Efficacy and Safety Comparison of Niraparib to Placebo in Participants with HER2 Negative BRCAmut or Triple-Negative Breast Cancer with Molecular Disease Based on Presence of ctDNA

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Glaxosmithkline Research & Development Limited

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

22 Jun 2021 → ongoing

Decision date (initial)

2024-08-12

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2023-504454-35-00

EudraCT number

2020-003973-23

ClinicalTrials.gov

NCT04915755

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

Study 213831 was designed as a study of niraparib as treatment for participants with tumor breast cancer susceptibility gene mutated (tBRCAmut, which includes participants with germline BRCAmut [gBRCAmut] and/or somatic BRCAmut [sBRCAmut]) human epidermal growth factor receptor 2−negative (HER2−) breast cancer or tumor BRCA wild-type (tBRCAwt) triple-negative breast cancer (TNBC), who have molecular disease based on the presence of circulating tumor DNA (ctDNA) levels after completion of definitive therapy, including neoadjuvant treatment, surgery, adjuvant radiotherapy, and adjuvant chemotherapy. As a result of the decision to stop enrollment in the ZEST study, safety and tolerability of niraparib are being assessed as the primary endpoint and will use the Safety (SAF) Population; efficacy endpoints are considered exploratory. Estimands are not applicable for the primary endpoint.

Conditions and MedDRA coding

Neoplasms, Breast

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. "Stage I-III breast cancer (BC) per AJCC for BC staging criteria 8th edition with surgical resection of the primary tumor that is confirmed to be either: •TNBC •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 testing. As of the date of the decision to stop enrollment, sample collection was stopped "
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 "
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. 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 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.) "
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) OR •Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), 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 of the protocol. •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. "
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: •Be abstinent from 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) 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) of the protocol. "

Exclusion criteria 20

1. "Prior PARP inhibitor treatment "
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 "
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) "

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. "Primary End Point - 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)"

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Glaxosmithkline Research & Development Limited

Sponsor organisation

Glaxosmithkline Research & Development Limited

Address

G S K House, 980 Great West Road 980 Great West Road

City

Brentford

Postcode

TW8 9GS

Country

United Kingdom

Scientific contact point

Organisation

Glaxosmithkline Research & Development Limited

Contact name

EU GSK Clinical Trials Call Center

Public contact point

Organisation

Glaxosmithkline Research & Development Limited

Contact name

EU GSK Clinical Trials Call Center

Third parties 9

Locations

4 EU/EEA countries · 13 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 66 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications