| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HER2 negative, BRCA germline mutated breast cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| HER2 negative, BRCA mutation-positive breast cancer |
|
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10006187 |
| E.1.2 | Term | 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 |
| The primary objective of this study is to compare progression-free survival (PFS), as assessed by blinded central review, of patients with advanced/metastatic HER2-negative gBRCAmut breast cancer when treated with niraparib as compared to those treated with physician’s choice single agent chemotherapy standards (eribulin, vinorelbine, gemcitabine or capecitabine). |
|
| E.2.2 | Secondary objectives of the trial |
To compare overall survival of patients with advanced/metastatic HER2-negative gBRCAmut breast cancer when treated with niraparib as compared to those treated with physician's choice single agent chemotherapy standards.
- Establish germline BRCA mutation status of screened patients using a centrally provided, validated test. Additional tests will be performed to determine concordance between tests for the purpose of developing a commercial diagnostic test.
- To evaluate safety and tolerability as measured by all AEs
- To compare PFS using investigator assessment of progression
- To evaluate time to treatment failure
- To compare response rate and duration of response
- To compare time to deterioration of health-related quality of life
- To describe subsequent therapies and potential relationships with outcomes
- To assess genetic and non-genetic biomarkers relating to treatment efficacy.
For a detailed listing and for objectives 9 to 10 please refer to the
Protocol. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histologically or cytologically confirmed HER2-negative metastatic or locally advanced breast cancer that is not amenable to resection or radiation with curative intent.
2. Female and male patients age at least 18 years.
3. Patients with a deleterious or suspected deleterious germline BRCA1 or BRCA2 mutation may be enrolled into the study and randomized based on either local or central laboratory testing of BRCA status (Myriad Genetic Laboratories, Salt Lake City, UT, USA). On- study central confirmation of BRCA status will be performed for those patients who were enrolled based on either a previous Myriad test or a local test. If after inclusion, based on a local test result or a previously done Myriad test, a patient turns out not to have a germline BRCA mutation per central laboratory results (Myriad Genetic Laboratories, Salt Lake City, UT, USA) the patient can still continue on study based on his/her physician discretion and his/her own preference.
4. Measurable disease by RECIST v1.1 or non- measurable disease that is clinically evaluable (except sclerotic-only bone disease; bone-only disease that has a lytic component is allowed).
5. Patients must not have symptomatic uncontrolled brain metastases To be considered controlled, central nervous system (CNS) disease must have undergone treatment (whole brain radiation, radiosurgery or equivalent) at least 1 month previously and the patient has no new or progressive signs or symptoms related to the CNS disease, and are off steroid therapy two weeks.
6. Up to 2 prior cytotoxic regimens for advanced or metastatic breast cancer (not including adjuvant or neo-adjuvant therapy); patients with no prior cytotoxic regimens for advanced or metastatic disease will only be allowed if they relapsed during or within 12 months of (neo-) adjuvant cytotoxic therapy.
7. Prior therapy should have included a taxane and/ or anthracycline (unless contraindication to those) in the neoadjuvant, adjuvant, or advanced/metastatic setting.
a. Hormone receptor positive patients must also have hormone resistant disease; either relapsed while on adjuvant endocrine treatment or within one year of completing adjuvant endocrine treatment, or progression on at least one line of endocrine treatment for advanced cancer.
8. Patients must not have received anticancer chemotherapy, radiotherapy (including palliative radiotherapy), hormonal therapy,
biological therapy, or any other investigational therapy within 3 weeks prior to the start of study treatment. Patients with persistent toxicity (except alopecia) > grade 1 from prior cancer therapy will also be excluded. Bisphosphonate and denosumab are allowed.
9. No prior treatment with a known or putative PARP inhibitor (except iniparib). No other anticancer agent (chemotherapy, hormonal therapy, or other agent) is to be permitted during the course of the study for any patient.
10. Patients who have previously received platinum chemotherapy in the metastatic setting are allowed to enroll in the study as long as they did not progress while on or within 8 weeks from the day of the last platinum administration. Patients who received platinum in the (neo-) adjuvant setting are eligible, as long as they relapsed 12 months or more after the last dose of platinum.
11. ECOG performance status 0-2 (Appendix G).
12. Adequate organ function (assessed within 72 hours prior to the first dose):
a. Absolute neutrophil count (ANC) ≥ 1,500 cells/μL
b. Platelets ≥ 100,000 cells/μL
c. Hemoglobin ≥ 9 g/dL
d. Serum creatinine ≤ 1.5 × upper limit of normal (ULN) or ≥ 50 mL/min using Cockcroft-Gault equation
e. Total bilirubin ≤ 1.5 × ULN
f. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 × ULN or < 5 × ULN with liver metastases
13. Patients able to swallow and retain oral tablets
14. Female patients must not be pregnant or breast feeding
a. Female patient of childbearing potential must have a negative serum pregnancy test.
15. Patients of childbearing potential who are sexually active and their partners must agree to the use of a highly effective form of
contraception throughout their participation during the study treatment and for 90 days after last dose of study treatment(s).
16. No known hypersensitivity to the components of niraparib or any of its analogs.
17. No major surgery within 2 weeks prior to registration. Patients must have recovered from earlier major surgery before registration.
18. No prior diagnosis of Stage IV ovarian cancer.
...
30. Patients must agree to peripheral blood samples during screening and at the end of treatment for mutational profile testing (for mutations of selected myeloid associated genes) that will be performed only if the patient develops MDS or acute myeloid leukemia (AML) during the study or the post- treatment follow-up (a third sample will be collected in this case).
For a detailed listing and for inclusion criteria 19 to 29 please refer to the Protocol. |
|
| E.4 | Principal exclusion criteria |
| No exclusion criteria are defined per protocol |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression free survival per central review |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Overall survival (key secondary efficacy endpoint).
2. Determine concordance between gBRCAmut tests for the purpose of developing a commercial companion diagnostic test.
3. Safety and tolerability, as documented by AEs and laboratory values
4. PFS using investigator assessment of progression
5. Time to treatment failure
6. Response rate and duration of response
7. Health-related quality of life: QLQ-C30 and EQ5D-5L (see chapter 10).
8. Subsequent therapies and potential relationships with outcomes
9. To assess outcomes by germline mutation BRCA1 vs BRCA2 |
|
| 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 | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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 |
| Belgium |
| Canada |
| France |
| Greece |
| Hungary |
| Iceland |
| Israel |
| Italy |
| Netherlands |
| Poland |
| Portugal |
| Spain |
| United Kingdom |
| United States |
|
| 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
|
End of study occurs when all of the following criteria have been satisfied:
1. Thirty days after all patients have stopped protocol treatment
2. The trial is mature for the analysis of overall survival as defined in the protocol
3. The database has been fully cleaned and frozen for this analysis |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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