| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| High-Risk HER2-Positive Breast Cancer |
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| E.1.1.1 | Medical condition in easily understood language |
| HER2 positive breast cancer |
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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 | 10065430 |
| E.1.2 | Term | HER2 positive 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 |
| To evaluate IDFS with T-DXd treatment as compared to T-DM1 |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate DFS with T-DXd treatment as compared to T-DM1
- To evaluate OS with T-DXd treatment as compared to T-DM1
- To evaluate DRFI with T-DXd treatment as compared to T-DM1
- To evaluate BMFI with T-DXd treatment as compared to T-DM1
- To evaluate safety of T-DXd
- To evaluate pharmacokinetics (PK) of T-DXd
- To evaluate immunogenicity of T-DXd |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Sign and date the tissue screening and main ICFs, prior to the start of any study-specific qualification procedures.
2. Adults ≥18 y old. (Please follow local regulatory requirements if the legal age of consent for study participation is >18 y old).
3. HER2-positive breast cancer, meeting all of the criteria listed in the protocol (see protocol for full details).
4. Histologically confirmed invasive breast carcinoma at time of disease presentation. Subjects with inflammatory breast cancer are allowed provided all eligibility criteria are met.
5. Clinical stage at disease presentation of T1-4, N0-3, M0 prior to neoadjuvant therapy (Note: Patients presenting with T1N0 tumors will not be eligible).
6. Pathologic evidence of residual invasive carcinoma in the breast and/or axillary lymph nodes following completion of neoadjuvant therapy meeting one of the high risk criteria described in detail in the protocol.
7. Completion of neoadjuvant systemic therapy, including taxane-based chemotherapy and HER2-directed treatment prior to surgery.
8. Adequate excision as confirmed per medical records: surgical removal of all clinically evident disease in the breast and axillary lymph nodes (see Section 8.1.2).
9. An interval of no more than 12 weeks between the date of last surgery and the date of randomization.
10. Known hormone receptor status, per local laboratory assessment, as defined by ASCO-CAP guidelines (≥1%): HR-positive status defined by either positive estrogen receptor (ER) or positive progesterone receptor (PR) status. HR-negative status defined by both known negative ER and known negative PR.
11. Left ventricular ejection fraction (LVEF) ≥ 50% within 28 days prior to randomization.
12. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
13. Has adequate organ function within 14 days before randomization as defined in the protocol.
14. Male and female subjects of reproductive/childbearing potential must agree to use a highly effective form of contraception or avoid intercourse during and upon completion of the study and for at least 4 months for males and 7 months for females after the last dose of study drug. See protocol for full details
15. Male subjects must not freeze or donate sperm starting at randomization and throughout the study period, and at least 4 months after the final study drug administration. Preservation of sperm should be considered prior to enrolment in this study.
16. Female subjects must not donate, or retrieve for their own use, ova from the time of randomization and throughout the study treatment period, and for at least 7 months after the final study drug administration. They should refrain from breastfeeding throughout this time. Preservation of ova may be considered prior to randomization in this study. |
|
| E.4 | Principal exclusion criteria |
1. Stage IV (metastatic) breast cancer.
2. History of any prior (ipsi- or contralateral) breast cancer except lobular carcinoma in situ (LCIS).
3. Evidence of clinically evident gross residual or recurrent disease following neoadjuvant therapy and surgery (see Section 8.1.2.1).
4. An overall response of progressive disease according to the investigator at the conclusion of preoperative systemic therapy
5. Prior treatment with T-DXd, T-DM1 or other anti-HER2 ADC or prior enrollment in any clinical trial with T-DXd (regardless of treatment arm).
6. History of exposure to the following cumulative doses of anthracyclines (see protocol for full details).
7. History of other malignancy within the last 5 years except for appropriately treated carcinoma in situ (CIS) of the cervix, non-melanoma skin carcinoma, Stage I melanoma skin carcinoma, Stage I uterine cancer, or other appropriately treated non-breast malignancies with an outcome similar to those mentioned above.
8. History of (noninfectious) ILD/pneumonitis that required steroids or has ILD/pneumonitis noted on computed tomography (CT) scan of the chest at Screening (asymptomatic interstitial changes confined to recent radiation therapy fields are not excluded).
9. Known pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (eg, pulmonary emboli within three months prior to randomization, severe asthma, severe chronic obstructive pulmonary disease (COPD), restrictive lung disease, etc.).
10. Any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement (eg, Rheumatoid arthritis, Sjogren's, sarcoidosis, etc.), where there is documented, or a suspicion of pulmonary involvement, or pneumonectomy at teh time of screening.
11. Uncontrolled or significant cardiovascular disease, including: Medical history of myocardial infarction within 6 months before randomization, symptomatic congestive heart failure (CHF) (New York Heart Association Class II to IV), troponin levels consistent with myocardial infarction as defined according to the manufacturer 28 days prior to randomization.
12. Has a corrected QT interval per Fridericia’s formula (QTcF) prolongation to > 470 msec (females) or > 450 msec (males) based on screening 12-lead electrocardiogram (ECG).
13. History of severe hypersensitivity reactions to either the drug substances or inactive ingredients in the drug product.
14. History of severe hypersensitivity reactions to other monoclonal antibodies (MAb).
15. Inadequate washout period before Randomization/Cycle 1 Day 1, as defined in the protocol.
16. Substance abuse or medical conditions such as clinically significant cardiac or psychological conditions, that may, in the opinion of the investigator, interfere with the subject’s participation in the clinical study or evaluation of the clinical study results.
17. Social, familial, or geographical factors that would interfere with study participation or follow-up.
18. Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.
19. Active primary immunodeficiency, known uncontrolled active HIV infection or active hepatitis B or C infection.
20. Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤ 1 or baseline.
21. Is pregnant or breastfeeding or planning to become pregnant.
22. Has history of receiving live, attenuated vaccine (mRNA and replication-deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first exposure to study intervention. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- IDFS is defined as the time from randomization to invasive local, axillary or distant recurrence, invasive contralateral breast cancer, or death from any cause.
- IDFS will be determined based on disease recurrence per Investigator assessment based on all available clinical assessments.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After at least 145 IDFS events are recorded for interim analysis and 207 IDFS events are recorded for final analysis |
|
| E.5.2 | Secondary end point(s) |
- DFS is defined as the time between randomization and the date of the first occurrence of an IDFS event including second primary non-breast cancer event or contralateral or ipsilateral DCIS. DFS will be determined based on disease recurrence per Investigator assessment.
- OS is defined as the time from randomization to death due to any cause.
- DRFI is defined as the time between randomization and the date of distant breast cancer recurrence. DRFI will be determined based on disease recurrence per Investigator assessment.
- BMFI is defined as time from randomization to documentation of involvement of the CNS by metastatic cancer including parenchymal brain and spinal cord metastases as well as leptomeningeal carcinomatosis. BMFI will be determined based on disease recurrence per Investigator assessment.
- AEs including SAEs, TEAEs, and AESIs
Physical examination findings, ECOG PS, vital sign measurements, standard clinical laboratory parameters, ECG parameters, ECHO/MUGA findings, and CT scans
- Serum concentrations of T-DXd, total anti HER2 antibody, and MAAA 1181a in the PK sampling cohort
- Percentage of subjects who are positive for ADAs at baseline, and post-baseline and treatment-emergent ADA positive. Titer and NAb will be determined for positive ADA samples. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Continuous monitoring and reported at the time of the final analysis. |
|
| 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 | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | Yes |
| 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 | 73 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 203 |
| 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 |
| Peru |
| Singapore |
| Hong Kong |
| Taiwan |
| Australia |
| Brazil |
| Canada |
| China |
| Israel |
| Japan |
| Korea, Republic of |
| Mexico |
| Russian Federation |
| United Kingdom |
| United States |
| Belgium |
| Czechia |
| Denmark |
| France |
| Germany |
| Greece |
| Ireland |
| Italy |
| Netherlands |
| Poland |
| Portugal |
| Romania |
| Spain |
| Türkiye |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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