E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
HER2-Low, Hormone Receptor Positive Breast Cancer which has Progressed on Endocrine Therapy in the Metastatic Setting. |
|
E.1.1.1 | Medical condition in easily understood language |
|
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 | SOC |
E.1.2 | Classification code | 10029104 |
E.1.2 | Term | Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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 |
• To assess the efficacy of Trastuzumab deruxtecan (T-DXd) compared with investigator’s choice chemotherapy in terms of PFS by BICR in the HR+, HER2-low (IHC 2+/ISH- and IHC 1+) populations. |
|
E.2.2 | Secondary objectives of the trial |
The key secondary objectives are:
• OS in the HR+, HER2-low population
• PFS by BICR and OS in the ITT population (HER2 IHC >0 <1+ and HER2-low)
The other secondary objectives are:
• PFS by Investigator assessment, ORR and DoR by BICR and Investigator assessment in the HR+, HER2-low population
• ORR and DoR by BICR and Investigator assessment in the ITT population.
• PFS2 according to Investigator assessment, time to first subsequent treatment or death (TFST) and time to second subsequent treatment or death (TSST) in the HR+, HER2-low population and the ITT population
• the safety and tolerability profile of T-DXd compared with investigator’s choice chemotherapy
• the PK of T-DXd
• symptoms, functioning and HRQoL in patients treated with T-DXd compared with investigator’s choice single agent chemotherapy
• the immunogenicity of T-DXd |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Key Inclusion Criteria:
• Patients must be ≥18 years of age.
• Pathologically documented breast cancer that:
1. is advanced or metastatic
2. has a history of HER2-low or negative expression defined as IHC 2+/ISH- or IHC 1+ (ISH- or untested) or HER2 IHC >0 <1+ (ISH- or untested)
3. has historical HER2-low or HER2 IHC >0 <1+ expression confirmed by central HER2 laboratory testing to have HER2-low expression or HER2 IHC >0 <1+ expression, respectively
4. was never previously HER2-positive
5. is documented HR+ disease in the metastatic setting.
• No prior chemotherapy for advanced or metastatic breast cancer.
• Has adequate tumor samples for assessment of HER2 status
• Disease progression on at least 2 previous lines of endocrine therapy with or without a targeted therapy (Progression of disease within 24 months on adjuvant ET is considered a line of therapy)
• Has protocol-defined adequate organ and bone marrow function. |
|
E.4 | Principal exclusion criteria |
Key Exclusion Criteria:
• Ineligible for all options in the investigator’s choice chemotherapy arm
• Uncontrolled intercurrent illness or significant cardiovascular disease
• Active or prior documented ILD/pneumonitis or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening
• Lung-specific intercurrent clinically significant illnesses
• Patients with spinal cord compression or clinically central nervous system metastasis. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
• PFS by BICR according to RECIST 1.1 in the HR+, HER2-low population |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Until progression or death, assessed up to approximately 60 months. |
|
E.5.2 | Secondary end point(s) |
The key secondary endpoints are:
1. Overall Survival (OS) - in HR+ HER2-low population
2. Progression Free Survival (PFS) - in intent to treat (ITT) population (HER2 IHC >0 <1+ and HER2-low)
3. OS - in ITT population (HER2 IHC >0 <1+ and HER2-low)
The other secondary endpoints are:
1. Objective Response Rate (ORR) and Duration of response (DoR) - in HR+, HER-2 low population
2. PFS by Investigator assessment - in the HR+, HER2-low population
3. ORR and DoR - in the ITT population
4. PFS2 by Investigator assessment, time to first subsequent therapy (TFST) and time to second subsequent treatment or death (TSST) - in HR+, HER2-low and the ITT population
5. Safety and tolerability of T-DXd compared to chemotherapy.
6. The pharmacokinetics (PK) of T-Dxd
7. Health-related quality of life
8. Immunogenicity of T-Dxd |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
The timepoints for key secondary endpoints are: Please see section secondary endpoints for corresponding timepoints below
1. Until death, assessed up to approximately 60 months
2. Until progression or death, assessed up to approximately 60 months
3. Until death, assessed up to approximately 60 months
The timepoints for other secondary endpoints are:
1. Until progression, assessed up to approximately 60 months
2. Until progression or death, assessed up to approximately 60 months
3. Until progression, assessed up to approximately 60 months
4. Assessed up to approximately 60 months
5. Up to follow-up period, approximately 60 months
6. Up to Cycle 8, approximately Week 24
7. Assessed up to approximately 60 months
8. Up to follow-up period, approximately 60 months |
|
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 | 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 | 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 | Yes |
E.8.2.3.1 | Comparator description |
Investigator’s choice single agent chemotherapy: capecitabine, paclitaxel, nab-paclitaxel |
|
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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 105 |
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 |
Australia |
Austria |
Belgium |
Brazil |
Canada |
China |
Denmark |
France |
Germany |
Hungary |
India |
Israel |
Italy |
Japan |
Korea, Republic of |
Mexico |
Netherlands |
Poland |
Russian Federation |
Saudi Arabia |
Spain |
Sweden |
Taiwan |
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
|
Completing the last expected visit/contact of the last patient undergoing the study.
He/she has completed all phases of the study as per SoAs (including follow-up for OS).
Patients may be withdrawn from the study if the study itself is stopped.
The study may be terminated at individual centers if the study procedures are not being performed according to ICH GCP or if recruitment rate does not allow to complete study in the planned timeframe. |
|
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 |