| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HER2-positive breast cancer. |
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| E.1.1.1 | Medical condition in easily understood language |
| HER2-positive breast cancer (a specific subtype of breast cancer that presents an excess of a protein known as human epidermal growth factor receptor 2 (HER2) in its cells). |
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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) |
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| 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 |
| 1. To evaluate the efficacy of T-DXd in the neo-adjuvant treatment of HER2 positive breast cancer using pathological complete response (pCR) as the primary endpoint. |
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| E.2.2 | Secondary objectives of the trial |
1. To determine the event-free survival (EFS) and overall survival (OS) of patients treated with only T-DXd and trastuzumab.
2. To determine EFS and OS of patients treated with systemic therapy other than trastuzumab in addition to T-DXd.
3. To determine EFS and OS of the entire study population.
4. To compare EFS and OS between patients achieving vs not achieving pCR at surgery.
5. To study molecular evolution of tumours during treatment and to develop a biomarker panel that optimises prediction of the pCR.
6. To determine the percentage of patients who achieve pCR after only 4 cycles of T-DXd.
7. To determine the sensitivity and specificity for prediction of pCR of RDI and imaging and tomosynthesis biopsy alone and in combination. |
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| 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 |
The following sub-studies will be conducted to facilitate the secondary objectives for the study.
• Blood Biomarker Assessments (Mandatory)
• Tumour tissue samples (Mandatory)
• Fresh Tumour Biopsy collected at C2D14 for RNA Disruption Index (RDI) score (Mandatory)
• MRI performance in detecting pCR after neoadjuvant chemotherapy (Mandatory)
• Tomosynthesis-Guided Core Biopsies sub-study (Mandatory)
• Touch preparation cytology sub-study (Cymantic) (Mandatory)
• Faecal sample collection: The impact of gut microbiome constitution on the response to neoadjuvant chemotherapy (Optional)
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| E.3 | Principal inclusion criteria |
Each patient must meet all of the following inclusion criteria to be eligible for the study:
1. Adult women and men ≥ 18 years of age.
2. Histologically confirmed HER2-positive breast cancer:
o Documented HER2 overexpression by local laboratory (IHC 3+ or positive by ISH on diagnostic breast biopsy (per ASCO-CAP guidelines).
3. Newly diagnosed breast cancer, planned for neoadjuvant therapy prior to surgery.
4. Stages 2-3 breast cancer.
5. Patients should not have received any prior therapy for breast cancer.
6. Patients must be willing to undergo mandatory tumour biopsy at Cycle 2 Day 14 (+/- 4 days) and before surgery.
7. ECOG performance status 0-1.
8. Availability of archival tumour biopsy tissue at screening.
9. Left ventricular ejection fraction (LVEF) ≥ 50%, as determined by ECHO or MUGA.
10. Adequate laboratory values collected no more than 14 days before registration.
o Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L
o Platelet count ≥ 100 x 10^9/L
o Haemoglobin ≥ 9.0 g/dL.
o Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × upper limit of normal (ULN)
o Total bilirubin ≤ 1.5xULN or < 3×ULN in the presence of documented Gilbert’s syndrome (unconjugated hyperbilirubinemia)
o Serum albumin ≥ 25 g/L
o Creatinine clearance (CrCL) ≥ 30ml/min as determined by Cockcroft Gault.
o Prothrombin time and either partial thromboplastin or activated partial thromboplastin time ≤ 1.5 × ULN.
11. Evidence of post-menopausal status or negative serum pregnancy test for females of childbearing potential who are sexually active with a non-sterilized male partner. For women of childbearing potential, a negative result for serum pregnancy test must be available at the screening visit.
Women of childbearing potential are defined as those who are not surgically sterile (i.e. underwent bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or post-menopausal. Postmenopausal women defined as:
i. Women aged <50 years will be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in the post-menopausal range for the site.
ii. Women aged ≥50 years will be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatments.
iii. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods outlined for women of child-bearing potential if they wish to continue their HRT during the study.
Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to registration. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the
type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.
12. Women of childbearing potential must agree to use a highly effective method of contraception according to current HMA CTFG guideline when sexually active. Such methods include:
i. Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal).
ii. Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable and implantable).
iii. Intrauterine device (IUD).
iv. Intrauterine hormone-releasing system (IUS).
v. Bilateral tubal occlusion.
vi. Successfully vasectomised partner.
vii. Sexual abstinence.
13. Non-sterilized male patients who are sexually active with a female partner of childbearing potential must use a condom with spermicide from screening to 4 months after the final dose of IMP. Complete heterosexual abstinence for the duration of the study and drug washout period is an acceptable contraceptive method if it is in line with the patient’s usual lifestyle (consideration must be made to the duration of the clinical trial); however, periodic or occasional abstinence, the rhythm method, and the withdrawal method are not acceptable. It is strongly recommended for the female partners of a male patient to also use at least one highly effective method of contraception throughout this period. Male patients should refrain from fathering a child, or freezing or donating sperm from the time of registration, throughout the study and for 4 months after the last dose of IMP.
14. Female patients must not donate, or retrieve for their own use, ova from the time of registration and throughout the study treatment period, and for at least 7 months after the final IMP administration. They should refrain from breastfeeding throughout this time.
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| E.4 | Principal exclusion criteria |
Patients are excluded from the study if any of the following exclusion criteria apply:
1. Known metastatic or stage 4 breast cancer.
2. Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months). Myocardial infarction (MI) less than 6 months before registration, symptomatic congestive heart failure (CHF) (New York Heart Association Class II to IV). Patients with troponin levels above ULN at screening and without any myocardial related symptoms, should have a cardiologic consultation before enrollment to rule out MI.
3. Corrected QT interval (QTcF) prolongation to >470 msec (females) or >450 msec (males) based on the screening 12-lead ECG.
4. Uncontrolled arterial hypertension despite optimal medical management (per investigator’s opinion).
5. Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 3 months before registration.
6. Non-healing wound, ulcer, or bone fracture.
7. Active, clinically serious infections > CTCAE Grade 2 (CTCAE v5.0) requiring IV antibiotics, antivirals, or antifungals.
8. Patients with evidence or history of bleeding diathesis. Any haemorrhage or bleeding event ≥CTCAE Grade 3 within 4 weeks prior to the start of study treatment.
9. Active primary immunodeficiency, known human immunodeficiency virus (HIV) infection, or active hepatitis B or C infection. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
10. History of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
11. Lung criteria:
a. Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (e.g. pulmonary emboli within three months before study registration, severe asthma, severe COPD, restrictive lung disease,
pleural effusion, etc.)
b. Any autoimmune, connective tissue or inflammatory disorders (e.g. Rheumatoid arthritis, Sjogren's, sarcoidosis etc.) where there is documented, or a suspicion of pulmonary involvement at the time of screening. Full details of the disorder should be
recorded in the eCRF for patients who are included in the study.
c. Prior pneumonectomy (complete)
12. Receipt of live, attenuated vaccine (mRNA and replication deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first dose of trastuzumab deruxtecan. Note: Patients, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of IMP.
13. Pregnant or breast-feeding female patients, or patients who are planning to become pregnant.
14. Concomitant use of prohibited medications (refer to protocol section 7.6.3: Prohibited Concomitant
Medications and Treatments).
15. Known hypersensitivity to the test drug, test drug class, or excipients in the formulation.
16. History of severe hypersensitivity reactions to other monoclonal antibodies.
17. Substance abuse, medical, psychological or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results.
18. Any illness or medical conditions that are unstable or could jeopardize the safety of patients and their compliance in the study.
19. Multiple primary malignancies within 3 years before study registration, with the exception of
a. adequately resected non-melanoma skin cancer
b. curatively treated in-situ disease
c. other solid tumours curatively treated
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1. The percentage of patients who achieve pCR after T-DXd treatment and thus avoid standard cytotoxic chemotherapy. pCR is defined by the absence of invasive carcinoma in the breast and lymph nodes at surgery. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
SECONDARY ENDPOINTS
1. 3-year EFS and OS of patients treated with only T-DXd and trastuzumab. EFS is defined as time from registration to disease recurrence, progression or death from any cause. OS is defined as the time from registration to date of death from any cause, censored at date last known to be alive for those who have not died.
2. 3-year EFS and OS of patients treated with systemic therapy other than trastuzumab in addition to T-DXd.
3. 3-year EFS and OS of the entire study population.
4. 3-year EFS and OS difference between patients achieving vs not achieving pCR at surgery.
5. Molecular evolution of tumours during treatment.
6. Percentage of patients who achieve pCR after 4 cycles of T-DXd.
7. The sensitivity and specificity for prediction of pCR of RDI and imaging and tomosynthesis biopsy alone and in combination.
EXPLORATORY ENDPOINTS
1. The potential application of computer vision-based technologies for the analysis of recently removed breast tumour tissue and evaluate the potential efficacy of these technologies for detecting cancerous cells and performing a margin assessment.
2. The composition of the gut microbiome (GM) before and after neoadjuvant treatment and any association between the GM and the pathological response at the time of surgery.
3. The utility of Tumour-Infiltrating Lymphocytes (TILs) as a biomarker of response to T-DXd in early stage HER2-positive breast cancer. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
| 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 | Yes |
| 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) | 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) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | Information not present in EudraCT |
| 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | |
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