Evaluation of Neratinib for Treatment and Prevention of Subsequent CNS Event(s) in Patients With Brain Metastasis of Advanced HER2 Positive Breast Cancer

Study Purpose

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).

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Interventional
Eligible Ages	18 Years and Over
Gender	Female

More Inclusion & Exclusion Criteria

Inclusion Criteria:

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. 11. Adequate bone marrow function as defined below:

- Absolute neutrophil count ≥1500/µL or 1.5x109/L.

- Hemoglobin ≥ 9 g/dL.

- Platelets ≥100000/µL or 100x109/L.

12. Adequate liver function as defined below:

- Serum total bilirubin ≤ 1.5 x ULN.

In case of known Gilbert's syndrome < 3 x ULN is allowed.

- AST (SGOT)/ALT (SGPT) ≤ 2.5 x ULN (except in case of liver metastases AST/ALT ≤ 5 x ULN) 13.

Adequate renal function as defined below: • Creatinine ≤ 1.5 x UNL or creatinine clearance >60 mL/min. 14. Signed Informed Consent form (ICF) obtained prior to any study related procedure. 15. LVEF > 55% Inclusion criterion applicable to FRANCE only 1)16) Affiliated to the French Social Security System.

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. 11. Pregnant and/or lactating women. 12. Subject with a significant medical, neuro-psychiatric, or surgical condition, currently uncontrolled by treatment, which, in the principal investigator's opinion, may interfere with completion of the study. 13. Contra-indication for contrast-enhanced MRI (either hypersensitivity to Gd chelate or absolute contra-indication for MRI such as non compatible cardiac stimulator) * Testing of subjects for DPD deficiency in case of capecitabine is proposed according to local practices Exclusion criterion applicable to FRANCE only Vulnerable persons according to the article L.1121-6 of the Public Health Code, adults who are the subject of a measure of legal protection or unable to express their consent according to article L.1121-8 of the Public Health Code

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT04856475
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.	Phase 2
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	Jules Bordet Institute
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	Nuria Kotecki, MD
Principal Investigator Affiliation	Jules Bordet Institute
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Other
Overall Status	Not yet recruiting
Countries
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Breast Cancer, Brain Metastases

Arms & Interventions

Arms

Experimental: HER2 metastatic breast cancer locally pretreated for previous CNS events and currently progressive

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).

Experimental: HER2 positive metastatic breast cancer patients with newly diagnosed brain metastases

Experimental: HER2 positive metastatic breast cancer patients with leptomeningeal carcinomatosis

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).

Interventions

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)