A Phase 2 interventional study of Neratinib in Breast Cancer and Brain Metastases, sponsored by Jules Bordet Institute. Withdrawn. Open to female participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2022-03-02.
Sponsored by Jules Bordet Institute · Phase 2, Interventional, and Treatment
This is an open-label, non-randomised, phase II study to evaluate the efficacy of neratinib in combination with SOC systemic therapy on CNS metastasis both as for secondary prevention (cohort 1), primary treatment (cohort 2) and for the treatment of LM disease (cohort 3) in subjects with HER2 positive metastatic BC.
Subjects with metastatic HER2 positive breast cancer will be eligible for the trial and will be enrolled in one of the following cohorts:
Cohort 1: Eligible subjects include HER2 positive metastatic breast cancer subjects treated with at least one line of systemic anti HER2 therapy and pre-treated with local approaches at least for the previous CNS event and currently progressive but locally treated CNS metastasis. Local therapy includes: stereotactic radiosurgery (SRS) or/and WBRT or/and surgery.
The study will measure the effect of the drug combination on the time to next CNS event(s).
Cohort 2: Eligible subjects include HER2 positive metastatic breast cancer subjects treated with at least one line of systemic anti HER2 therapy or progressing less than 12 months after end of adjuvant therapy with a first diagnosis of brain metastases.
The study will measure the objective CNS response in each subject.
Cohort 3: Eligible subjects include HER2 positive metastatic breast cancer subjects treated with at least one line of systemic anti HER2 therapy with confirmed LM defined as the presence of malignant cells in the cerebrospinal fluid (CSF) or combination of typical symptoms and MRI.
The study will measure the effect of the drug combination on the time to CNS progression including LM progression.
As per investigator's choice, eligible subjects in all cohort will receive neratinib in combination with capecitabine or with T-DM1 or with paclitaxel or with vinorelbine as per investigator's choice. Trastuzumab can be added as per investigator's choice to those regimens except for T-DM1.
At screening and during the study treatment period (every 9 weeks), brain MRI for cohort 1 and cohort 2 or contrast-enhanced neuraxis brain and spine MRI for cohort 3 and tumour assessment by thoracic and abdomino-pelvic CT scan for all cohorts should be performed. For cohort 3 only, CSF cytological assessment should also be performed.
Additionally, at screening and at each cycle during the study treatment period, subjects must fill quality of life questionnaires: EORTC core questionnaire (QLQ-C30) and brain module (QLQ-BN20).
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Adequate bone marrow function as defined below:
Adequate liver function as defined below:
Adequate renal function as defined below:
Exclusion Criteria:
Eligible subjects will receive neratinib in combination with capecitabine or with T-DM1 or with paclitaxel or with vinorelbine as per investigator's choice. Trastuzumab can be added as per investigator's choice to those regimens except for T-DM1. At screening and during the study treatment period (every 9 weeks), brain MRI and tumour assessment by thoracic and abdomino-pelvic CT scan should be performed. Additionally, at screening and at each cycle during the study treatment period, subjects must fill quality of life questionnaires: EORTC core questionnaire (QLQ-C30) and brain module (QLQ-BN20).
Drug: Neratinib
Eligible subjects will receive neratinib in combination with capecitabine or with T-DM1 or with paclitaxel or with vinorelbine as per investigator's choice. Trastuzumab can be added as per investigator's choice to those regimens except for T-DM1. At screening and during the study treatment period (every 9 weeks), brain MRI and tumour assessment by thoracic and abdomino-pelvic CT scan should be performed. Additionally, at screening and at each cycle during the study treatment period, subjects must fill quality of life questionnaires: EORTC core questionnaire (QLQ-C30) and brain module (QLQ-BN20).
Drug: Neratinib
Eligible subjects will receive neratinib in combination with capecitabine or with T-DM1 or with paclitaxel or with vinorelbine as per investigator's choice. Trastuzumab can be added as per investigator's choice to those regimens except for T-DM1. At screening and during the study treatment period (every 9 weeks), contrast-enhanced neuraxis brain and spine MRI and tumour assessment by thoracic and abdomino-pelvic CT scan should be performed. CSF cytological assessment should also be performed. Additionally, at screening and at each cycle during the study treatment period, subjects must fill quality of life questionnaires: EORTC core questionnaire (QLQ-C30) and brain module (QLQ-BN20).
Drug: Neratinib
As per investigator's choice, eligible subjects in all cohort will receive: * Neratinib, administered continuously at a dose of 240 mg orally once a day in combination with: * Capecitabine, administered continuously at a dose of 750 mg/m2, orally, twice a day (=daily dose of 1500 mg/m2) from D1 toD14 (21 days cycle) (preferred option) or * Vinorelbine, I.V. 25 mg/m2 on D1 and D8 (21 days cycle) or * Paclitaxel, I.V. 80 mg/m2 on D1, D8, and D15 (21 days cycle) Important note: The possibility to combine trastuzumab, loading dose 8 mg/kg IV followed by 6 mg/kg Q3W IV or SC 600 mg Q3W, to one of these above treatments is left at investigator's discretion OR * Neratinib, administered continuously at a dose of 160 mg, orally, once a day in combination with: * T-DM1, I.V. 3.6mg/m2 on D1 (21 days cycle) (preferred option)
For cohort1: 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
The efficacy will be assessed by calculating 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
Time frame: From date of enrolment until the date of subsequent documented CNS event, assessed up to 6 months
For cohort 2: Efficacy of neratinib in combination with systemic treatment at investigator's choice on previously untreated brain metastasis from HER2 metastatic breast cancer
The efficacy will be assessed by calculating the 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).
Time frame: From date of enrolment until the date of first documented CNS event, assessed up to 6 months
For cohort 3: Efficacy of neratinib in combination with systemic treatment at investigator's choice on LM disease from HER2 metastatic breast cancer
The efficacy will be assessed by measuring 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.
Time frame: From date of enrolment until the date of first documented leptomeningeal progression or date of death from any cause, whichever came first, assessed up to 6 months
Efficacy of neratinib in combination with systemic treatment according to investigator's choice on brain metastasis
Occurrence of new brain metastases according to RECIST 1.1
Time frame: From date of enrolment until the date of next documented progression or date of death from any cause, whichever came first, assessed up to 6 months
For cohort 2 only: Evaluation of the time to the first CNS local treatment
Mesure of the time to the first CNS local treatment
Time frame: From date of enrolment until the date of first documented CNS event, assessed up to 6 months
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)
Mesure of the time to whole brain radiotherapy (WBRT)
Time frame: From date of enrolment until the date of next documented progression or date of death from any cause, whichever came first, assessed up to 6 months
Safety of neratinib
Evaluation of the adverse events
Time frame: Assessed up to 6 months
Evaluation of the overall survival (OS)
Mesure of the number of overall survival
Time frame: up to 2 years
Brain, systemic and bi-comportemental efficacy
Mesure of Clinical Benefit (CB) according to RANO-BM criteria and RECIST 1.1
Time frame: Through study completion, up to 2 years
Brain, systemic and bi-comportemental efficacy
Mesure of Objective Response Rate (ORR) - including intracranial ORR according to RANO-BM criteria and RECIST 1.1
Time frame: Through study completion, up to 2 years
Brain, systemic and bi-comportemental efficacy
Mesure of Best Response (BR) according to RANO-BM criteria and RECIST 1.1
Time frame: Through study completion, up to 2 years
Brain, systemic and bi-comportemental efficacy
Mesure of CNS Progression-Free survival according to RANO-BM criteria and RECIST 1.1
Time frame: Through study completion, up to 2 years
Brain, systemic and bi-comportemental efficacy
Mesure of Extra CNS Progression-Free survival. Assessment of extra-CNS lesions will use the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
Time frame: Through study completion, up to 2 years
Brain, systemic and bi-comportemental efficacy
Mesure of overall Progression-Free Survival (PFS) according to RANO-BM criteria and RECIST 1.1
Time frame: Through study completion, up to 2 years
Brain, systemic and bi-comportemental efficacy
Mesure of Duration of Response (DoR) according to RANO-BM criteria and RECIST 1.1
Time frame: Through study completion, up to 2 years
Brain, systemic and bi-comportemental efficacy
Mesure of Duration of Clinical Benefit (DCB) according to RANO-BM criteria and RECIST 1.1
Time frame: Through study completion, up to 2 years
Assessment of the quality of life
Analysis of Quality of life questionnaire "EORTC QLQ-C30"
Time frame: Assessed up to 6 months
Assessment of the quality of life
Analysis of Quality of life questionnaire "Brain module QLQ-BN20"
Time frame: Assessed up to 6 months
No study locations are listed for this record.
Plan to share: Undecided
No publications or documents are linked to this record.
This study is withdrawn, as verified in Jun 2021. You cannot join it, but the record below documents what was studied.
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Jules Bordet Institute