Statement: Neither the primary trial or the secondary trial are measuring Dose Limiting Toxicity of BYL719 in Combination With T-DM1.
Primary_evidence: Outcome Measurement:    Dose Limiting Toxicity (DLT) of Dose-escalating BYL719 in Combination With T-DM1   DLTs of BYL719 in combination with T-DM1 will be assessed using National Cancer Institute's Common Toxicity Criteria for adverse events version 4.0 (except for hyperglycemia). A DLT is described any grade 3 or higher, clinically significant toxicity (excluding alopecia) experienced during the first 21 days following first dose of BYL719 that is determined to be at least possibly related to study medication. Lower grades may also be considered DLTs if they lead to a dose interruption of more than 7 consecutive days of BYL719. In general adverse events (AEs) will be graded according to the following:   Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE   Time frame: The 1st 21 days (Cycle 1) of treatment Results 1:    Arm/Group Title: Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1)   Arm/Group Description: Patients receive 250 mg PO daily PI3K inhibitor BYL719 on days 1-21 and 3.6mg/kg IV over 30-90 minutes on day 1 ado-trastuzumab emtansine (T-DM1). Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.   PI3K inhibitor BYL719: Given PO   Ado-trastuzumab emtansine: Given IV   Pharmacological study: Correlative studies   Laboratory biomarker analysis: Optional correlative studies   Overall Number of Participants Analyzed: 3   Measure Type: Count of Participants   Unit of Measure: Participants  Thrombocytopenia: 0   0.0% Rash Maculopapular: 0   0.0% Results 2:    Arm/Group Title: Cohort 1 (300mg BYL719, 3.6mg/kg T-DM1)   Arm/Group Description: Patients receive 300 mg PO daily PI3K inhibitor BYL719 on days 1-21 and 3.6mg/kg IV over 30-90 minutes on day 1 ado-trastuzumab emtansine (T-DM1). Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.   PI3K inhibitor BYL719: Given PO   Ado-trastuzumab emtansine: Given IV   Pharmacological study: Correlative studies   Laboratory biomarker analysis: Optional correlative studies   Overall Number of Participants Analyzed: 5   Measure Type: Count of Participants   Unit of Measure: Participants  Thrombocytopenia: 1  20.0% Rash Maculopapular: 2  40.0%
Secondary_evidence: Outcome Measurement:    Endoxifen Concentrations in Participants Receiving Tamoxifen Citrate Dose of 20 mg or 40 mg Stratified by the Metabolizing CYP2D6 Genotypes   Measurements of plasma concentrations of the key active metabolite of tamoxifen, endoxifen, were measured at baseline and after 4 months of treatment; The most common CYP2D6 alleles have been grouped by functional activity classifications with descending activity: ultra-rapid (UM), extensive (EM), intermediate (IM) or poor (PM) metabolism. A given patient has two alleles, giving them 10 possible allelic combinations, or diplotypes (UM/UM, UM/EM, EM/EM, etc.). These diplotypes are collapsed into four phenotypes, UM, EM, IM or PM.   Time frame: 4 months Results 1:    Arm/Group Title: Ultra-rapid Metabolizers   Arm/Group Description: Those with the highest transformation of the CYP2D6 genotype to allelic activity   Overall Number of Participants Analyzed: 5   Mean (Standard Deviation)   Unit of Measure: ng/mL  Baseline endoxifen concentration: 5 participants   8.4         (4.59)   4-Month endoxifen concentration: 4 participants   15.35         (5.48) Results 2:    Arm/Group Title: Extensive Metabolizers   Arm/Group Description: Those with the most normal transformation of the CYP2D6 genotype to allelic activity   Overall Number of Participants Analyzed: 119   Mean (Standard Deviation)   Unit of Measure: ng/mL  Baseline endoxifen concentration: 119 participants   10.00         (6.00)   4-Month endoxifen concentration: 106 participants   9.30         (5.03)