Metastatic HER2-positive breast cancer with brain metastasis MedDRA version: 20.0 Level: PT Classification code 10065430 Term: HER-2 positive breast cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 20.0 Level: LLT Classification code 10027475 Term: Metastatic breast cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: Kadcycla
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Trastuzumab emtansine
CAS Number: 1018448-65-1
Other descriptive name: TRASTUZUMAB EMTANSINE
Conc
Sponsors
Institut Jules Bordet
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Female patients (= 18 years); 2. Histologically confirmed HER2-positive metastatic breast cancer patients (IHC 3+ and/or ISH positive) according to ASCO guidelines for HER2 testing49; 3. Patients should have previously received trastuzumab and a taxane, separately or in combination. Patients should have either received prior therapy for locally advanced or metastatic disease, or developed disease recurrence during or within six months of completing adjuvant therapy; 4. At least one measurable brain metastasis as defined by RECIST 1.1 (= 10 mm); 5. Any hormone receptor status; 6. Predicted life expectancy > 3 months; 7. Any previous anti-HER2 therapies are allowed, other than T-DM1; 8. ECOG performance score 0-2; 9. No significant cardiac history and a current LVEF = 50%. LVEF should be determined within 21 days before enrolment; 10. Adequate organ function, evidenced by the following laboratory results. These are to be performed at a maximum of 7 days before enrolment: Absolute neutrophil count > 1,500 cells/mm3 without growth factor support (14 days after last peg-filgrastim, 7 days for regular filgrastim), Platelet count > 100,000 cells/mm3 without transfusion 2 weeks prior assessment, Hemoglobin > 9 g/dL without transfusion 2 weeks prior assessment, Aspartate aminotransferase and alanine aminotransferase < 2.5 x upper limit of normal (ULN), Total bilirubin = 1.5 x ULN unless the patient has documented Gilbert’s syndrome, in which case direct (conjugated) bilirubin level needs to be within normal limits, Serum alkaline phosphatase = 2.5 x ULN. Patients with bone metastases: alkaline phosphatase = 5 x ULN, Serum creatinine < 2.0 mg/dL or < 177 µmol/L, International normalized ratio and activated partial thromboplastin time or partial thromboplastin time < 1.5 ULN unless patient receiving anticoagulant therapy; 11. For women of childbearing potential a serum pregnancy test will be done up to 7 days before enrolment (and it must be negative) and an agreement to use one highly-effective form of non-hormonal contraception (true abstinence, vasectomy,oophorectomy, /hysterectomy, IUD) or two effective forms of non-hormonal contraception (e.g., condoms plus spermicidal agent) at study entry (to be put in place within 2 weeks prior to enrolment), during the administration of T-DM1 and for 7 months after the last administration of T-DM1 will be obtained; 12. Signed informed consent obtained before any study-specific procedure; 13. Able and willing to comply with the protocol; including the willingness to provide samples (primary if available and blood) for translational research. Cohort 1 Specific Criteria: 14. No corticosteroids at enrolment for metastasis related symptoms (low dose (max 4mg dexamethasone or equivalent per day due to other comorbidities is acceptable) 15. Oligosymptomatic (defined as not requiring immediate intervention for symptom control) or asymptomatic brain metastases not requiring immediate local therapy. Cohort 2 Specific Criteria: 16. Radiologically confirmed brain progression after previous local therapy (neurosurgery, radiosurgery to the brain, stereotactic radiotherapy to the brain, or whole brain radiotherapy) with at least 3 months between end of local therapy and brain progression. 17. Decreasing corticosteroid dose or stable dose for at least one week prior to enrolment Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects fo
Exclusion criteria
Exclusion criteria: 1. Single brain metastasis with indication of surgical resection; 2. Pregnant or breast-feeding women; 3. Documented leptomeningeal disease; 4. Having received any investigational therapy within = 28 days or 5 half-lives prior to enrolment, whichever is longer; 5. Having received hormonal therapy within 14 days prior to enrolment; 6. Having received trastuzumab within 21 days prior to enrolment; 7. History of treatment with trastuzumab emtansine; 8. Prior enrolment in a T-DM1containing study, regardless of whether the patient received T-DM1 or not; 9. History of intolerance (including Grade 3 or 4 infusion reaction) or hypersensitivity to trastuzumab or murine proteins or any component of the investigational medicinal product; 10. Current peripheral neuropathy of Grade = 3 according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v.4.0.3; 11. History of other malignancy within the last 5 years, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, or other cancers with a similar outcome as those mentioned above; 12. Current unstable ventricular arrhythmia requiring treatment; 13. History of symptomatic congestive heart failure (CHF) (New York Heart Association [NYHA] Classes II-IV);History of myocardial infarction or unstable angina within 6 months prior to first study drug administration; 15. Current dyspnoea at rest due to complications of advanced malignancy or currently requiring continuous oxygen therapy; 16. Current severe, uncontrolled disease other than cancer (e.g., clinically significant pulmonary, hypertension or metabolic disease, among others); 17. Concurrent, serious, uncontrolled infections or current known infection with HIV, active hepatitis B and/or hepatitis C; 18. Major surgical procedure or significant traumatic injury within 28 days before enrolment or anticipation of the need for major surgery during the course of study treatment; 19. Known contraindications for undergoing MRI or CT, including receiving contrast media. Cohort 1 : Additional Specific Criteria 20. Previous neurosurgery or radiotherapy (including radiosurgery, stereotactic radiotherapy. or whole brain radiotherapy) to the brain. Cohort 2 : Additional Specific Criteria There are none.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective of this study is to evaluate the Clinical Benefit Rate (CBR) of T-DM1 in brain lesions of patients with HER2-positive breast cancer with brain metastasis according to RECIST 1.1 as determined by local investigators;Secondary Objective: This study has the following secondary objectives: 1. To evaluate the CBR in brain lesions of patients with HER2-positive breast cancer with brain metastasis according to RECIST 1.1 as determined by central review; 2. To evaluate the CBR in brain lesions of patients with HER2-positive breast cancer with brain metastasis according to RANO criteria as determined by local investigators; 3. To evaluate the safety and cardiac-specific safety of the agent T-DM1; 4. To evaluate the following efficacy parameters, in brain and systemic and bi-compartmental (as applicable) according to RANO criteria and RECIST 1.1: CBR, Overall Response Rate (ORR), Best Response (BR), PFS, DoR, Duration of Clinical Benefit (DCB) 5. To evaluate the Overall Survival (OS) of this specific population; 6. To assess the quality of life via multiple validated tools (EORTC core questionnaire (QLQ-C30) and brain module (QLQ-BN20)).;Primary end point(s): The primary endpoint of this study is the CB at first radiological assessment (after 3 cycles or earlier if clinically indicated), defined as complete response plus partial response plus stable disease in the brain, as measured by RECIST 1.1 and as determined by local investigators.;Timepoint(s) of evaluation of this end point: at first radiological assessment | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): The secondary endpoints of this study are: 1. CB in the brain as measured by RECIST 1.1 (see appendix 1), as determined by central review; 2. CB in the brain measured by RANO (see appendix 2) brain metastases criteria, as determined by local investigators; 3. General and cardiac-specific safety; Incidence, type and severity of all adverse events (AEs) and serious adverse events (SAEs) based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v4.03); Incidence and type of AEs leading to discontinuation, modification, or delay of T-DM1 dose; 4. The following additional efficacy parameters. All of them will be determined both by RANO and RECIST 1.1: CB: Systemic and bi-compartmental (see definition above), Overall Response (OR): defined as complete response plus partial response in: (1) brain, (2) systemically, (3) bi-compartmentally, Best Response (BR): in the brain, systemic and bi-compartmental defined as the best obtained response (be it PD, SD, PR or CR), among all imaging assessments, PFS: PFS defined as time between enrolment in the study and progression (systemic, brain and bi-compartmental) or death, DoR: defined as time from documentation of tumour response to in the brain (PR or CR) disease progression in the brain; systemic defined as time from documentation of non-brain tumour response (PR or CR) to non-brain progression, Bi-compartmental defined as time between response and progression, Duration of Clinical Benefit (DCB): is defined as the time elapsed between determination of SD, PR or CR and determination of disease progression; 5. OS defined as time between enrolment in the study and death 6. Quality of life (QoL).;Timepoint(s) of evaluation of this end point: As per protocol. | — |
Countries
Austria, Belgium
Contacts
Public ContactCTSU
Institut Jules Bordet
Outcome results
None listed