HER2+ early breast cancer MedDRA version: 20.0 Level: LLT Classification code 10006192 Term: Breast cancer NOS System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 23.0 Level: PT Classification code 10065430 Term: HER2 positive breast cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Trade Name: Enhertu
Product Name: Trastuzumab-Deruxtecan (T-DXd)
Product Code: DS-8201a
Pharmaceutical Form: Powder for concentrate for solution for infusion
INN or Proposed INN: Trastuzumab deruxteca
Sponsors
Westdeutsche Studiengruppe GmbH
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Patients eligible for inclusion in this study must meet all the following criteria: 1. Female patients with invasive, untreated HER2+ breast cancer (as assessed by local pathology) maximum 6 weeks before registration (standard-of-care diagnostic biopsy according to current AGO guidelines) 2. Age =18 years 3a. Cohort 1: low- to intermediate-risk for recurrence as per investigator´s decision (recommendation: cT1c – cT2 (1 - =3cm) and cN0; cT1a/b, cNO is excluded), OR 3b. Cohort 2: intermediate- to high-risk for recurrence as per investigator´s decision (recommendation: cT2 (>3 - =5cm), cN0) 3c. Elderly patients (= 65 years) may be assigned to any cohort as per investigator’s decision 4. Written informed consent 5. LVEF = 50% within 28 days before randomisation 6. Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 7. Adequate bone marrow and organ function within 14 days before randomisation as defined by the following laboratory values: • absolute neutrophil count = 1.5 × 109/L, • platelets = 100 × 109/L, • hemoglobin = 9.0 g/dL: • estimated glomerular filtration rate (eGFR) = 30 mL/min by a Cockcroft-Gault formula, • INR = 1.5, • serum creatinine =65 years) yes F.1.3.1 Number of subjects for this age range 22
Exclusion criteria
Exclusion criteria: Patients eligible for inclusion in this study must not meet any of the following criteria: 1. Non-operable breast cancer including inflammatory breast cancer 2. cT1a/b, cN0 breast cancer 3. Any previous history of invasive breast cancer 4. Primary malignancies within 5 years, with the exception of • adequately resected non-melanoma skin cancer • curatively treated in-situ disease 5. Any evidence for existing metastatic disease (confirmed by CT Thorax/Abdomen, bone scan, or other methods according to clinical practice 6. Previous or concurrent treatment with cytotoxic agents for any reason (except non-oncological reasons) 7. Concurrent treatment with other experimental drugs and participation in another clinical trial with any investigational drug within 30 days prior to study entry 8. Severe and relevant co-morbidity that would interact with the application of cytotoxic agents or the participation in the study/inadequate organ function 9. Reasons indicating risk of poor compliance 10. Woman of child-bearing potential defined as a woman physiologically capable of becoming pregnant, and not using highly effective methods of contraception during the study treatment and for 7 months after stopping the treatment. 11. Use of oral (oestrogen and progesterone), transdermal, injected, or implanted hormonal methods of contraception as well as hormonal replacement therapy. 12. Has substance abuse or any other 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. 13. Patients with a medical history of myocardial infarction (MI) within 6 months before randomisation, symptomatic congestive heart failure (CHF) (New York Heart Association Class II to IV), Subjects with troponin levels above ULN at screening (as defined by the manufacturer), and without any myocardial related symptoms, should have a cardiologic consultation before enrolment to rule out MI. 14. Corrected QT interval (QTcF) prolongation to > 470 msec (females) or >450 msec (males) based on average of the screening triplicate12-lead ECG. 15. 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. 16. Lung criteria: - Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder - 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 randomisation. - Prior pneumonectomy (complete) Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals 17. 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. Patients should be tested for HIV prior to randomisation if required by local regulations or ethics committee (EC). 18. 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 or carboplatin. Note: Patients, if enrolled, should not receive live
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 1. The first co-primary objective of the study is the comparison of the pathologic complete response (pCR) rates after 12 or 18 weeks of neoadjuvant treatment with T-DXd versus standard-of-care (PAC+T+P or DOC/PAC+Carbo+T+P) in pooled risk cohorts 2. The second co-primary objective is to evaluate whether 3-year distant-disease-free survival equals or exceeds 92% in T-DXd treated patients from both risk cohorts.;Secondary Objective: Secondary objectives • To assess clinical response after 6, 12, and 18 (cohort 2) weeks of treatment • To assess 3-year dDFS in patients with pCR after neoadjuvant treatment without further chemotherapy • Comparison of pCR rates after different treatment durations (12 versus 18 weeks) of both treatments in pooled cohorts • Comparison of pCR rates in T-DXd 12 weeks versus PAC+T+P • Comparison of pCR rates in T-DXd18 weeks versus DOC/PAC+Carbo+T+P • Assessment of further survival endpoints according to STEEP 2.0 criteria: iDFS, OS, LRFS, BCFS • Assessment of health-related quality of life (EORTC-QLQ-C30, version 3.0, EORTC QLQ-BR45, version 1.0);Primary end point(s): Primary endpoints The two primary endpoints are as follows: 1. pCR rate after neoadjuvant treatment, defined as ypT0is/ypN0, to be compared between all T-DXd treated patients versus standard-of-care (PAC+T+P or DOC/PAC+Carbo+T+P) (pooled across cohorts) Hypotheses: H0: pCR T-DXd = pCR standard-of-care H1: pCR T-DXd ? pCR standard-of-care 2. 3-year distant disease-free survival (dDFS, according to STEEP 2.0 criteria) in T-DXd treated patients (pooled across cohorts) H0: 3-year dDFS rate in the T-DXd group < 92.0% H1: 3-year dDFS rate in the T-DXd group = 92.0%;Timepoint(s) of evaluation of this end point: 1. primary endpoint: - After 12 or 18 weeks of neoadjuvant treatment 2. primary endpoint: - After 3 years. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary endpoints • Clinical response after 6, 12, and 18 weeks of treatment by treatment and cohort • 3-year dDFS in patients with pCR after neoadjuvant treatment without further chemotherapy • pCR rates after different treatment durations (12 versus 18 weeks) to be compared by treatment in pooled cohorts • interaction between treatment arm and risk cohort • pCR rates in T-DXd12 weeks versus PAC+T+P in cohort 1 • pCR rates in T-DXd18 weeks versus DOC/PAC+Carbo+T+P in cohort 2 • STEEP 2.0 survival endpoints: - Invasive disease-free survival (IDFS) - Overall survival (OS) - Local recurrence-free survival (LRFS) - Breast cancer-free survival (BCFS) - Distant recurrence-free interval (DRFI) To be compared across T-DXd cohorts versus standard-of-care in pooled cohorts • Change of health-related quality of life between baseline and after 1 year;Timepoint(s) of evaluation of this end point: At defined visit points for each patient. A descriptive interim analysis of safety parameters will be performed after pCR assessment of the first 200 patients. The final analysis will be done after the study is closed. | — |
Countries
Germany
Contacts
Public ContactSenior Manager Regulatory
Westdeutsche Studiengruppe GmbH
Outcome results
None listed