Kadcyla In pAtients With bRAin Metastasis (KIARA)

This is an interventional treatment trial for Metastatic HER2-positive Breast Cancer With Brain Metastasis Read More

Inclusion Criteria:

Participants must meet all these criteria in order to be eligible for the study:

General Criteria:

• Female patients (≥ 18 years);
• Histologically confirmed HER2-positive breast cancer patients (IHC 3+ and/or ISH positive);
• 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;
• At least one measurable brain metastasis as defined by RECIST 1.1 (≥ 10 mm);
• Any hormone receptor status;
• Predicted life expectancy > 3 months;
• Any previous anti-HER2 therapies are allowed, other than T-DM1;
• ECOG performance score 0-2;
• No significant cardiac history and a current LVEF ≥ 50%. LVEF should be determined within 21 days before enrolment;

• Adequate organ function, evidenced by the following laboratory results. Exams 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-filgrastrim, 7 days for regular filgrastrim).
  • 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 (INR) and activated partial thromboplastin time or partial thromboplastin time < 1.5 ULN unless patient receiving anticoagulant therapy
• 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
• Signed informed consent obtained before any study-specific procedure;
• Able and willing to comply with the protocol; including the willingness to provide samples (primary if available and blood) for translational research.

Cohort 1 additional specific criteria:

• No corticosteroids at enrolment
• Oligosymptomatic or asymptomatic brain metastases not requiring immediate local therapy.

Cohort 2 additional specific criteria:

• 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.
• Decreasing corticosteroid dose or stable dose for at least one week prior to enrolment

Exclusion Criteria:

Patients who exhibit any of the following conditions at screening will be ineligible for admission into the study:

General Criteria:

• Single brain metastasis with indication of surgical resection
• Pregnant or breast-feeding women
• Documented leptomeningeal disease
• Having received any investigational therapy within ≤ 28 days or 5 half-lives at ICF signature, whichever is longer
• Having received hormonal therapy within 14 days of enrolment
• Having received trastuzumab within 21 days of enrolment
• Prior enrolment in a T-DM1-containing study, regardless of whether the patient received T-DM1 or not
• History of intolerance (including Grade 3 or 4 infusion reaction) or hypersensitivity to trastuzumab or murine proteins or any component of the product.
• Current peripheral neuropathy of Grade ≥ 3 according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v.4.0.3
• 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.
• Current unstable ventricular arrhythmia requiring treatment.
• 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.
• Current dyspnoea at rest due to complications of advanced malignancy or currently requiring continuous oxygen therapy.
• Current severe, uncontrolled systemic disease other than cancer (e.g., clinically significant pulmonary, hypertension or metabolic disease)
• Concurrent, serious, uncontrolled infections or current known infection with HIV, active hepatitis B and/or hepatitis C.
• 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.
• Known contraindications for undergoing MRI or CT, including to receive contrast media,

Cohort 1 : additional specific criteria:

• Previous neurosurgery or radiotherapy (radiosurgery, stereotactic radiotherapy, whole brain radiotherapy) to the brain Cohort 2 : no additional specific criteria