dose	1.45 (74.1)
Cycle 2 Day 1: 4 hrs post-dose	2.51 (57.2)
Cycle 2 Day 1: 6 hrs post-dose	3.32 (56.4)
Cycle 2 Day 1: 8 hrs post-dose	3.55 (57.8)
Treatment discontinuation visit	0.0112 (NA)

8. Secondary Outcome

Title	Plasma Concentrations of Fulvestrant (in Presence of Venetoclax)
Time Frame	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)

Outcome Measure Data

Analysis Population Description

PK evaluable population included all participants who received at least one dose of the study drugs (either venetoclax or fulvestrant) and had evaluable PK data. Number analyzed is the number of participants with data available for analyses at the given time-point.

Arm/Group Title	Fulvestrant
Arm/Group Description	Participants were administered Venetoclax 800mg orally QD and Fulvestrant 500mg IM on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days)
Measure Participants	42
Cycle 2 Day 1: pre-dose	0.0129 (37.1)
Cycle 6 Day 1: pre-dose	0.0145 (31.8)
Treatment discontinuation visit	0.00985 (29.1)

9. Secondary Outcome

Title	Plasma Concentrations of Fulvestrant (in Absence of Venetoclax)
Time Frame	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)

Outcome Measure Data

Analysis Population Description

PK evaluable population included all participants who received at least one dose of the study drugs (either venetoclax or fulvestrant) and had evaluable PK data. Number of participants analyzed is the number of participants analyzed for this outcome measure. Number analyzed is the number of participants with data available for analyses at the given time-point.

Arm/Group Title	Fulvestrant
Arm/Group Description	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).
Measure Participants	5
Cycle 2 Day 1: pre-dose	0.0103 (29.4)
Treatment discontinuation visit	0.0139 (NA)

Adverse Events

Time Frame	Baseline up until 28 days after the last dose of study drug (venetoclax or fulvestrant, whichever is later) up to approximately 32 months.
Adverse Event Reporting Description	The 1 additional death in the Venetoclax + Fulvestrant arm compared to in the Participant Flow section, relates to a participant who had withdrawn consent from the study and later died. Their death was reported in public records (reported as a post study reporting death). All-cause mortality is for ITT population and serious and other AEs are reported for safety population.
Arm/Group Title	Venetoclax + Fulvestrant		Fulvestrant
Arm/Group Description	Participants were administered Venetoclax 800mg orally QD and Fulvestrant 500mg IM on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).		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).
All Cause Mortality
	Venetoclax + Fulvestrant		Fulvestrant
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	26/51 (51%)		18/52 (34.6%)
Serious Adverse Events
	Venetoclax + Fulvestrant		Fulvestrant
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/50 (8%)		2/51 (3.9%)
General disorders
Pyrexia	1/50 (2%)	1	0/51 (0%)	0
Infections and infestations
Lower respiratory tract infection	1/50 (2%)	1	0/51 (0%)	0
Urosepsis	1/50 (2%)	1	0/51 (0%)	0
Investigations
Ejection fraction decreased	1/50 (2%)	1	0/51 (0%)	0
Musculoskeletal and connective tissue disorders
Flank pain	0/50 (0%)	0	1/51 (2%)	1
Bone pain	0/50 (0%)	0	1/51 (2%)	1
Respiratory, thoracic and mediastinal disorders
Pleural effusion	0/50 (0%)	0	1/51 (2%)	1
Other (Not Including Serious) Adverse Events
	Venetoclax + Fulvestrant		Fulvestrant
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	45/50 (90%)		34/51 (66.7%)
Blood and lymphatic system disorders
Anaemia	2/50 (4%)	2	3/51 (5.9%)	3
Leukopenia	3/50 (6%)	3	1/51 (2%)	1
Lymphopenia	7/50 (14%)	7	0/51 (0%)	0
Neutropenia	8/50 (16%)	11	0/51 (0%)	0
Gastrointestinal disorders
Abdominal distension	5/50 (10%)	5	1/51 (2%)	1
Abdominal pain	4/50 (8%)	4	0/51 (0%)	0
Abdominal pain upper	4/50 (8%)	4	1/51 (2%)	1
Constipation	8/50 (16%)	8	2/51 (3.9%)	2
Diarrhoea	28/50 (56%)	39	5/51 (9.8%)	6
Dry mouth	4/50 (8%)	4	0/51 (0%)	0
Nausea	32/50 (64%)	40	9/51 (17.6%)	10
Vomiting	15/50 (30%)	23	1/51 (2%)	1
General disorders
Chest pain	4/50 (8%)	4	0/51 (0%)	0
Fatigue	18/50 (36%)	20	9/51 (17.6%)	9
Injection site reaction	11/50 (22%)	15	15/51 (29.4%)	21
Oedema peripheral	4/50 (8%)	6	1/51 (2%)	2
Hepatobiliary disorders
Hepatic pain	3/50 (6%)	3	0/51 (0%)	0
Infections and infestations
Upper respiratory tract infection	3/50 (6%)	3	1/51 (2%)	1
Injury, poisoning and procedural complications
Injection related reaction	4/50 (8%)	6	5/51 (9.8%)	5
Investigations
Alanine aminotransferase increased	2/50 (4%)	2	4/51 (7.8%)	4
Aspartate aminotransferase increased	4/50 (8%)	4	3/51 (5.9%)	3
Blood alkaline phosphatase increased	2/50 (4%)	2	4/51 (7.8%)	4
Blood creatine phosphokinase increased	4/50 (8%)	4	2/51 (3.9%)	2
Weight decreased	3/50 (6%)	3	0/51 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	9/50 (18%)	9	2/51 (3.9%)	2
Musculoskeletal and connective tissue disorders
Arthralgia	5/50 (10%)	6	6/51 (11.8%)	10
Back pain	3/50 (6%)	3	5/51 (9.8%)	6
Musculoskeletal chest pain	1/50 (2%)	2	8/51 (15.7%)	9
Pain in extremity	4/50 (8%)	4	1/51 (2%)	2
Nervous system disorders
Dizziness	5/50 (10%)	5	2/51 (3.9%)	2
Headache	7/50 (14%)	8	8/51 (15.7%)	8
Psychiatric disorders
Insomnia	8/50 (16%)	8	4/51 (7.8%)	4
Respiratory, thoracic and mediastinal disorders
Cough	8/50 (16%)	9	4/51 (7.8%)	4
Dyspnoea	5/50 (10%)	5	3/51 (5.9%)	3
Skin and subcutaneous tissue disorders
Pruritus	4/50 (8%)	5	1/51 (2%)	1
Vascular disorders
Hot flush	1/50 (2%)	1	9/51 (17.6%)	9

Limitations/Caveats

The study was terminated due to Sponsor's decision and there were no safety concerns. Primary and secondary efficacy endpoints have been updated to report 95% confidence interval (CI) for Clinical Benefit estimate and 95% CI for the Cox proportional hazards model for PFS, following reporting conventions.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the study but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.