The purpose of this study is to see whether a combination of two different drugs - trastuzumab-MCC-DM1 (T-DM1) and BYL719 is safe, and if it might be effective in treating metastatic breast cancer. T-DM1 is a type of drug that contains an antibody (trastuzumab) linked to chemotherapy. The antibody in T-DM1 targets a marker on breast cancer cells called HER2, which allows the drug to go directly to the cancer cells. The use of T-DM1 in this study is considered standard treatment for the type of cancer in this study. Participants in this study have already been treated with trastuzumab and chemotherapy in the past, and their cancer has gotten worse in spite of those treatments. BYL719 is an oral drug (taken by mouth) that the researchers think may help T-DM1 to work better.
PRIMARY OBJECTIVES: I. Determine safety, tolerability, feasibility, and the maximum-tolerated dose (MTD) of dose-escalating BYL719 in combination with ado-trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer (MBC) after progression on trastuzumab and taxane-based therapy. SECONDARY OBJECTIVES: I. Evaluate pharmacokinetics (PK) of BYL719 administered in combination with T-DM1. II. Assess any preliminary evidence of efficacy of BYL719 and T-DM1 in combination in patients with HER2-positive MBC. TERTIARY OBJECTIVES: I. Explore efficacy in patients whose tumors have an alteration (mutation or amplification) of the PIK3CA gene and decrease of phosphatase and tensin homolog gene (PTEN) expression. (Optional) II. Examine other v-akt murine thymoma viral oncogene homolog 1 (Akt)/mechanistic target of rapamycin (mTOR) downstream markers by immunohistochemistry. (Optional) OUTLINE: This is a dose-escalation study of PI3K inhibitor BYL719. Patients receive PI3K inhibitor BYL719 orally (PO) daily on days 1-21 and ado-trastuzumab emtansine (T-DM1) intravenously (IV) over 30-90 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity, or at the discretion of the treating physician. After completion of study treatment, patients are followed up every 3 months.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
17
Northwestern University
Chicago, Illinois, United States
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
Maximum Tolerated Dose (MTD) of BYL719 in Combination With T-DM1.
Safety of BYL719 in combination with T-DM1 will be assessed during the first 21 days (1 cycle=21 days) which will assist in providing the MTD. Adverse Events including dose limiting toxicities (DLT), changes in physical findings, or clinical laboratory results as well as cardiac toxicity (changes in cardiac function, which will be measured by use of echocardiogram or MUGA scan) will be evaluated. For each dose level, 3 patients will be treated. If none (0 of 3) show a DLT, dose will be escalated for the next cohort of patients. If 2 or 3 have a DLT, then the previous dose will be considered the MTD. If 2 or 3 in cohort 1 (starting dose) experience a DLT, then the dose in -1 cohort will be used. If 1 of 3 patients has a DLT, then an additional 3 patients will be added to that dose level. If 1 of 6 has a DLT, then the dose will be escalated. If 2 of 6 have a DLT, then this dose will be considered the MTD. If 3 or more of 6 have a DLT, then the previous dose will be the MTD.
Time frame: The 1st 21 days (Cycle 1) of treatment
Pharmacokinetics (PK) of BYL719 Administered in Combination With T-DM1.
To assess the pharmacokinetics (PK)of BYL719, blood will be drawn from patients on Day 1, 8, and 15 of Cycles 1, 2 and 3 where 1 Cycle = 21 days. After that blood will be drawn once every 3 cycles. PK parameters of BYL719 including peak and trough concentrations as an estimate of the steady-state concentration, elimination clearance, interindividual variability of the elimination clearance, and the effect of PK parameters with prolonged administration of BYL719 will be obtained. Steady state concentration will be analyzed to see if there is any relationship with efficacy or toxicity.
Time frame: Day 1, 8, and 15 of Cycles 1, 2, and 3, then every 3 Cycles (1 Cycle =21 days) while on treatment where the median number of cycles is 11 and range is 3-19 cycles.
Progression-Free Survival (PFS) of BYL719 Administered in Combination With T-DM1 for All Patients Treated on Study.
Progression-Free Survival (PFS) for patients treated with BYL719 and T-DM1 in combination is measured for all patients from the time of treatment initiation until the first documentation of progressive disease or death from any cause. It will be assessed every 3 months up to 1 year after discontinuation of the study drugs. Patients that completed at least 3 cycles of treatment and had imaging at 1st response time point were considered evaluable for this objective.
Time frame: From the start of treatment and every 3 months up to 1 year after discontinuation of treatment. 1 Cycle = 21 days. Median number of cycles is 11 and range is 3-19 cycles.
Objective Response Rate (ORR) of BYL719 Administered in Combination With T-DM1 by Cohort
ORR for patients treated with BYL719 in combination with T-DM1 assessed every 3 cycles (every 9 weeks) with imaging and Best Response defined by RECIST v1.1. ORR is defined as number of patients with Complete Response (CR)+Partial Response (PR) documented as their Best Response (confirmed 4 weeks later). Response is based on evaluation of target and non-target lesions. Clinical lesions will only be considered measurable when they are superficial. Patients that completed at least 3 cycles of treatment and had imaging at 1st response time point were considered evaluable for this objective. Target Lesions: CR: Disappearance of all target lesions. PR: At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum of LD. For Non-Target Lesions: CR: Disappearance of all non-target lesions and normalization of tumor marker level Non-complete Response (Non-CR): Persistence of one or more non-target lesion(s)
Time frame: From the start of treatment and every 3 cycles during treatment where 1 cycle =21 days, median number of cycles is 11 and range of cycles is 3-19.
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