This is a multicentre, non-randomised, open label, single arm, phase II study of T-DM1 in patients with metastatic breast cancer and with brain metastasis who have already failed at least one line of anti-HER2 therapy for systemic disease. The study sample is composed of 2 distinct cohorts of patients.
Cohort number 1 is composed of patients with asymptomatic or oligosymptomatic brain metastasis (single or multiple), measurable according to RECIST 1.1, who have not received any local therapy (neither surgery, radiosurgery nor whole brain radiotherapy) for brain metastasis.
Cohort number 2 is composed of patients with brain metastasis (single or multiple), measurable according to RECIST 1.1, previously treated with local therapy (surgery, radiosurgery or whole brain radiotherapy) and with radiologically confirmed brain progression, with a minimum period of 3 months between the end of local therapy and brain progression.
A total number of 110 are planned for screening, in order to enrol 97 patients. A minimum of 87 evaluable patients is necessary. Inclusion of patients in both cohorts will follow a two-stage Simon optimal design. During the study, both brain assessments via magnetic-resonance imaging (MRI) and systemic assessments with computerised tomography (CT) will be performed every 3 cycles (9 weeks) of therapy.
Study treatment consists of T-DM1, 3.6 mg/kg every 3 weeks. Patients will receive study medication until unacceptable toxicity, voluntary withdrawal from study treatment, disease progression, death or pregnancy, whichever occurs first. Patients who experience only progression in the brain and who receive local therapy may remain in the study until systemic progression (or any of the other reasons stated previously), at the investigator's discretion.
After the end of study treatment, all patients will have a safety visit within 30 days (+/- 7 days) from the last T-DM1 administration date. After the safety visit, according the reason of end of study treatment, the follow-up period will begin, as described below:
* If study treatment stopped due to progression of disease Patients will enter directly in survival follow-up. No visits are mandatory per protocol after the safety visit. Chart review and/or phone call to check if the patient is still alive are to be performed, every 6 months, in order to acquire data for the overall survival endpoint. Patients in survival follow-up who are of childbearing potential must be tested for pregnancy at 3 months and at 7 months after end of study treatment. These tests can be ordered by the investigator during regular out of study follow-up visits.
* If study treatment stopped for any other reason than progression (either toxicity or voluntary withdrawal from study treatment) Patients will enter first in efficacy follow-up after the safety visit and then in survival follow-up when progression disease is observed.
During efficacy follow-up, 9 weekly efficacy assessments continue according to the same timetable they would have followed had treatment interruption not occurred. This consists of imaging assessments (MRI and CT) and medical visits, as well as QoL evaluations. During this period, treatment is at the discretion of the local physician/investigator.
This follow-up is to continue until disease progression or until voluntary withdrawal of the patient from the study. In case this follow-up is impossible (due to patient refusing to perform assessments or other reasons), survival data can be collected every 6 months via chart review or telephone. Patients in follow-up who are of childbearing potential must be tested for pregnancy at 3 months and at 7 months after end of study treatment. Once a patient has progressed while on efficacy follow-up, they will enter into survival follow-up as per description above.
