| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| 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.
|
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| 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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| -Evaluation of the efficacy of niraparib relative to placebo as measured by disease-free survival (DFS) |
|
| E.2.2 | Secondary objectives of the trial |
-Evaluation of overall survival (OS)
-Evaluation of time to progression on next anticancer therapy
-Evaluation of distant recurrence-free survival (DRFS)
-Evaluation of the safety and tolerability of niraparib
-Evaluation of disease-related symptoms that impact health-related quality of life
-Evaluation of patient-reported treatment-related symptoms |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Objective of PK sub-study is to assess the effect of niraparib on endocrine therapy (anastrozole, letrozole, exemestane, and tamoxifen) steady-state exposure. |
|
| 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
•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
5.An archival tumour tissue specimen of the primary tumor sufficient in quality and quantity for ctDNA assay design and tBRCA and HRD testing (a minimum of fifteen 5-μm sections or 1 FFPE tumour block for ctDNA assay design and tBRCA testing and a minimum of 1 FFPE tumour block for 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
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 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.
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) |
| -DFS is defined as the time until disease recurrence, measured from the time of randomization to the earliest date of assessment of disease recurrence or death by any cause, as assessed by Investigator using RECIST v1.1. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| -Median DFS for the placebo arm is expected to be ~9 months from randomization. |
|
| E.5.2 | Secondary end point(s) |
-OS is defined as the time of randomization to the date of death by any cause
-Evaluation of time to progression on next anticancer therapy is defined as
The time from randomization to the earliest progression event subsequent to that used for the primary variable DFS or death by any cause. The date of progression will be based on Investigator assessment during or after the next anticancer therapy and will be defined according to local standard clinical practice. Progression may involve any of the following: objective radiological, histopathological, or symptomatic progression or death.
-DRFS is defined as the time from randomization to the first detection of distant metastasis or death by any cause as assessed by Investigator using RECIST v1.1.
-Safety and tolerability as measured by the incidence of TEAEs, SAEs and AESIs TEAEs leading to death, and TEAEs leading to dose modifications, and TEAEs leading to discontinuation will be assessed. Clinically relevant laboratory parameters, vital signs, ECOG performance status, physical examinations, and use of concomitant medications will be collected and evaluated as defined in the Statistical Analysis Plan (SAP).
-Evaluation of disease-related symptoms that impact participant health-related quality of life measured by change from baseline as assessed using the following instruments: EORTC-QLQ-C30
-Evaluation of patient-reported treatment-related symptoms measured by descriptive data presented using items from the PRO-CTCAE and FACT-GP5
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| -Median overall survival for the placebo arm is expected to be ~30 months from randomization; final OS analysis will be ~8 years after the date on which the first participant was randomized. Patient-reported outcomes to assess quality of life will be measured monthly during the trial, at end of treatment, and then post-dose at +30, +90, and +180 days |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| 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 | 4 |
| 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 | No |
| 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 |
| 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 |
|
| 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
|
The end of the study is defined as the date of the last scheduled procedure shown in the Schedule of Activities for the last participant in the study.
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
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