HER2-positive breast cancer with brain metastasis
Conditions
Interventions
Product Name: Buparlisib
Product Code: BKM120
Pharmaceutical Form: Capsule
INN or Proposed INN: buparlisib
CAS Number: 944396-07-0
Sponsors
University of Liverpool
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: • Female 16 years or above • Histologically confirmed HER2-positive breast cancer (immunohistochemistry 3+ or fluorescence in situ hybridization with an amplification ratio =2.0) • Newly diagnosed brain metastasis • At least one brain metastasis measuring =2.5cm (to minimise partial volume effects in PET imaging and quantification) • Previous treatment with Trastuzumab with or without Pertuzumab either in the adjuvant or metastatic setting • Discussed with neuro-oncology MDT and considered a candidate for macroscopic resection • ECOG performance status 0 to 2 • Patient has adequate bone marrow and organ function as defined by the following laboratory values: o Absolute Neutrophil Count (ANC) > 1.0 x 109/L o Platelets (plt) >100 x 109/L o Haemoglobin (Hgb) = 9 g/dl o INR = 1.5 o Potassium, calcium (corrected for serum albumin) and magnesium within normal limits o Serum creatinine = 1.5 x ULN and/or creatinine clearance > 50% LLN o Alanine aminotransferase (AST) and aspartate aminotransferase (ALT) within normal range (or 50 % as determined echocardiogram • Life expectancy > 3 months • Ability to swallow and retain oral medication • Written informed consent, able to comply with treatment and follow up Are the trial subjects under 18? no Number of subjects for this age range: 0 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 24 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range 0
Exclusion criteria
Exclusion criteria: •Prior treatment with Lapatinib or other HER2-directed tyrosine kinase inhibitor (given such patients will have already received some form of local therapy) • Cystic brain metastasis with minimal solid component (defined on MRI) • Prior treatment with either a P13K or AKT inhibitor • Receiving treatment with other antineoplastic agents (except for HER2-directed monoclonal antibody therapy) • Treated with any hematopoietic colony-stimulating growth factors (e.g., G-CSF, GM-CSF) = 2 weeks prior to starting study drug. Erythropoietin or darbepoetin therapy, if initiated before enrollment, may be continued • Wide field radiotherapy = 4 weeks or limited field radiation for palliation = 2 weeks prior to starting study drug or who have not recovered to grade 1 or better from related side effects of such therapy (exceptions include alopecia, bone marrow and organ functions) • Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major side effects • Medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (e.g. risk of doing harm to self or others), or patients with active severe personality disorders (defined according to DSM- IV). For patients with psychotropic treatments ongoing at baseline, the dose and the schedule should not be modified within the previous 6 weeks prior to start of study drug. For patients receiving psychotropic treatments at baseline, the dose and the schedule should not be modified within the previous 6 weeks prior to start of study drug • GAD-7 mood scale = 15 • A score = 12 on the PHQ-9 questionnaire • Selection of response “1, 2 or 3” to question number 9 on the PHQ-9 questionnaire regarding potential for suicidal thoughts or ideation (independent of the total score of the PHQ-9) • CTCAE grade 3 anxiety •Patient has active cardiac disease or a history of cardiac dysfunction including any of the following: a. Unstable angina pectoris within 6 months prior to study entry b. Symptomatic pericarditis c. Documented myocardial infarction within 6 months prior to study entry d. History of documented congestive heart failure (New York Heart Association functional classification III-IV) e. Documented cardiomyopathy • QTcF > 480 msec on the screening ECG (using the QTcF formula) • Currently receiving treatment with medication that has a known risk to prolong the QT interval or inducing Torsades de Pointes, and the treatment cannot be discontinued or switched to a different medication prior to registration. •Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of buparlisib• Prior malignancies (other than breast cancer) within the last 5 years, except for adequately treated in situ carcinoma of the cervix or basal cell/squamous cell carcinoma of the skin • Currently receiving warfarin or other coumarin derived anti-coagulant, for treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin (LMWH),
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective of this study is to evaluate changes in tumour-cell proliferation (as determined by changes in FLT uptake by PET scanning), in patients with HER2-positive brain metastasis. ; Secondary Objective: - Determine the concentration of Buparlisib within resected brain metastasis as compared with serum levels - Determine the concentration of Buparlisib within cerebrospinal fluid as compared with serum levels - Determine the tumour cell proliferation, as measured by Ki67 expression, within resected brain metastasis following Buparlisib - Determine the changes in tumour cell proliferation (as measured by changes in FLT uptake between pre and post treatment scans) with and without P13K mutations - Determine if there is any change in the size of brain metastasis following 2 weeks of pre operative therapy - Determine safety and tolerability of the study treatment in the population ; Primary end point(s): -The change in FLT uptake as measured by PET scan between diagnosis (baseline) and Day 14. ; Timepoint(s) of evaluation of this end point: This end point will evaluated after 14 days of treatment (Visit 4) Response to buparlisib will be defined as a 25% or greater reduction in FLT uptake after 14 days of treatment. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1) Determine if there is any change in the size of brain metastasis following 2 weeks of pre operative therapy Determine the concentration of Buparlisib with resected brain metastasis as compared with serum levels - Determine the concentration of Buparlisib with cerebrospinal fluid as compared with serum levels - Determine the tumour cell proliferation, as measured by ki67 expression, within resected brain metastasis following Buparlisib - Determine the changes in tumour cell proliferation (as measured by changes in FLT uptake between pre and post treatment scans) with and without P13K mutations - Determine safety and tolerability of the study treatment in the population ; Timepoint(s) of evaluation of this end point: 1) The time point of evaluation for this end point will be pre-surgery at Visit 3 (surgery visit). 2) The time point of evaluation for this end point will be Visit 3 (surgery visit). 3) The time point of evaluation for this end point will be Visit 3 (surgery visit). 4) The time point of evaluation for this end point will be Visit 3 (surgery visit). 5) The time point for this end point will be Visit 3 (surgery visit). 6) This end point will be evaluated based on occurrence of SAEs and toxicities at Visit 1 (Day 7), Visit 2 (Day 14), 4 (14 days post surgery) & visit 5 (End of study). | — |
Countries
United Kingdom
Contacts
Public ContactHelen Scott
Liverpool Cancer Trials Unit
Outcome results
None listed