E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
HER2-positive Breast Cancer with newly diagnosed or progressing Brain Metastases |
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E.1.1.1 | Medical condition in easily understood language |
HER2-positive Breast Cancer with newly diagnosed or progressing Brain Metastases |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the ability of trastuzumab-deruxtecan to induce CNS responses in patients with HER2-positive breast cancer and newly diagnosed multiple brain metastases. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the activity of trastuzumab-deruxtecan on extracranial disease, safety and tolerability of trastuzumab-deruxtecan in the patient population and QoL of study subjects. Exploratory Objectives: To evaluate biomarkers associated with response to trastuzumab-deruxtecan.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Histologically confirmed breast cancer • Radiologically documented metastatic disease • HER2-positive as defined by IHC 3+ and/or HER2/neu gene amplification • Newly diagnosed brain metastases or brain metastases progressing after prior local therapy • Measurable disease (RANO-BM criteria) • No indication for immediate local treatment • No indication of leptomeningeal disease • KPS >70%, ECOG <2 • Indication for systemic anti-HER2 treatment • Prior exposure to trastuzumab and pertuzumab • Prior exposure to T-DM1 allowed • Life expectancy of at least 3 months • Age ≥18 years • Patient must be able to tolerate therapy, and have adequate cardiac function (defined by baseline left ventricular ejection fraction ≥50%) • Adequate bone-marrow, liver and kidney function • Adequate treatment washout period before enrolment, defined as: • Major Surgery: ≥4 weeks • Radiation therapy: ≥4 weeks • Chemotherapy, small-molecule targeted agents, anticancer hormonal therapy: ≥3 weeks • Antibody-based treatment: ≥4 weeks • Patient must be capable of understanding the purpose of the study and have given written informed consent
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E.4 | Principal exclusion criteria |
• Metastatic breast cancer other than HER2-positve disease • Use of any investigational agent within 28 days prior to initiation of treatment • History of malignancy other than squamous cell carcinoma, basal cell carcinoma of the skin or carcinoma in situ of the cervix within the last 3 years including contralateral breast cancer • Major surgery, other than diagnostic surgery, within the last 4 weeks • Indication for immediate local therapy by local standard • Leptomeningeal involvement • Other anticancer therapy, including cytotoxic, targeted agents, immunotherapy, antibody, retinoid, or anti-cancer hormonal treatment • Concomitant radiotherapy • Prior radiotherapy to the thorax other than breast irradiation or irradiation of bone metastases • A history of uncontrolled seizures, central nervous system disorders or psychiatric disability judged by the investigator to be clinically significant and adversely affecting compliance to study drugs • Clinically significant cardiac disease including unstable angina, acute myocardial infarction within six months prior to randomization, congestive heart failure (NYHA III-IV), left ventricular ejection fraction <50%, arrhythmia unless controlled by therapy, with the exception of extra systoles or minor conduction abnormalities, and long QT syndrome (QTc interval >450 ms) • Subjects who have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment) including acute and chronic infections with hepatitis B and C • Inadequate haematological status at baseline prior to study entry: Dependency on red blood cell and/or platelet transfusions, ANC (absolute neutrophil count (segmented + bands) <1.0 x 109/L; platelets <100 x 109/L • Inadequate kidney function: serum-creatinine >1.5 times upper normal limit • Hepatic dysfunction: total bilirubin >1.5 times upper normal limit (>3 in patients with liver metastases or known history of Gilbert’s disease); ALT, AST >3 times upper normal limit (>5 in patients with liver metastases); serum albumin <2.5 g/dL; INR ≥1.5 • Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (i.e. pulmonary emboli within three months of the study enrolment, severe asthma, severe COPD, restrictive lung disease, pleural effusion etc.), and any autoimmune, connective tissue or inflammatory disorders with potential pulmonary involvement (i.e. rheumatoid arthritis, Sjogren's syndrome, sarcoidosis etc.), or prior pneumonectomy • Subjects with bronchopulmonary disorders who require intermittent use of bronchodilators (such as albuterol) will not be excluded from this study • Patients with active opportunistic infections • Known HIV infection • Pregnant or lactating women. Women with childbearing potential must have a negative pregnancy test at screening • Women with childbearing potential, including women whose last menstrual period was less than one year prior to screening, unable or unwilling to use adequate contraception from study start to one year after the last dose of protocol therapy. Acceptable contraception methods included the application of an intrauterine device, barrier method or total abstinence • Male subjects unable or unwilling to use adequate contraception methods from study start to one year after the last dose of protocol therapy • Patients with known hypersensitivity to trastuzumab • Patients not able to provide written informed consent • Patients with known 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 requiring concomitant use of chronic systemic (IV or oral) corticosteroids at doses higher than 4 mg dexamethasone per day or other immunosuppressive medications except for managing adverse events; (inhaled steroids or intra articular steroid injections are permitted in this study)
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint of this study is the rate of best responses of BM at any assessment after the administration of at least one cycle of the IMP defined as CR, PR, SD and PD according to the RANO criteria and as determined by the local investigator. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
The secondary endpoints of this study consist of Clinical Benefit Rate CNS (CBR CNS; CR+PR+SD ≥6 months), extracranial response rate defines as CR, PR, SD and PD according to RECIST 1.1 criteria, progression-free survival defined as the interval from study inclusion until progression or death, time-to-WBRT defined as the interval from study inclusion until WBRT, overall survival defined as the interval from study inclusion until death, safety and QoL. Exploratory Endpoints: Exploratory endpoints of this study include the number of HER/neu gene copies and the rate of TILs. For ancillary biomarker studies, blood samples (3 ml EDTA, 3 ml serum) will be drawn before administration of the IMP at cycles 1 and 4 and at EOT.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |