Clinical Trials Register

Summary
EudraCT Number:	2020-003973-23
Sponsor's Protocol Code Number:	213831
National Competent Authority:	Poland - Office for Medicinal Products
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2021-04-07
Trial 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

Poland - Office for Medicinal Products

A.2

EudraCT number

2020-003973-23

A.3

Full title of the trial

A Randomized Phase 3 Double-Blinded Study Comparing the Efficacy and Safety of Niraparib to Placebo in Participants with Either HER2-Negative BRCA-‑Mutated or Triple-Negative Breast Cancer with Molecular Disease Based on Presence of Circulating Tumor DNA After Definitive Therapy (ZEST)

Randomizowane badanie fazy III, prowadzone metodą podwójnie ślepej próby porównujące skuteczność i bezpieczeństwo stosowania niraparybu z placebo u pacjentów po radykalnym leczeniu HER-2 ujemnego raka piersi z obecnością mutacji BRCA lub potrójnie ujemnego raka piersi pozostających w molekularnej fazie choroby określonej na podstawie obecności krążącego nowotworowego DNA (ZEST).

A.3.1

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

The Efficacy and Safety of Niraparib vs Placebo to Treat Breast Cancer in Participants Who Have Tumour DNA in Their Blood After Completing Treatment (ZEST)

Porównanie skuteczności i bezpieczeństwa stosowania niraparybu z placebo u pacjentów z HER2-ujemnym z mutacją BRCA lub potrójnie ujemnym rakiem piersi w fazie molekularnej choroby na podstawie obecności ctDNA (ZEST).

A.3.2

Name or abbreviated title of the trial where available

Niraparib vs Placebo in Participants with HER2- BRCAmut breast cancer or TNBC with Detectable ctDNA

A.4.1

Sponsor's protocol code number

213831

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	GlaxoSmithKline Research and Development Ltd.
B.1.3.4	Country	United Kingdom
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	GlaxoSmithKline Research & Development Ltd.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	GlaxoSmithKline Research & Development Ltd
B.5.2	Functional name of contact point	GSK Clinical Support Help Desk
B.5.3	Address:
B.5.3.1	Street Address	980 Great West Road
B.5.3.2	Town/ city	Brentford, Middlesex
B.5.3.3	Post code	TW8 9GS
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+44 0800 783 9733
B.5.6	E-mail	GSKClinicalSupportHD@gsk.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	Yes
D.2.1.1.1	Trade name	Zejula
D.2.1.1.2	Name of the Marketing Authorisation holder	GSK Ireland
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	Niraparib
D.3.2	Product code	GSK3985771
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	NIRAPARIB
D.3.9.1	CAS number	1038915-60-4
D.3.9.2	Current sponsor code	GSK3985771
D.3.9.3	Other descriptive name	Niraparib tosylate monohydrate
D.3.9.4	EV Substance Code	SUB177208
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.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Breast Cancer

E.1.1.1

Medical condition in easily understood language

Breast cancer that is either triple negative or hormone-positive. Participants with hormone-positive disease must also have a BRCA mutation in the tumour.

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	PT
E.1.2	Classification code	10083232
E.1.2	Term	HER2 negative breast cancer
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

-Evaluation of safety and tolerability of niraparib

E.2.2

Secondary objectives of the trial

E.2.3

Trial contains a sub-study

E.2.3.1

Full title, date and version of each sub-study and their related objectives

The PK sub-study is no longer applicable as of PA03

E.3

Principal inclusion criteria

Participants are eligible to be included in Cohorts 1 and 2 of the study only if all of the following criteria are met:
1.Stage I to III breast cancer per AJCC for breast cancer staging criteria 8th edition with surgical resection of the primary tumor that is confirmed to be either:
•TNBC, irrespective of BRCA status
•HR+/HER2− breast cancer with a known and documented deleterious or suspected deleterious tBRCA mutation (either sBRCA or gBRCA positive)
2.Completed prior standard therapy for curative intent, including all of the following, if indicated: neoadjuvant treatment, surgery, adjuvant radiotherapy, and adjuvant chemotherapy
3.Participants with HR+ breast cancer must be on a stable regimen of endocrine therapy, if indicated, for at least 3 months prior to randomization. Ovarian suppression, if indicated, must also have been started at least 3 months prior to randomization.
4.Detectable ctDNA as measured by central Signatera testing (refer to
Table 2 in the protocol for the timing of ctDNA testing). As of the date of the decision to stop enrollment, sample collection was stopped as outlined in Section 1.3 of the Protocol.
5.An archival tumour tissue specimen of the primary tumor sufficient in quality and quantity for ctDNA assay design and tBRCA and HRD testing is required. Sponsor requirements for tissue sufficiency are outlined in the Study Reference Manual.
6.An Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
7.Must be ≥18 years of age.
8.Must have adequate organ and bone marrow function, as defined below. If these criteria are not met, randomization and treatment may be delayed up to 3 weeks.
Absolute neutrophil count:≥1,500/μL
Platelets:≥100,000/μL
Hemoglobin:≥9 g/dL or 5.6 mmol/L
Renal function Calculated creatinine clearance ≥30 mL/min
Serum creatinine:<2× ULN
Total bilirubin:≤3×ULN
ALT: ≤2.5×ULN
9.Participants with toxicity from prior cancer therapy must have recovered to Grade 1. (A participant with Grade 2 neuropathy or any grade of alopecia is an exception to this criterion and may qualify for this study.) Randomization and treatment may be delayed up to 3 weeks to allow for this criterion to be met.
10.Must be able to swallow and retain orally administered study treatment.
11.A female participant is eligible if she is not pregnant or breastfeeding, and at least 1 of the following conditions applies:
•Is not a woman of childbearing potential (WOCBP), as defined in Appendix 4.
OR
•Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, as described in Appendix 4, during the Treatment Period and for at least 180 days after the last dose of study treatment and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The Investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study treatment.
•A WOCBP must have a negative pregnancy test (highly sensitive urine test or serum test as required by local regulations) within 72 hours before the first dose of study treatment.
•If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
•Additional requirements for pregnancy testing during and after study treatment are described in Section 8.4.6.
•The Investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
See Appendix 4 for a list of acceptable birth control methods. Information must be captured appropriately within the site’s source documents.
12.Male participants are eligible if they agree to the following during the Treatment Period and for at least 90 days after the last dose of study treatment (see Appendix 4 for a list of acceptable birth control methods):
•Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent
OR
•Must agree to use contraception/barrier as detailed below:Agree to use a male condom (and should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak) when having sexual intercourse with a WOCBP who is not currently pregnant
PLUS
•Male participants must refrain from donating sperm for at least 90 days after the last dose of study treatment
13. Must be able to understand the study procedures and agree to participate in the study by providing written informed consent (as described in Appendix 5) of the protocol.
Please refer to the study protocol Section 5.1 for detailed inclusion criteria

E.4

Principal exclusion criteria

Participants are excluded from Cohorts 1 and 2 of the study if any of the following criteria are met:
1.Prior treatment with a PARP inhibitor.
2.Current treatment with a CDK4/6 inhibitor or endocrine therapy other than anastrozole, letrozole, exemestane, and tamoxifen with or without ovarian suppression.
3.Participants have any sign of metastasis or local recurrence after
comprehensive assessment conducted per protocol.
4.Participants have shown no definitive response to preoperative
chemotherapy by pathologic, radiological, or clinical evaluation, in cases where preoperative chemotherapy was administered (see Appendix 1).
5.Participants have systolic BP >140 mmHg or diastolic BP >90 mmHg
that has not been adequately treated or controlled.
6.Participants have any clinically significant gastrointestinal
abnormalities that may alter absorption such as malabsorption
syndrome or major resection of the stomach and/or bowels.
7.Participants have received colony-stimulating factors (eg, granulocyte macrophage colony-stimulating factor or recombinant erythropoietin) within 4 weeks prior to the first dose of study treatment.
8.Participants have previously or are currently participating in a
treatment study of an investigational agent within 4 weeks of the first
dose of therapy preceding the study.
9.Participants have received live vaccine within 30 days of planned start of study randomization. Study participants can be vaccinated against Corona virus disease 2019 (COVID-19) using vaccines authorized via the appropriate regulatory mechanisms (i.e. Emergency Use Authorization, Conditional Marketing Authorization or Marketing Authorization Application).
10.Participants have known hypersensitivity to the components of
niraparib, placebo, or their formulation excipients.
11.Participants have undergone major surgery within 4 weeks of starting the first dose of study treatment or have not recovered from any effects of any major surgery.
12.Participants have a second primary malignancy. Exceptions are the
following:
•Adequately treated nonmelanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS) of the breast, Stage I Grade 1 endometrial carcinoma
•Other solid tumors and lymphomas (without bone marrow
involvement) diagnosed ≥5 years prior to randomization and treated
with no evidence of disease recurrence and for whom no more than 1 line of chemotherapy was applied
13.Participants have current active pneumonitis or any history of
pneumonitis requiring steroids (any dose) or immunomodulatory
treatment within 90 days of planned start of the study.
14.Participants have any clinically significant concomitant disease or
condition (such as transfusion-dependent anemia or thrombocytopenia) that could interfere with, or for which the treatment might interfere with, the conduct of the study or that would, in the opinion of the Investigator, pose an unacceptable risk to the participants in this study.
15.Participants have any psychological, familial, sociological, or
geographical condition potentially hampering compliance with the study requirements and/or follow up procedures. Those conditions should be discussed with the participants before study entry.
16.Participants have high medical risk due to a serious, uncontrolled
medical disorder; nonmalignant systemic disease; or active, uncontrolled infection (including COVID-19). Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 90 days) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, active uncontrolled coagulopathy, bleeding disorder, or any psychiatric disorder that prohibits obtaining informed consent.
17.Participant is pregnant, breastfeeding, or expecting to conceive
children while receiving study treatment and/or for up to 180 days after the last dose of study treatment.
18.Participants have presence of hepatitis B surface antigen or a positive hepatitis C antibody test result at Screening or within 3 months prior to first dose of study treatment. Participants with presence of hepatitis B core antibody should also be excluded.
19. Participant is immunocompromised. Participants with splenectomy are allowed. Participants with known human immunodeficiency virus (HIV) are allowed if they meet the required criteria (refer to study protocol)
20.Participants have a known history of myelodysplastic syndrome
(MDS) or acute myeloid leukemia (AML).
Please refer to the study protocol Section 5.2 for detailed exclusion
criteria

E.5 End points

E.5.1

Primary end point(s)

- The incidence of TEAEs, SAEs, and AESIs; TEAEs leading to death,
TEAEs leading to dose modifications, and TEAEs leading to
discontinuation will be assessed. Clinically relevant laboratory
parameters, vital signs, ECOG performance status, and use of
concomitant medications will be collected and evaluated as defined in the Statistical Analysis Plan (SAP).
PK is no longer being analyzed due to the limited number of samples that were collected prior to stopping enrollment that are evaluable.

E.5.1.1

Timepoint(s) of evaluation of this end point

TEAEs, SAEs, and AESIs will be collected for the duration of the study

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

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

Yes

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

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)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

As of the date of decision to stop enrollment in the ZEST study, this is no longer applicable

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

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

124

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

Argentina

Chile

Colombia

New Zealand

Switzerland

Australia

Brazil

Canada

Israel

Japan

Mexico

Russian Federation

South Africa

United Kingdom

United States

Austria

Belgium

Finland

France

Germany

Hungary

Ireland

Italy

Netherlands

Norway

Poland

Portugal

Romania

Spain

Sweden

E.8.7

Trial has a data monitoring committee

Yes

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

Participants who continue to receive study treatment (niraparib) during the PACT Phase will be monitored and receive follow-up care in accordance with standard local clinical practice. Safety assessments will revert to the standard of care at a participant's particular study site. SAEs, AESIs, AEs leading to discontinuation of study treatment, overdose and pregnancy reports will continue to be reported directly to the Sponsor via paper form through 30 days after the last dose of study treatment.

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

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:

2195

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

538

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

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

F.4 Planned number of subjects to be included

F.4.1

In the member state

100

F.4.2

For a multinational trial

F.4.2.1

In the EEA

415

F.4.2.2

In the whole clinical trial

2733

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)

As of the date of the decision to stop enrollment, upon discontinuation
from assigned study treatment, participants may receive additional
(non-protocol) therapy at the discretion of the treating physician. For participants who discontinue study treatment, any poststudy intervention will not be
provided as part of the protocol unless otherwise specified in Section
1.3 (Table 4, Table 5, Table 6 of the Protocol). Refer section 6.7 of the
Protocol for further details.

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

2021-06-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-04-22

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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