HER2-positive breast cancer. 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
Product Name: Trastuzumab deruxtecan
Product Code: DS-8201, DS-8201a
Pharmaceutical Form: Powder for concentrate for solution for infusion
INN or Proposed INN: Trastuzumab deruxtecan
Other descriptive
Sponsors
Cancer Trials Ireland
Eligibility
Sex/Gender
All
Inclusion criteria
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 ovulatio
Exclusion criteria
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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.;Secondary Objective: 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.;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.;Timepoint(s) of evaluation of this end point: End of trial. | — |
Secondary
| Measure | Time frame |
|---|---|
| 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.;Timepoint(s) of evaluation of this end point: End of trial. | — |
Countries
Ireland
Contacts
Public ContactHead of Clinical Operations
Cancer Trials Ireland
Outcome results
None listed