trastuzumab deruxtecan for Early breast cancer | HER2-positive early breast cancer | HER2-low early breast cancer

Inclusion criteria

• {"criterion_text":"- Written informed consent for all study procedures according to local regulatory requirements prior to beginning specific protocol procedures.\n- Left ventricular ejection fraction (LVEF) ≥50% within 28 days prior to randomization\n- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at Screening\n- 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.\n- Adequate treatment washout period before treatment with trastuzumab deruxtecan (in case of randomization into cohort A)\n- 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.\n- 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.\n- Females or males, ≥ 18 years and ≤ 75 years of age.\n- 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.\n- Complete resection of the tumor with resection margins free of invasive carcinoma (R0).\n- Participation in the SURVIVE study and evidence of molecular relapse (as assessed based on a positive ctDNA result obtained in the SURVIVE-study)\n- 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).\n- Completion of surgery, (neo-)adjuvant chemotherapy (if applicable) and radiation therapy (if applicable, whichever occurred last) at least 6 months before randomization.\n- 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.\n- 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"}

Exclusion criteria

• {"criterion_text":"- Stage IV (metastatic) breast cancer\n- 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).\n- 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)\n- 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.\n- 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.\n- 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)\n- Known allergy or hypersensitivity to study treatment or any of the study drug excipients.\n- History of severe hypersensitivity reactions to other monoclonal antibodies.\n- Pregnant or breastfeeding female patients, or patients who are planning to become pregnant.\n- 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\n- Prior treatment with T-DXd.\n- Combination of T-Dxd with any other anti-cancer treatment is not permitted, except for endocrine therapy.\n- 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.\n- 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.\n- Corrected QT interval (QTcF) prolongation to > 470 msec (females) or > 450 msec (males) based on average of the screening triplicate12-lead ECG.\n- 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.\n- Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals"}

Primary endpoints

• {"endpoint_text":"- ctDNA clearance rate is defined as the proportion of patients with a ctDNA negative blood test result at a given time point","definition_or_measurement_approach":"ctDNA clearance rate is defined as the proportion of patients with a ctDNA negative blood test result at a given time point"}

Secondary endpoints

• {"endpoint_text":"- OS is defined as time from randomization until death from any cause. If a patient is not known to have died, OS is censored at the date of last contact.","definition_or_measurement_approach":"Time from randomization until death from any cause; censored at date of last contact if death not known."}
• {"endpoint_text":"- IDFS is defined as time from randomization until first IDFS event, including any invasive ipsilateral, regional, contralateral, and distant disease recurrence, second primary tumors, or death from any cause as event (non-invasive, in-situ cancer events are excluded). If a patient has not had an event, IDFS is censored at the date of last adequate tumor assessment. In addition to median IDFS, the 24 months IDFS rate will be calculated.","definition_or_measurement_approach":"Time from randomization until first invasive disease-free survival (IDFS) event as defined; censored at last adequate tumor assessment if no event. 24-month IDFS rate will be calculated."}
• {"endpoint_text":"- DDFS is defined as time from randomization until first DDFS event including metastasis, second primary tumors and death from any cause as event. If a patient has not had an event, DDFS is censored at the date of last adequate tumor assessment.","definition_or_measurement_approach":"Time from randomization until first distant disease-free survival (DDFS) event including metastasis, second primary tumors, or death; censored at last tumor assessment if no event."}
• {"endpoint_text":"- DRFS is defined as time from randomization until first DRFS event including metastasis and second primary tumors; death from any cause is not included as event. If a patient has not had an event, DRFS is censored at the date of last adequate tumor assessment. If a patient has died, DRFS is censored at the date of death.","definition_or_measurement_approach":"Time from randomization until first distant recurrence-free survival (DRFS) event (metastasis or second primary); death not an event (censoring rules apply as stated)."}
• {"endpoint_text":"- BCSS is defined as time from randomization until breast cancer associated death of the patient. If a patient is not known to have died, BCSS is censored at the date of last contact. If a patient has died for reasons not associated with breast cancer (by clinical assessment), BCSS is censored at the date of death.","definition_or_measurement_approach":"Time from randomization until death due to breast cancer; censoring rules as specified."}
• {"endpoint_text":"- IBCFS is defined as time from randomization until first IBCFS event, including any invasive ipsilateral, regional, contralateral and distant disease recurrence or death from any cause as event (non-invasive, in-situ cancer events and second primary tumors are excluded). If a patient has not had an event, IBCFS is censored at the date of last adequate tumor assessment.","definition_or_measurement_approach":"Time from randomization until first invasive breast cancer-free survival (IBCFS) event as defined; censored at last adequate tumor assessment if no event."}
• {"endpoint_text":"- ctDNA clearance rate is defined as the proportion of patients with a ctDNA negative blood test result at a given time point.","definition_or_measurement_approach":"Proportion of patients with ctDNA negative blood test result at specified time points (3,6,9,12,15,18,21,24 months also listed in secondary objectives)."}
• {"endpoint_text":"- QoL will be monitored and assessed in both groups using the two questionnaires EORTC QLQ-C30 and PA-F12, which must be completed before infusion of cycle 1 and at 3, 6, 9, 12, 15, 18, and 24 months after randomization.","definition_or_measurement_approach":"Quality of life measured using EORTC QLQ-C30 and PA-F12 at specified time points pre-treatment and at 3,6,9,12,15,18,24 months."}
• {"endpoint_text":"- Safety and tolerability of study treatments will be assessed based on the frequencies and grades of serious adverse events (SAEs) and adverse events (AEs) during the course of the study. AE of special interest will include ILD, CHF and left ventricular dysfunction.","definition_or_measurement_approach":"Assessment based on frequencies and grades of SAEs and AEs; AEs of special interest include ILD, CHF and left ventricular dysfunction."}

Germany

Earliest CTIS Part Ii Submission Date

25-11-2024

Latest Decision Or Authorization Date

07-04-2026

Processing Time Days

498

Number Of Sites

27

Number Of Participants

180

Primary sponsor

Full Name

Universitaetsklinikum Ulm AöR

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Germany

Third parties

• {"country":"","full_name":"Astra Zeneca GmbH","duties_or_roles":"Source of monetary support","organisation_type":""}
• {"country":"","full_name":"DAIICHI SANKYO EUROPE GMBH","duties_or_roles":"Named organisation in product dictionary for investigational product (Enhertu)","organisation_type":""}