Randomized Study of Trastuzumab Deruxtecan Versus Standard of Care in HER2-Positive or HER2-Low Early Breast Cancer with Molecular Relapse
- Trial ID
- 2024-516173-76-01
- Protocol
- ESR-22-21837
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the **circulating tumor DNA (ctDNA)** clearance rate twelve months after randomization between patients with HER2-positive or HER2-low early breast cancer receiving Trastuzumab-Deruxtecan versus those receiving standard of care therapy. This objective is clinically relevant as ctDNA clearance is a potential biomarker for treatment efficacy and could provide insights into the effectiveness of the experimental treatment in achieving molecular remission.
Secondary objectives include:
- Comparing overall survival (OS) between the experimental arm and the standard of care arm.
- Comparing invasive disease-free survival (IDFS) between the two arms.
- Comparing distant disease-free survival (DDFS) between the two arms.
- Comparing distant recurrence-free survival (DRFS) between the two arms.
- Comparing breast cancer-specific survival (BCSS) between the two arms.
- Comparing invasive breast cancer-free survival (IBCFS) between the two arms.
- Comparing ctDNA clearance rate at multiple time points (3, 6, 9, 15, 18, 21, and 24 months) post-randomization between the two arms.
- Comparing quality of life (QoL) between the two arms.
- Assessing safety and tolerability of Trastuzumab-Deruxtecan and comparing it between the two arms.
These secondary objectives aim to provide a comprehensive evaluation of the treatment's impact on survival outcomes, disease progression, quality of life, and safety, which are critical factors in determining the overall benefit of the experimental therapy for patients with early breast cancer experiencing molecular relapse.
Participants
The clinical trial involves participants diagnosed with **HER2-positive** or **HER2-low early breast cancer**. The study population includes both male and female subjects aged between 18 and 75 years. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial does not specify the total number of participants, as this information was not provided by the sponsor. The selection criteria include individuals who have completed surgery, (neo-)adjuvant chemotherapy, and radiation therapy at least six months prior to randomization, with no evidence of metastatic relapse. Participants must have adequate organ and bone marrow function and a left ventricular ejection fraction of at least 50%. Lifestyle considerations such as diet and physical activity are not detailed in the available data. The trial includes a vulnerable population, but specific details regarding this aspect are not disclosed. The study requires participants to have completed the SURVIVE study and show evidence of molecular relapse, as indicated by a positive ctDNA result. The trial population is selected based on these criteria, ensuring a focus on individuals with specific medical and treatment histories relevant to the study's objectives.
Plans and Procedures
The clinical trial is designed as a **randomized**, double-blind, controlled study to evaluate the efficacy of **trastuzumab deruxtecan** in patients with **HER2-positive** or **HER2-low early breast cancer**. The primary objective is to compare the **ctDNA clearance rate** twelve months after randomization between patients receiving trastuzumab deruxtecan and those receiving standard of care therapy. The trial is expected to last until October 2031, with recruitment starting in October 2024. Participants will be involved in the study for a maximum treatment period of 365 days, with the possibility of early termination if specific conditions arise, such as adverse events or withdrawal of consent.
The sequence of study visits begins with an inclusion (screening) visit, where eligibility criteria are assessed, including a **left ventricular ejection fraction** of ≥50%, an **ECOG performance status** of 0 or 1, and adequate organ and bone marrow function. Following randomization, participants will undergo regular follow-up visits to monitor treatment response and safety, with assessments including **ctDNA** testing, imaging studies, and quality of life evaluations using the EORTC QLQ-C30 and PA-F12 questionnaires. These assessments will occur at baseline and at 3, 6, 9, 12, 15, 18, and 24 months post-randomization. The end-of-study visit will conclude the participant's involvement, ensuring all necessary data is collected and any ongoing safety concerns are addressed.
Participants may be withdrawn from the study if they experience significant adverse events, fail to comply with study procedures, or choose to withdraw consent. The trial will adhere to strict ethical guidelines, ensuring informed consent is obtained from all participants prior to any study-related procedures. The study drug, **Enhertu 100 mg powder for concentrate for solution for infusion**, will be administered via **intravenous infusion**. The trial will not include pediatric formulations, and the maximum daily dose is set at 5.4 mg/kg. The study aims to provide valuable insights into the treatment of early breast cancer, with a focus on improving patient outcomes through innovative therapeutic approaches.
Treatment
The clinical trial involves the administration of **Enhertu**, a pharmaceutical product containing the active substance **trastuzumab deruxtecan**. This medication is provided in the form of a **powder for concentrate for solution for infusion**. The product is manufactured by Daiichi Sankyo Europe GmbH and is identified by the marketing authorization number EU/1/20/1508/001. The active substance, trastuzumab deruxtecan, is a protein-based compound, specifically categorized under "Protein - Other". The medication is administered via **intravenous infusion**. The dosing regimen for this trial specifies a maximum daily dose of 5.4 mg/kg, with the same amount being the maximum total dose per administration. The treatment period is set for a maximum of 365 days. The product is labeled as a study drug for the purposes of this trial.
In addition to the experimental treatment, the study includes a comparator treatment, which is the standard-of-care (SOC) therapy. The SOC therapy serves as a control to evaluate the efficacy of the experimental medication. The trial aims to compare the ctDNA clearance rate twelve months after randomization between patients receiving trastuzumab deruxtecan and those receiving the SOC therapy. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment protocol.
Efficacy
Efficacy in the clinical trial will be assessed primarily through the **ctDNA clearance rate**, which is defined as the proportion of patients with a ctDNA negative blood test result at a given time point. This primary endpoint will be evaluated twelve months after randomization. Secondary endpoints include overall survival (OS), invasive disease-free survival (IDFS), distant disease-free survival (DDFS), distant recurrence-free survival (DRFS), breast cancer-specific survival (BCSS), and invasive breast cancer-free survival (IBCFS). These endpoints will be measured from the time of randomization until the occurrence of specific events such as disease recurrence, second primary tumors, or death, with censoring at the date of last adequate tumor assessment or last contact if no event has occurred.
Quality of life (QoL) will be monitored using the EORTC QLQ-C30 and PA-F12 questionnaires, which participants will complete before the infusion of cycle 1 and at 3, 6, 9, 12, 15, 18, and 24 months post-randomization. Safety and tolerability will be assessed by recording the frequencies and grades of serious adverse events (SAEs) and adverse events (AEs), with particular attention to adverse events of special interest such as interstitial lung disease (ILD), congestive heart failure (CHF), and left ventricular dysfunction. The data collection and analysis will adhere to the predefined schedule and methodologies to ensure the reliability and validity of the efficacy assessments.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Written informed consent for all study procedures according to local regulatory requirements prior to beginning specific protocol procedures.
- Females or males, ≥ 18 years and ≤ 75 years of age.
- Invasive breast carcinoma as revealed by local pathology that is either: a. HER2-positive defined as an immunohistochemistry (IHC) score of 3+ and/or positive by in situ hybridization (ISH) in Her2 2+ tumors (as defined in 2018 American Society of Clinical Oncology – College of American Pathologists [ASCO-CAP] guidelines) b. HER2-low defined as an immunohistochemistry (IHC) score of 1+ or an IHC score of 2+ with a mandatory negative in situ hybridization (ISH), as defined in 2018 American Society of Clinical Oncology – College of American Pathologists [ASCO-CAP] guidelines.
- Complete resection of the tumor with resection margins free of invasive carcinoma (R0).
- Participation in the SURVIVE study and evidence of molecular relapse (as assessed based on a positive ctDNA result obtained in the SURVIVE-study)
- No evidence of metastatic relapse as revealed by a CT-scan (Abdomen/Chest) and a SPECT bone scan that must be performed within 8 weeks before randomization (M0).
- Completion of surgery, (neo-)adjuvant chemotherapy (if applicable) and radiation therapy (if applicable, whichever occurred last) at least 6 months before randomization.
- Adjuvant/Postneoadjuvant treatment with Trastuzumab, Pertuzumab, TDM1, Capecitabine, Pembrolizumab, and Olaparib must be discontinued upon randomization into Arm A (treatment with trastuzumab deruxtecan). The washout periods (see Table 2) must be complied with. Endocrine therapy (i.e. Tamoxifen, Letrozol, Anastrozol, Fulvestrant or Exemestane) can be administered simultaneously to treatment with trastuzumab deruxtecan.
- Known HR status, per local laboratory assessment, as defined by ASCO-CAP guidelines (≥1%): HR-positive status defined by either positive estrogen receptor (ER) and/or positive progesterone receptor (PR) status. HRnegative status defined by both known negative ER and known negative PR
- Left ventricular ejection fraction (LVEF) ≥50% within 28 days prior to randomization
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at Screening
- Adequate organ and bone marrow function within 28 days before randomization as described in the table below. Organ and bone marrow function criteria must also be met when laboratory tests are repeated within 3 days before Cycle 1 Day 1. Transfusion (red blood cell or platelet) or G-CSF administration is not allowed within 2 weeks prior to the day on which marrow function is assessed.
- Adequate treatment washout period before treatment with trastuzumab deruxtecan (in case of randomization into cohort A)
- Female subjects: 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 (test must have a sensitivity of at least 25 mIU/mL) must be available at the screening visit and urine betahuman chorionic gonadotropin (β-HCG) pregnancy test prior to each administration of Investigational Medicinal Product (IMP). a. Women of childbearing potential are defined as those who are not surgically sterile (underwent bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or post-menopausal. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. b. Female patients of childbearing potential who are sexually active with a non-sterilized male partner must use at least one highly effective method of contraception (see 5.5.1.) from the time of screening and must agree to continue using such precautions for 7 months after the last dose of IMP. Not all methods of contraception are highly effective. Female patients must refrain from breastfeeding while on study and for 7 months after the last dose of IMP. Complete heterosexual abstinence for the duration of the study and drug washout period is an acceptable contraceptive method if it is 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. c. Female subjects must not donate, or retrieve for their own use, ova from the time of randomization and throughout the study treatment period, and for at least 7 months after the final study drug administration. They should refrain from breastfeeding throughout this time. Preservation of ova may be considered prior to enrollment in this study.
- Male subjects: 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, as described in section 5.5.1. In addition, male patients should refrain from fathering a child, or freezing or donating sperm from the time of randomization/enrolment, throughout the study and for 4 months after the last dose of IMP. Preservation of sperm should be considered prior to enrolment in this study.
Exclusion Criteria
- Stage IV (metastatic) breast cancer
- Patients with a history of any secondary primary malignancy are ineligible with the following exceptions: - ipsi- or contralateral non-invasive carcinoma of the breast (DCIS) - other, curatively treated in-situ disease - adequately treated non-melanoma carcinoma of the skin
- Prior treatment with T-DXd.
- Combination of T-Dxd with any other anti-cancer treatment is not permitted, except for endocrine therapy.
- 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.
- Patients with a medical history of myocardial infarction (MI) within 6 months before first exposure to study intervention, 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 enrollment to rule out MI.
- Corrected QT interval (QTcF) prolongation to > 470 msec (females) or > 450 msec (males) based on average of the screening triplicate12-lead ECG.
- History of (non-infectious) Interstitial lung disease (ILD) / pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
- Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals
- Active primary immunodeficiency, known uncontrolled active 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. Subjects should be tested for HIV prior to randomization/enrolment if required by local regulations or institutional review board (IRB)/ethics committee (EC).
- Lung criteria: a. Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (for example pulmonary emboli within three months of the study enrollment, severe asthma, severe COPD, restrictive lung disease, pleural effusion etc.) b. Any autoimmune, connective tissue or inflammatory disorders (for example Rheumatoid arthritis, Sjogren's, sarcoidosis et cetera) 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 electronic case report form (eCRF) for patients who are included in the study. c. Prior pneumonectomy (complete)
- Participants with past or resolved HBV infection are eligible only if they meet all of the following criteria: · HBsAg (-) (for > 6 months off anti-viral treatment), · Anti-HBc (+) (IgG or total Ig), · HBV DNA undetectable, · Liver architecture normal (absence of any liver pathology including absence of cirrhosis or fibrosis on prior imaging or biopsy, · Absence of HCV co-infection or history of HCV co-infection. · Access to a local Hepatitis B expert during and after the study. Such participants should be closely monitored for HBV reactivation.
- 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 T-Dxd. Note: Patients, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of IMP.
- Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤ 1 or baseline. Note: Toxicities related to endocrine therapy should be documented but does not lead to exclusion of patient from the study. Also, subjects may be enrolled with chronic, stable Grade 2 toxicities (defined as no worsening to >Grade 2 for at least 3 months prior to first exposure to study intervention and managed with standard of care treatment) that the investigator deems related to previous anticancer therapy, such as: a. Chemotherapy-induced neuropathy b. Fatigue c. Residual toxicities from prior immune-oncology treatment: Grade 1 or Grade 2 endocrinopathies which may include: i. Hypothyroidism/hyperthyroidism ii. Type 1 diabetes iii. Hyperglycaemia iv. Adrenal insufficiency v. Adrenalitis vi. Skin hypopigmentation (vitiligo)
- Known allergy or hypersensitivity to study treatment or any of the study drug excipients.
- History of severe hypersensitivity reactions to other monoclonal antibodies.
- Pregnant or breastfeeding female patients, or patients who are planning to become pregnant.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Recruiting | 21 Oct 2024 | 180 |
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 |
|---|---|---|---|---|---|---|
Enhertu 100 mg powder for concentrate for solution for infusion | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 5.4 | 365 | PRD8681525 |