Phase 2 Trial of Neoadjuvant Trastuzumab Deruxtecan in Early Stage HER2-Positive Breast Cancer with Response-Directed Therapy
- Trial ID
- 2024-516582-36-00
- Protocol
- CTRIAL‐IE-22‐01
- Sponsor
- Cancer Trials Ireland
Trial statistics
Objectives
The primary objective of this study is to evaluate the efficacy of **trastuzumab deruxtecan (T-DXd)** in the neoadjuvant treatment of early stage **HER2-positive breast cancer**. The primary endpoint is the achievement of imaging complete response (iCR) after 4 cycles of treatment. This is clinically relevant as achieving iCR can be indicative of a favorable response to treatment, potentially leading to improved surgical outcomes and long-term prognosis.
Secondary objectives include:
- Determining the event-free survival (EFS) and overall survival (OS) of patients treated with T-DXd and adjuvant trastuzumab, as well as those receiving systemic therapy other than adjuvant trastuzumab.
- Comparing EFS and OS between patients achieving versus not achieving pathological complete response (pCR) at surgery, and by relative dose intensity (RDI) score.
- Assessing the percentage of patients achieving iCR and pCR after 4 or 8 cycles of treatment, and by RDI score.
- Studying the molecular evolution of tumors during treatment and developing a biomarker panel to optimize pCR prediction.
- Exploring performance metrics for predicting non-pCR/pCR using RDI, imaging, and tomosynthesis biopsy.
- Assessing the safety and tolerability of T-DXd and THP treatment.
- Investigating the application of computer vision-based technologies for analyzing breast tumor tissue and evaluating their efficacy in detecting cancerous cells and performing margin assessments.
- Assessing the gut microbiome composition before and after neoadjuvant treatment and its association with pathological response at surgery.
- Investigating the utility of tumor-infiltrating lymphocytes (TILs) as a biomarker of response to T-DXd in early stage HER2-positive breast cancer.
Participants
The clinical trial involves participants diagnosed with **early stage HER2-positive breast cancer**. The study population includes both adult women and men aged 18 years and older. Participants are required to have adequate laboratory values, including specific thresholds for absolute neutrophil count, platelet count, hemoglobin, liver enzymes, bilirubin, serum albumin, and creatinine clearance. The trial does not involve a vulnerable population. Participants must have newly diagnosed breast cancer, planned for neoadjuvant therapy prior to surgery, and should not have received any prior therapy for breast cancer. The trial includes individuals with stages 2-3 breast cancer and requires a histologically confirmed HER2-positive status. Participants must have an ECOG performance status of 0-1 and a left ventricular ejection fraction of at least 50%. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet, physical activity, or habits are not specified. Key inclusion criteria include the willingness to undergo mandatory tumor biopsy and the availability of archival tumor biopsy tissue at screening. The trial population was selected based on these criteria, ensuring a focus on individuals who meet the specific health and diagnostic requirements for the study.
Plans and Procedures
The clinical trial is designed as a **single-arm phase 2 study** to evaluate the efficacy of **trastuzumab deruxtecan (T-DXd)** in the neoadjuvant treatment of early-stage **HER2-positive breast cancer**. The primary objective is to assess the imaging complete response (iCR) after four cycles of T-DXd treatment, with the aim of avoiding standard cytotoxic chemotherapy. The trial is expected to commence recruitment on October 26, 2023, and conclude by November 30, 2026. Participants will be involved in the study for a maximum treatment period of 12 weeks, with the possibility of early termination if they do not meet the inclusion criteria or if adverse events occur.
Study visits are structured to ensure comprehensive monitoring and data collection. The initial inclusion visit involves screening to confirm eligibility based on criteria such as age, laboratory values, and histologically confirmed HER2-positive breast cancer. Participants will undergo mandatory tumor biopsies at specific intervals, including Cycle 2 Day 14, to assess treatment response. Follow-up visits will occur regularly to monitor safety, efficacy, and any adverse events. The end-of-study visit will evaluate the overall treatment outcomes and collect final data on efficacy and safety.
Participants are expected to adhere to the study protocol, including the use of effective contraception methods for both male and female participants, as outlined in the eligibility criteria. Conditions that may lead to early termination from the study include failure to achieve the required laboratory values, non-compliance with study procedures, or the occurrence of significant adverse events. The trial will utilize intravenous administration of the investigational product, with the primary endpoint being the percentage of patients achieving iCR after four cycles of T-DXd treatment. Secondary endpoints include 3-year event-free survival (EFS) and overall survival (OS) metrics, as well as the evaluation of safety and tolerability according to the NCI Common Terminology Criteria for Adverse Events (CTCAE version 5.0).
Treatment
The clinical trial involves the administration of several experimental medications, each with specific characteristics and administration protocols. **Paclitaxel**, marketed as "Paclitaxel 6 mg/ml concentrate for solution for infusion," is a **novel antimicrotubule agent** provided in a concentrate form for solution for infusion. It is administered intravenously with a maximum daily dose of 80 mg/m² and a total maximum dose of 960 mg/m² over a treatment period of up to 84 days. The pharmaceutical form is a solution for infusion, and the product is manufactured by Accord Healthcare Ireland Limited.
**Pertuzumab**, known commercially as "Perjeta 420 mg concentrate for solution for infusion," is a **humanised IgG1 monoclonal antibody**. This medication is also administered intravenously, with a maximum daily dose of 840 mg and a total maximum dose of 2100 mg over a treatment period of up to 84 days. The pharmaceutical form is a solution for infusion, and the product is manufactured by Roche Registration GmbH.
**Trastuzumab deruxtecan**, referred to as "DS-8201a," is a **HER2 targeted antibody and topoisomerase I inhibitor conjugate**. It is provided as a solution for infusion and administered intravenously. The dosing regimen includes a maximum daily dose of 5.4 mg/kg and a total maximum dose of 21.6 mg/kg over a treatment period of up to 12 weeks. The product is manufactured by Daiichi Sankyo, Inc.
**Trastuzumab**, marketed as "Herceptin 150 mg powder for concentrate for solution for infusion," is another **humanised IgG1 monoclonal antibody**. It is administered intravenously, with a maximum daily dose of 8 mg/kg and a total maximum dose of 26 mg/kg over a treatment period of up to 84 days. The pharmaceutical form is a solution for infusion, and the product is manufactured by Roche Registration GmbH.
All medications are administered intravenously, and participant compliance is monitored throughout the trial. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. The focus is on evaluating the efficacy of these experimental medications in the treatment of early-stage HER2-positive breast cancer.
Efficacy
The efficacy of the investigational treatment in this clinical trial will be assessed using the primary endpoint of imaging complete response (**iCR**) after 4 cycles of treatment with trastuzumab deruxtecan (T-DXd) in patients with early-stage HER2-positive breast cancer. The iCR is defined as the resolution of all previously described suspicious abnormalities. This endpoint will determine the percentage of patients who achieve iCR and thus avoid standard cytotoxic chemotherapy.
Secondary endpoints include the evaluation of 3-year event-free survival (EFS) and overall survival (OS) of patients treated with T-DXd and adjuvant trastuzumab, as well as those treated with systemic therapy other than adjuvant trastuzumab. EFS is defined as the time from registration to disease recurrence, progression, or death from any cause, while OS is defined as the time from registration to the date of death from any cause. Additional secondary endpoints involve the assessment of the percentage of patients achieving pathological complete response (pCR) at surgery, the molecular evolution of tumors during treatment, and the utility of Tumor-Infiltrating Lymphocytes (TILs) as a biomarker of response to T-DXd.
The trial will also explore the performance metrics of the Residual Disease Index (RDI) Score, imaging, and tomosynthesis biopsy in predicting non-pCR/pCR, as well as the potential application of computer vision-based technologies for analyzing breast tumor tissue. The composition of the gut microbiome before and after neoadjuvant treatment and its association with pathological response at surgery will be evaluated. Safety and tolerability will be assessed by the incidence of adverse events and toxicity evaluation according to the NCI Common Terminology Criteria for Adverse Events (CTCAE version 5.0).
Inclusion and Exclusion Criteria
Inclusion Criteria
- Adult women and men ≥ 18 years of age.
- Histologically confirmed HER2-positive breast cancer: o Documented HER2 overexpression by local laboratory (IHC 3+ or positive by ISH on diagnostic breast biopsy (as defined in 2018 American Society of Clinical Oncology – College of American Pathologists [ASCO-CAP] guidelines)).
- Newly diagnosed breast cancer, planned for neoadjuvant therapy prior to surgery.
- Stages 2-3 breast cancer.
- Patients should not have received any prior therapy for breast cancer.
- Patients must be willing to undergo mandatory tumour biopsy at Cycle 2 Day 14 (+/- 4 days) and (if applicable) at Cycle 5 Day 14-21.
- ECOG performance status 0-1.
- Availability of archival tumour biopsy tissue at screening.
- Left ventricular ejection fraction (LVEF) ≥ 50%, as determined by ECHO or MUGA.
- Adequate laboratory values collected no more than 14 days before registration. All parameters must meet the inclusion criteria on the same day, and must be the most recent results available: o Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L (granulocyte-colony stimulating factor administration is not allowed within 1 week prior to C1D1) o Platelet count ≥ 100 x 109/L (Platelet transfusion is not allowed within 1 week prior to C1D1) o Haemoglobin ≥ 9.0 g/dL. NOTE: Participants requiring ongoing transfusions or growth factor support to maintain haemoglobin ≥9.0 g/dL are not eligible (Red blood cell transfusion is not allowed within 1 week prior to C1D1). 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 (using actual body weight) (refer to Appendix C). o Prothrombin time and either partial thromboplastin or activated partial thromboplastin time ≤ 1.5 × ULN.
- 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.
- Women of childbearing potential must agree to use a highly effective method of contraception according to current HMA CTFG guideline when sexually active. This applies from signing of the informed consent form until at least 7 months after the last IMP administration. The investigator or a designated associate is required to advise the patient how to achieve an adequate birth control. Highly effective contraception is defined in the study as methods that achieve a failure rate of less than 1% per year when used consistently and correctly. 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.
- 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. In addition, 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. Preservation of sperm should be considered prior to enrollment in this study.
- 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. Preservation of ova may be considered prior to enrollment in this study.
Exclusion Criteria
- Known metastatic or stage 4 breast cancer.
- 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.
- Corrected QT interval (QTcF) prolongation to >470 msec (females) or >450 msec (males) based on the screening 12-lead ECG.
- Uncontrolled arterial hypertension despite optimal medical management (per investigator’s opinion).
- 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.
- Non-healing wound, ulcer, or bone fracture.
- Active, clinically serious infections > CTCAE Grade 2 (CTCAE v5.0) requiring IV antibiotics, antivirals, or antifungals.
- 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.
- Active primary immunodeficiency, known human immunodeficiency virus (HIV) infection, or active hepatitis B (HBV) or C (HCV) infection. Patients positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Patients with current active or history of hepatitis B infection with either HBsAg(+) or anti-HBc(+) are not eligible.
- 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.
- 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)
- 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.
- Pregnant or breast-feeding female patients, or patients who are planning to become pregnant.
- Concomitant use of prohibited medications (refer to section 7.6.3: Prohibited Concomitant Medications and Treatments).
- Known hypersensitivity to the test drug, test drug class, or excipients in the formulation.
- History of severe hypersensitivity reactions to other monoclonal antibodies.
- Substance abuse, medical, psychological or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results.
- Any illness or medical conditions that are unstable or could jeopardize the safety of patients and their compliance in the study.
- 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
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Ireland | Recruiting | 26 Oct 2023 | 77 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Herceptin 150 mg powder for concentrate for solution for infusion | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 8 | 84 | PRD2154035 |
DS-8201a | Test | SOLUTION FOR INFUSION | INTRAVENOUS | 5.4 | 12 | PRD5308994 |
Perjeta 420 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 840 | 84 | PRD2154581 |
Paclitaxel 6 mg/ml concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 80 | 84 | PRD7723262 |