E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pre and post-menopausal women and men with locally advanced or metastatic HR+/HER2-negative endocrine resistant breast cancer |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
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 |
To assess the efficacy in terms of Progression-Free Survival at 6 months (PFS6) of neratinib in combination with endocrine therapy in HR+/HER2- HER2-E subtype advanced breast cancer defined by the PAM50 assay. |
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E.2.2 | Secondary objectives of the trial |
1.To determine the clinical benefit of neratinib in combination with endocrine therapy in terms of: 1.1.Clinical Benefit Rate at 6 months (CBR6) determined locally by the investigator according to RECIST v1.1. 1.2.Overall response rate (ORR) determined locally by the investigator according to RECIST v1.1. 1.3.Progression free survival (PFS), as determined locally by the investigator according to RECIST v.1.1, or death from any cause, whichever occurs first. 1.4 Duration of response (DOR) determined locally by the investigator according to RECIST v1.1.. 1.5 Time to response (TtR) defined as the time from first treatment administration to the first objective tumor response (tumor shrinkage of >=30%) observed for patients who achieved a CR or PR 1.6 PFS on study treatment compared to PFS on prior line of therapy (pre-PFS) 2 To evaluate the safety and tolerability of neratinib + letrozole |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patients of both sexes, over 18 years of age with locally advanced or metastatic breast cancer with hormonal receptors and HER2-negative 2. Postmenopausal or Premenopausal Women, 3. No more than one previous line of chemotherapy for locally advanced or metastatic recurrent disease. 4. Disease refractory to CDK4/6 inhibitors. 5. Subtype HER2-E according to the PAM50 analysis confirmed by the designated laboratory. 6. ECOG ≤1. |
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E.4 | Principal exclusion criteria |
1. Prior treatment with any TKI directed to ERBB2 (eg, lapatinib, afatinib, dacomitinib, neratinib, tucatinib). 2. Previous treatment with a cumulative dose of epirubicin> 900 mg / m2 or a cumulative dose of doxorubicin> 450 mg / m2. If another anthracycline, or more than one anthracycline, has been used, the cumulative dose should not exceed 450 mg / m2 equivalent of doxorubicin. 3. Uncontrolled heart disease 4. Major chronic digestive disorder with diarrhea as the main symptom 5.Women of childbearing or pregnant age 6. Pleural effusion, pericardial effusion 7. Uncontrolled hypercalcemia 8. * Additional malignant neoplasm confirmed to be in progression or have needed active treatment in the last 3 years. 9. Presence of active metastases in the CNS or carcinomatous meningitis. 10. * History of pneumonitis (non-infectious) that has required steroids or active pneumonitis. 11. * Previous solid organ transplant 12. Presence of an active infection that requires systemic treatment. 13. * Known history of human immunodeficiency virus (HIV) infection. 14. * Known history of hepatitis B virus infection or known active hepatitis C virus infection 15. Inability or unwillingness to swallow tablets. 16. Known hypersensitivity to any of the components of the product under investigation, the need for combined treatment or loperamide. 17. Patients being treated with drugs recognized as being strong inhibitors or inducers of the isoenzyme CYP3A4/P-gp isoform of cytochrome P450 within 5 days prior to inclusion. 18. * Presence of a psychiatric or substance abuse disorder 19. Being pregnant or breastfeeding |
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression-Free Survival at 6 months (PFS6) defined as the proportion of patients alive and without progression (according to RECIST v1.1 criteria). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
at 24 weeks after first treatment administration. |
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E.5.2 | Secondary end point(s) |
1.Clinical Benefit Rate at 6 months (CBR6) defined as a Complete response (CR), Partial response (PR) or Stable Disease (SD) for at least 24 weeks, as determined locally by the investigator according to RECIST v1.1. 2. Overall Response rate (ORR) as determined locally by the investigator according to RECIST v1.1 3.Progression free survival (PFS) defined as the time from first treatment administration to the first occurrence of disease progression, as determined locally by the investigator according to RECIST v.1.1, or death from any cause, whichever occurs first. 4.Duration of response (DoR) defined as the time from the first occurrence of a documented objective response to disease progression, as determined locally by the investigator through use of RECIST v.1.1, or death from any cause, whichever occurs first. 5.Time to response (TtR) defined as the time from first treatment administration to the first objective tumor response (tumor shrinkage of ≥30%) observed for patients who achieved a CR or PR. 6.PFS on study treatment compared to PFS on prior line of therapy (pre-PFS). 7. Incidence, duration and severity of Adverse Events (AEs) assessed by the NCI Common Terminology for Classification of Adverse Events (CTCAE) version 5.0, including dose reductions, delays and treatment discontinuations. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
-6 month for CBR6 -Rest of secondary objective will be mesure upon lost of follow up |
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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 | Yes |
E.6.4 | Safety | No |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
to assess the proportion of patients who are alive without disease progression at 24 weeks based on local investigator assessment per RECIST v1.1 (PFS6) as determined locally by the investigator. |
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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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 18 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 8 |