TRASTUZUMAB DERUXTECAN for HER2-positive early breast cancer

Inclusion criteria

• {"criterion_text":"- 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)"}
• {"criterion_text":"- Female subjects must not donate, or retrieve for their own use, ova from the time of randomisation and throughout the study treatment period, and for at least 7 months after the final study drug administration. (refer to protocol for detailed information)"}
• {"criterion_text":"- Age ≥18 years"}
• {"criterion_text":"- a) Cohort 1: low- to intermediate-risk for recurrence as per investigator´s decision (recommendation: cT1c – cT2 (1 - ≤3cm) and cN0; cT1a/b, cN0 is excluded!), OR b) Cohort 2: intermediate- to high-risk for recurrence as per investigator´s decision (recommendation: cT2 (>3 - ≤5cm), cN0) c) Cohort 3: intermediate- to high-risk for recurrence as per investigator´s decision, (recommendation: clinical stage II (cT2, cN0); cT1c, cN0 only if neoadjuvant treatment intended)"}
• {"criterion_text":"- Written informed consent"}
• {"criterion_text":"- LVEF ≥ 50% within 28 days before randomisation"}
• {"criterion_text":"- Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1"}
• {"criterion_text":"- 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, • haemoglobin ≥ 9.0 g/dL: • estimated glomerular filtration rate (eGFR) ≥ 30 mL/min by a Cockcroft-Gault formula, • INR ≤ 1.5, • serum creatinine < 1.5 mg/dL, • total bilirubin < 1.5 ULN, except for patients with Gilbert’s Syndrome who may only be included if the total bilirubin is ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN, • aspartate transaminase (AST) < 2.5 × ULN, • alanine transaminase (ALT) < 2.5 × ULN."}
• {"criterion_text":"- Adequate treatment washout period before randomisation (refer to protocol for detailed information)"}
• {"criterion_text":"- Evidence of post-menopausal status or negative serum pregnancy test for females of childbearing potential (refer to protocol for detailed information). Post-menopausal status is accepted for women, who at the time of initiation of study medication, either • had underwent bilateral oophorectomy, or • are ≥ 60 years of age, or • are < 60 years of age and amenorrhoeic for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifen, or ovarian suppression) • and/or whose FSH- and oestradiol-blood values are within the postmenopausal range per local laboratory normal range."}

Exclusion criteria

• {"criterion_text":"- Non-operable breast cancer including inflammatory breast cancer"}
• {"criterion_text":"- 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."}
• {"criterion_text":"- Use of oral (oestrogen and progesterone), transdermal, injected, or implanted hormonal methods of contraception as well as hormonal replacement therapy."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- Corrected QT interval (QTcF) prolongation to > 470 msec (females) based on average of the screening 12-lead ECG."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- Lung criteria: o Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder o 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. o Prior pneumonectomy (complete) Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals"}
• {"criterion_text":"- 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)."}
• {"criterion_text":"- 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 vaccine during the study and up to 30 days after the last dose of IMP."}
• {"criterion_text":"- Known allergy or hypersensitivity to study treatment (T-DXd), to comparator (SoC-) treatment, or any of the study drug / comparator (SoC-) excipients."}
• {"criterion_text":"- cT1a/b, cN0 breast cancer"}
• {"criterion_text":"- History of severe hypersensitivity reactions to other monoclonal antibodies."}
• {"criterion_text":"- Pregnant or breastfeeding female patients, or patients who are planning to become pregnant."}
• {"criterion_text":"- Any previous history of invasive breast cancer"}
• {"criterion_text":"- Primary malignancies within 5 years, with the exception of • adequately resected non-melanoma skin cancer • curatively treated in-situ disease"}
• {"criterion_text":"- Any evidence for existing metastatic disease (confirmed by CT Thorax/Abdomen, bone scan, or other methods according to clinical practice"}
• {"criterion_text":"- Previous or concurrent treatment with cytotoxic agents for any reason (except non-oncological reasons)"}
• {"criterion_text":"- Concurrent treatment with other experimental drugs and participation in another clinical trial with any investigational drug within 30 days prior to study entry"}
• {"criterion_text":"- Severe and relevant co-morbidity that would interact with the application of cytotoxic agents or the participation in the study/inadequate organ function"}
• {"criterion_text":"- Reasons indicating risk of poor compliance"}

Primary endpoints

• {"endpoint_text":"- Proportion of patients with adverse drug reactions with CTCAE-grade 3 or higher, compared between patients treated with T-DXd neoadjuvant monotherapy for 18 weeks (part 1, cohort 2) and patients treated with SoC for 18 weeks (part 1 and 2, cohorts 2 and 3 pooled) H0: proportion in T-DXd 18 weeks (part 1, cohort 2) = proportion in SoC 18 weeks (part 1 and 2, cohorts 2 and 3 pooled) H1:proportion in T-DXd 18 weeks (part1,cohort 2)≠proportion in SoC 18weeks (part1 and 2, cohorts 2 and 3 pooled)","definition_or_measurement_approach":"Proportion of patients with adverse drug reactions graded CTCAE grade 3 or higher; comparison between treatment groups as described (statistical null and alternative hypotheses provided)."}
• {"endpoint_text":"- 3-year dDFS (according to STEEP 2.0 criteria36) in patients with TDXd neoadjuvant monotherapy (pooled experimental treatment arms of part 1, pooled cohorts 1 and 2) H0: 3-year dDFS rate in the T-DXd pool (part 1, pooled cohorts 1 and 2) < 92.0% H1: 3-year dDFS rate in the T-DXd pool (part 1, pooled cohorts 1 and 2) ≥ 92.0%","definition_or_measurement_approach":"3-year distant disease-free survival (dDFS) assessed according to STEEP 2.0 criteria; hypothesis test versus threshold of 92%."}
• {"endpoint_text":"- 3-year dDFS (according to STEEP 2.0 criteria36) in patients with TDXd neoadjuvant therapy followed by CHT (pooled experimental treatment arms of part 2, cohort 3) H0: 3-year dDFS rate in the T-DXd - CHT pool (part 2, cohort 3) < 92.0% H1: 3-year dDFS rate in the T-DXd - CHT pool (part 2, cohort 3) ≥ 92.0%","definition_or_measurement_approach":"3-year dDFS per STEEP 2.0 criteria in the T-DXd followed by chemotherapy pool; hypothesis test versus 92% threshold."}
• {"endpoint_text":"- Prespecified endpoint for part 1 (pooled cohorts 1 and 2): pCR (defined as ypTis/ypN0) rate, compared between patients treated with T-DXd neoadjuvant monotherapy (pooled experimental treatment arms of part 1, pooled cohorts 1 and 2) compared to patients of corresponding standard-of-care treatments (DOC/PAC+T+P or DOC/PAC+Carbo+T+P) (pooled SoC treatment arms of part1, pooled cohorts1and2) H0:pCR T-DXd=pCR SoC in part1 (pooled cohorts1and2) H1:pCR T-DXd≠pCR SoC in part1 (pooled cohorts1and2)","definition_or_measurement_approach":"Pathologic complete response (pCR) defined as ypTis/ypN0; comparison of pCR rates between pooled T-DXd monotherapy arms and pooled SoC arms."}

Secondary endpoints

• {"endpoint_text":"- 3-year dDFS (according to STEEP 2.0 criteria36) compared between patients treated with T-DXd neoadjuvant monotherapy for a different time and different following therapies (the 4 specific compared treatment could not be enter here due to lack of space. Please see protocol for complete and detailed information)","definition_or_measurement_approach":"3-year dDFS per STEEP 2.0 criteria; comparison across different durations and subsequent therapies as specified in protocol."}
• {"endpoint_text":"- 3-year dDFS in patients with pCR after neoadjuvant treatment without further chemotherapy: It should be tested whether 3-year dDFS exceeds 93% (literature data)","definition_or_measurement_approach":"3-year dDFS in subset of patients with pCR and no further chemotherapy; hypothesis test versus 93% (literature benchmark)."}
• {"endpoint_text":"- 3-year dDFS in patients treated with neoadjuvant T-DXd: It should be tested whether 3-year dDFS of each arm exceeds 92% (literature data)","definition_or_measurement_approach":"3-year dDFS per arm with threshold test versus 92%."}
• {"endpoint_text":"- pCR (defined as ypTis/ypN0) rates compared between patients treated with T-DXd neoadjuvant monotherapy for a different time and different following therapies (the 4 specific compared treatments could not be entered here due to lack of space. Please see protocol for complete and detailed information)","definition_or_measurement_approach":"pCR (ypTis/ypN0) rate comparisons across different T-DXd durations and subsequent therapies as specified in protocol."}
• {"endpoint_text":"- Proportion of patients with clinical response at 6, 12 and 24 weeks of neoadjuvant treatment compared between T-DXd treated patients and SoC treated patients as stated above","definition_or_measurement_approach":"Clinical response rates assessed at weeks 6, 12 and 24 comparing T-DXd and SoC."}
• {"endpoint_text":"- Further 3-year survival endpoints according to STEEP 2.0 criteria (iDFS, OS, LRFS, BCFS, DRFI) to be compared between T-DXd treated patients and SoC treated patients as stated above","definition_or_measurement_approach":"Additional 3-year survival endpoints (iDFS, OS, LRFS, BCFS, DRFI) assessed per STEEP 2.0 criteria and compared between treatment groups."}

Germany

Earliest CTIS Part Ii Submission Date

02-08-2024

Latest Decision Or Authorization Date

11-05-2026

Processing Time Days

648

Number Of Sites

68

Number Of Participants

705

Primary sponsor

Full Name

WSG Westdeutsche Studiengruppe GmbH

Organisation Type

Pharmaceutical company

Country Of Registered Address

Germany

Third parties

• {"country":"Germany","full_name":"Fisher Clinical Services GmbH","duties_or_roles":"code:14","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Universitätsklinikum Bonn, Studienzentrum Bonn","duties_or_roles":"code:8","organisation_type":"Health care"}
• {"country":"Sweden","full_name":"Viedoc Technologies AB","duties_or_roles":"code:7","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Germany","full_name":"Medizinische Hochschule Hannover","duties_or_roles":"code:4","organisation_type":"Educational Institution"}
• {"country":"Germany","full_name":"Hannover Unified Biobank","duties_or_roles":"code:15; Future Biomedical Research","organisation_type":"Health care"}