Clinical Trials Register

Summary
EudraCT Number:	2017-005118-74
Sponsor's Protocol Code Number:	WO40181
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-04-25
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Germany - BfArM

A.2

EudraCT number

2017-005118-74

A.3

Full title of the trial

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

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A 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 CDK4/6Inhibitor Therapy

A.4.1

Sponsor's protocol code number

WO40181

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	F. Hoffmann-La Roche Ltd
B.1.3.4	Country	Switzerland
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	F. Hoffmann-La Roche Ltd
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	F. Hoffmann-La Roche Ltd
B.5.2	Functional name of contact point	Trial Information Support Line-TISL
B.5.3	Address:
B.5.3.1	Street Address	Grenzacherstrasse 124
B.5.3.2	Town/ city	Basel
B.5.3.3	Post code	4070
B.5.3.4	Country	Switzerland
B.5.6	E-mail	global.rochegenentechtrials@roche.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/12/1080
D.3 Description of the IMP
D.3.1	Product name	Venetoclax
D.3.2	Product code	RO5537382
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	VENETOCLAX
D.3.9.1	CAS number	1257044-40-8
D.3.9.2	Current sponsor code	RO5537382
D.3.9.3	Other descriptive name	GDC-0199, Venclexta, Venclyxto
D.3.9.4	EV Substance Code	SUB176260
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Faslodex
D.2.1.1.2	Name of the Marketing Authorisation holder	AstraZeneca UK Ltd
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Faslodex
D.3.2	Product code	RO3208209
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intramuscular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	FULVESTRANT
D.3.9.1	CAS number	129453-61-8
D.3.9.2	Current sponsor code	RO3208209
D.3.9.3	Other descriptive name	FULVESTRANT, Faslodex
D.3.9.4	EV Substance Code	SUB13933MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	250
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Estrogen receptor-positive (ER+)/human epidermal growth factor receptor (HER2)-negative locally advanced or metastatic breast cancer (MBC)

E.1.1.1

Medical condition in easily understood language

Locally advanced or metastatic breast cancer is breast cancer that has spread beyond the breast and continues to grow locally or spread to other parts of the body (metastatic)

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	23.0
E.1.2	Level	LLT
E.1.2	Classification code	10070575
E.1.2	Term	Estrogen receptor positive breast cancer
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

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)

E.2.2

Secondary objectives of the trial

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/treatmentrelated 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

E.2.3

Trial contains a sub-study

E.3

Principal 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 < 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

- Have at least one measurable lesion via RECIST v1.1

- Have an Eastern Cooperative Oncology Group Performance Score of 0-1

- Have adequate organ and marrow function

- Have adequate blood coagulation

- Have a life expectancy > 3 months

E.4

Principal 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

E.5 End points

E.5.1

Primary end point(s)

1. Clinical benefit defined as CR, PR or SD lasting ≥24 weeks

E.5.1.1

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)

E.5.2

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

E.5.2.1

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, 4 and at study drug discontinuation visit
10-11. At baseline, Day 1 of each cycle and at study drug discontinuation visit

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

Canada

United States

France

Germany

United Kingdom

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

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)

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

Yes

F.3.3.7.1

Details of other specific vulnerable populations

ESTROGEN RECEPTOR−POSITIVE, HER2−NEGATIVE LOCALLY ADVANCED OR METASTATIC BREAST CANCER

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

105

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

An eligible patient will receive free of charge venetoclax after completing the study under the following conditions, and in accordance to Roche Global Policy on Continued Access to IMP:
· The patient has a life-threatening or severe medical condition and requires continued Roche IMP treatment
· There are no appropriate alternative treatments available
· The patient and his or her doctor comply with and satisfy any legal or regulatory requirements that apply to them

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2018-10-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-01-10

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-05-05

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