HER2 positive breast cancer patients with brain metastases MedDRA version: 20.0 Level: LLT Classification code 10027475 Term: Metastatic breast cancer System Organ Class: 100000004864
Conditions
Sponsors
Institut Jules Bordet
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Subjects must meet all of the following criteria in order to be eligible for this study: 1) Age = 18 years old 2) ECOG performance status = 2 3) Female 4) Diagnosis : histologically or cytologically confirmed HER2-positive tumour status according to the ASCO-CAP guidelines (defined as a 3+ score on immunohistochemistry (IHC) and/or positive by in situ hybridisation (ISH)) with brain metastases, estrogen receptor and progesteron receptor status Cohort 1: with CNS metastases pre-treated with local approaches for the previous CNS events and currently progressive but locally treated CNS metastasis Cohort 2: with a first diagnosis of CNS metastases, asymptomatic or paucisymptomatic not needing immediate local therapy Cohort 3: with confirmed LM defined as the presence of malignant cells in the CSF or combination of typical symptoms and MRI findings 5) Specific criteria for cohorts 1 and 2 only: Must have radiologically confirmed metastatic brain lesion by MRI measurable by RANO-BM criteria 6) Specific criteria for cohort 3 only: LM defined as the presence of malignant cells in the CSF or combination of typical symptoms and MRI findings for cohort 3 7) Subjects should have received at least 1 previous line for the metastatic disease including taxanes based chemotherapy in combination with trastuzumab and pertuzumab (if available) unless contraindicated. Prior tucatinib is not an exclusion criteria. 8) Corticosteroids may be used as long as subjects are on a stable or decreasing dose for at least 7 days prior to study enrolment 9) Serum pregnancy test (for subjects of childbearing potential) negative within 7 days prior to first neratinib administration 10) Women of childbearing potential must agree to use 1 highly effective or 2 effective methods of contraception (as defined at the protocol section 6.8.1) during the course of the study and at least 7 months after the last administration of study treatment. 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 for this age range 75 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 50
Exclusion criteria
Exclusion criteria: 1) CNS disease requiring immediate neurosurgical intervention (e.g. resection, shunt placement, etc.) 2) Any unresolved toxicity = CTCAE grade 2 (except alopecia) from previous anti-cancer therapy 3) Is ineligible for or has already received all chemotherapy options among the physician’s choice 4) Any evidence of severe or uncontrolled systemic disease such as clinically significant cardiovascular, pulmonary, hepatic, renal or metabolic disease 5) Specific criteria for cohort 2 only: Previous local treatment for CNS metastases 6) Specific criteria for cohort 2 only: Oligometastatic disease restricted to the CNS and for which a local treated is considered as the most appropriate treatment by the investigator. 7) Known DPD deficiency* tested by measuring the level of uracil in the blood, or by checking for the presence of certain mutations in the gene for DPD according to EMA recommendation in case investigator’s choice is capecitabine 8) Received an investigational anti-cancer drug within four weeks or five half-lives (whichever is shorter) of study drug administration 9) Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of drugs 10) Known HIV, Hepatitis B or Hepatitis C infection
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: • Cohort 1: To investigate the efficacy of neratinib in combination with systemic treatment at investigator’s choice in preventing the next CNS event in HER2 breast cancer with known and treated brain metastasis according to Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. A CNS event occurring in a subject is defined as a disease evolution in the brain and/or leptomeninges (progression of existing lesions and/or new CNS lesions). • Cohort 2: To investigate the efficacy of neratinib in combination with systemic treatment at investigator’s choice on previously untreated brain metastasis from HER2+ metastatic breast cancer (mBC) according to RANO-BM criteria (objective response rate). • Cohort 3: To investigate the efficacy of neratinib in combination with systemic treatment at investigator’s choice on LM disease from HER2+mBC defined according to clinical-neurological or imaging criteria. ;Secondary Objective: • To investigate the efficacy of neratinib in combination with systemic treatment according to investigator’s choice on brain metastasis according to RECIST 1.1 • To evaluate time to the first CNS local treatment (cohort 2 only) • To investigate the efficacy of neratinib in delaying the time to whole brain radiotherapy (WBRT) in HER2 breast cancer with known brain metastasis (for subject not previously submitted to WBRT) • To evaluate the safety of the agent neratinib in those specific populations • To evaluate overall survival (OS) • To evaluate the following efficacy parameters, in brain and systemic and bi-compartmental (as applicable). Assessment of extra-CNS lesions will use the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; assessment of CNS metastases will use the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM). ;Primary end point(s): • Cohort 1: The ratio of the time to the subsequent CNS event (T2) according to RANO-BM criteria to the time between the current CNS | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Primary endpoints: • Cohort 1: The ratio of the time to the subsequent CNS event (T2) according to RANO-BM criteria to the time between the current CNS event and previous CNS event (T1) both treated locally (T2/T1). The subsequent CNS event is defined as progression of known and treated brain lesions as well as the development of new brain lesions as assessed on magnetic resonance imaging (MRI) using the RANO-BM criteria. The time to a subsequent CNS event is defined as the time from treatment start of a CNS event to the occurrence of the following one for both T1 and T2 • Cohort 2: Proportion of subjects with an objective CNS response, according to RANO-BM criteria in the absence of progressive extra-CNS disease (according to RECIST 1.1). • Cohort 3: CNS progression-free survival defined as the time between treatment start and date of first leptomeningeal progression (defined according to clinical-neurological or imaging criteria) in the absence of progressive extra-CNS disease (according to RECIST 1.1) or date of death (death from any cause) whatever occurs first. Secondary endpoints: • Occurrence of new brain metastases. • Time to WBRT • Time to the first CNS local treatment (cohort 2) • Adverse events • Overall survival (OS) • Following efficacy parameters, in brain and systemic and bi-compartmental (as applicable) according to RANO-BM criteria and RECIST 1.1: o Clinical Benefit (CB) o Objective Response Rate (ORR) – including intracranial ORR o Best Response (BR) o CNS Progression-Free survival o Extra CNS Progression-Free survival o Overall Progression-Free Survival (PFS) o Duration of Response (DoR) o Duration of Clinical Benefit (DCB) o Quality of life (EORTC QLQ-C30, Brain module QLQ-BN20) ;Timepoint(s) of evaluation of this end point: end of trial | — |
Countries
Belgium, France, Serbia
Contacts
Public ContactCTSU
Institut Jules Bordet
Outcome results
None listed