HER2-positive Breast Cancer, Recurrent Breast Cancer, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer, Stage IV Breast Cancer
Conditions
Brief summary
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.
Detailed description
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.
Interventions
Given PO
BIOLOGICALado-trastuzumab emtansine
Given IV
OTHERpharmacological study
Correlative studies
OTHERlaboratory biomarker analysis
Optional correlative studies
Sponsors
Novartis
National Cancer Institute (NCI)
Northwestern University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have histologically-confirmed HER2-positive breast cancer that is locally advanced or metastatic (stage 4); ideally this should be from biopsy of the metastatic disease; however if this is not available, histologic confirmation from the primary tumor is acceptable * Patients must have had progression on a trastuzumab and taxane-based chemotherapy regimen during or after treatment for locally advanced or metastatic disease or within 6 months after treatment for early-stage HER2-positive disease documented by one of the following results using Food and Drug Administration (FDA)-approved testing methods: * Fluorescence in situ hybridization (FISH)-positive (with an amplification ratio \>= 2.0 indicating positive status) and/or * Immunohistochemistry (IHC) 3 + by local laboratory assessment * Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 * Patients must have a life expectancy \>= 90 days * Patients must have baseline laboratory tests within the following parameters at least 4 weeks (28 days) prior to registration: * Hemoglobin \> 8 g/dL (which may be reached by transfusion) * Platelet count \>= 100 x 10\^9/L (no transfusion allowed within 2 weeks) * Absolute neutrophil count (ANC) \>= 1.5 x 10\^9/L without growth factor support * Serum bilirubin =\< 1.5 x upper limit of normal (ULN) * Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and/or alanine aminotransferase (ALT)/serum glutamate pyruvate transaminase (SGPT) =\< 2.5 x upper limit of normal (ULN) or =\< 5 x ULN if liver metastases are present * Serum creatinine =\< 1.5 x ULN or calculated or directly measured creatinine clearance (CrCl) \>= 50% LLN (lower limit of normal) * Fasting plasma glucose (FPG) \< 140 mg/dL/7.8 mmol/L * Patients with child-bearing potential must have a negative urine pregnancy test within 7 days prior to registration * Patients must have a baseline electrocardiogram (ECG) showing QT interval =\< 460 msec within 14 days prior to registration * Patients must provide written informed consent prior to any registration on study * Patients must be willing and able to comply with scheduled visits, treatment plan and laboratory tests * Patient must be able to swallow and retain oral medication
Exclusion criteria
* Patients with prior sensitivity or intolerance to PI3K inhibitors are not eligible for participation * Patients with a history of grade \>= 3 hypersensitivity reaction to trastuzumab, OR grade \>= 1 with the most recent trastuzumab infusion before study entry, OR continued requirement for prolonged trastuzumab infusions to prevent hypersensitivity reactions are not eligible for participation * Patients with a history of intolerance to trastuzumab and/or adverse events related to trastuzumab that resulted in trastuzumab being permanently discontinued are not eligible for participation * Patients who have received prior treatment with T-DM1 are not eligible for participation * Patients who have received prior anti-cancer therapy (e.g., biologic or other targeted therapy, chemotherapy, hormonal therapy) within 2 weeks prior to registration are not eligible for participation * Patients with central nervous system (CNS) involvement may participate if the patient meets all of the following criteria: * At least 4 weeks from prior therapy completion (including radiation and/or surgery) to starting the study treatment * Clinically stable with respect to the CNS tumor at the time of screening * Not receiving steroid therapy * Not receiving enzyme inducing anti-epileptic medications that were started for brain metastases * Patients who have received radiotherapy =\< 4 weeks prior to registration, with the exception of palliative radiotherapy, who have not recovered from side effects of such therapy to baseline or grade =\< 1 and/or from whom \>= 30% of the bone marrow was irradiated are not eligible for participation * Patients who have undergone major surgery =\< 4 weeks prior to registration or who have not recovered from side effects of such procedure are not eligible for participation * Patients with clinically significant cardiac disease or impaired cardiac function are not eligible for participation; this includes patients with: * Congestive heart failure (CHF) requiring treatment (New York Heart Association \[NYHA\] grade \>= 2) * Left ventricular ejection fraction (LVEF) \< 50% as determined by multi-gated acquisition (MUGA) scan or echocardiogram (ECHO) * Uncontrolled arterial hypertension defined by blood pressure \> 140/100 mm Hg at rest (average of 3 consecutive readings) * History or current evidence of unstable, clinically significant cardiac arrhythmias or patients that require medications with a narrow therapeutic window, atrial fibrillation and/or conduction abnormality (e.g. congenital long QT syndrome, high-grade/complete atrioventricular \[AV\]-blockage) * Acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass graft \[CABG\], coronary angioplasty, or stenting), \< 3 months prior to screening * QT interval adjusted according to Fridericia (QTcF) \> 460 msec on screening ECG * Patients with diabetes mellitus requiring insulin treatment and/or with clinical signs or with fasting plasma glucose (FPG) \>= 140 mg/dL/7.8 mmol/L, or history of documented steroid-induced diabetes mellitus are not eligible for participation * Patients exhibiting any other condition that would, in the Investigator's judgment, preclude patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures are not eligible for participation; this might include, but is not limited to, infection/inflammation, intestinal obstruction, and/or social/psychological complications * Patients with impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral BYL719 (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) are not eligible for participation * Patients who are currently receiving medication with a known risk of prolonging the QT interval or inducing Torsades de Pointes (TdP) AND are unable to discontinue this medication or switch to a different medication prior to beginning study treatment are not eligible for participation * Patients with a history of another malignancy within 2 years prior to registration are not eligible for participation; NOTE: the exceptions to this include cured basal cell carcinoma of the skin or excised carcinoma in situ of the cervix * Patients receiving therapeutic doses of warfarin are not eligible for participation; NOTE: Patients with a need for therapeutic anticoagulation should be given low molecular weight heparin or other non-warfarin product * Pregnant or nursing (lactating) women are not eligible for participation; NOTE: Pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test (\> 5 mIU/mL) * Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, are not eligible for participation UNLESS they agree to use highly effective methods of contraception during dosing and for 5 weeks after study drugs discontinuation; highly effective contraception methods include: * Total abstinence (when this is in line with the preferred and usual lifestyle of the subject); periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception * Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least 5 weeks before receiving study treatment. In case of oophorectomy alone, the reproductive status of the woman must have been confirmed by follow up hormone level assessment * Male sterilization (at least 6 months prior to screening); for female subjects on the study the vasectomized male partner should be the sole partner for that subject * Combination of the following: * Placement of an intrauterine device (IUD) or intrauterine system (IUS) * Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository * NOTE: Oral contraceptives (OC), injected or implanted hormonal methods are not allowed as the sole method of contraception, as BYL719 has not been characterized with respect to its potential to interfere with the PK and/or the effectiveness of OCs
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Limiting Toxicity (DLT) of Dose-escalating BYL719 in Combination With T-DM1 | The 1st 21 days (Cycle 1) of treatment | 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 |
| Maximum Tolerated Dose (MTD) of BYL719 in Combination With T-DM1. | The 1st 21 days (Cycle 1) of treatment | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) of BYL719 Administered in Combination With T-DM1 for All Patients Treated on Study. | 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. | 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. |
| Pharmacokinetics (PK) of BYL719 Administered in Combination With T-DM1. | 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. | 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. |
| Objective Response Rate (ORR) of BYL719 Administered in Combination With T-DM1 by Cohort | 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. | 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) |
Other
| Measure | Time frame | Description |
|---|---|---|
| Clinical Benefit Rate (CBR) of BYL719 Administered in Combination With T-DM1 by Cohort | From the start of treatment and every 3 cycles (1 cycle =21 days) while on treatment where the median number of cycles is 11 and range is 3-19 cycles. | Clinical Benefit Rate (CBR) patients treated BYL719 and T-DM1 combination treatment is defined as the number of patients with Complete Response + Partial Response + Stable Disease for over 6 months documented as their best response, assessed every 3 cycles (every 9 weeks) with physical exam and imaging (CT chest/abdomen/pelvis and bone scan, or PET/CT) and defined by RECIST guidelines. Patients that completed at least 3 cycles of treatment and had imaging at 1st response time point were considered evaluable for this objective. |
| Best Response of BYL719 Administered in Combination With T-DM1 by Cohort | 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. | Best Response (BR) of patients treated with BYL719 and T-DM1 combination treatment is assessed every 9 weeks with physical exam and imaging and defined by Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0). BR 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. Complete Response (CR): Disappearance of all target lesions Partial Response (PR): \>=30% decrease in the sum of the longest diameter (LD) of target lesions Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum of LD recorded since the treatment started or the appearance of one or more new lesions |
| Number of Patients With Changes in PIK3CA Gene, PTEN Expression and Akt/mTOR Downstream Markers | Baseline | Patients tumor tissue collected during biopsy will be evaluated by immunohitochemistry (IHC) and Next Generation Sequencing (NGS) to see if the study drugs are efficacious on patients who have this alteration. |
Countries
United States
Participant flow
Recruitment details
The study opened for accrual on February 26, 2014 with an accrual goal of up to 28 patients. The first patient started treatment May 21 2014. The study was designed as a 3 + 3 escalation. 6 patients were enrolled in Cohort 1 and 11 patients enrolled in Cohort -1. The study closed February 12, 2016 with accrual for the study design having been met.
Participants by arm
| Arm | Count |
|---|---|
| BYL719 and T-DM1 Treatment Patients receive either 250 mg (Cohort -1) or 300 mg (Cohort 1) 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 | 17 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Completed 1st Cycle and Started Cycle 2 | Patient Non Compliance | 1 | 0 | 0 | 0 |
| Completed 1st Cycle and Started Cycle 2 | Progressive Disease | 0 | 1 | 0 | 0 |
| Completed 1st Cycle and Started Cycle 2 | Withdrawal by Subject | 0 | 1 | 0 | 0 |
| Completed 3 Cycles/Reached 1st Response | Progressive Disease | 1 | 1 | 0 | 0 |
| Follow Up | Death | 4 | 3 | 0 | 0 |
| Follow Up | Other | 3 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | BYL719 and T-DM1 Treatment |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 3 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Hormone Receptor Status Negative | 9 Participants |
| Hormone Receptor Status Positive | 8 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 17 Participants |
| Region of Enrollment United States | 17 Participants |
| Sex: Female, Male Female | 17 Participants |
| Sex: Female, Male Male | 0 Participants |
| T-DM1 Systemic Therapy in Metastatic Setting Patients had not had prior TDM1 therapy | 7 Participants |
| T-DM1 Systemic Therapy in Metastatic Setting Patients had prior T-DM1 therapy | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 11 | 3 / 6 |
| other Total, other adverse events | 11 / 11 | 6 / 6 |
| serious Total, serious adverse events | 3 / 11 | 3 / 6 |
Outcome results
Primary
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
Population: 5 patients enrolled into Cohort 1 were assess for DLTs, one patient in Cohort 1 was determined not to be evaluable after review; the patient only received one dose of treatment total. Only the first 3 patients in Cohort -1 were assessed for DLTs due to 3+3 design.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) | Dose Limiting Toxicity (DLT) of Dose-escalating BYL719 in Combination With T-DM1 | Thrombocytopenia | 0 Participants |
| Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) | Dose Limiting Toxicity (DLT) of Dose-escalating BYL719 in Combination With T-DM1 | Rash Maculopapular | 0 Participants |
| Cohort 1 (300mg BYL719, 3.6mg/kg T-DM1) | Dose Limiting Toxicity (DLT) of Dose-escalating BYL719 in Combination With T-DM1 | Thrombocytopenia | 1 Participants |
| Cohort 1 (300mg BYL719, 3.6mg/kg T-DM1) | Dose Limiting Toxicity (DLT) of Dose-escalating BYL719 in Combination With T-DM1 | Rash Maculopapular | 2 Participants |
Primary
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
Population: 5 patients enrolled into Cohort 1 were assess for DLTs, one patient in Cohort 1 was determined not to be evaluable after review; the patient only received one dose of treatment total. Only the first 3 patients in Cohort -1 were assessed for DLTs due to 3+3 design in assessing for DLTs and determining the MTD.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) | Maximum Tolerated Dose (MTD) of BYL719 in Combination With T-DM1. | 250 mg per day |
Secondary
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) | Objective Response Rate (ORR) of BYL719 Administered in Combination With T-DM1 by Cohort | 4 participants |
| Cohort 1 (300mg BYL719, 3.6mg/kg T-DM1) | Objective Response Rate (ORR) of BYL719 Administered in Combination With T-DM1 by Cohort | 2 participants |
Secondary
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.
Population: No data from the blood draws was collected or analyzed for this objective.
Secondary
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.
Population: The sample size was so small for each cohort that it was decided that there wouldn't any merit to separating out the dose cohorts and Kaplan Meier curves were completed on all patients combined and patients with or without prior T-DM1 treatment. No data was collected and no analysis was completed on each dose cohort separately.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) | Progression-Free Survival (PFS) of BYL719 Administered in Combination With T-DM1 for All Patients Treated on Study. | All Patients | 8.1 Months |
| Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) | Progression-Free Survival (PFS) of BYL719 Administered in Combination With T-DM1 for All Patients Treated on Study. | Patients without Prior TDM1 Exposure | 10.8 Months |
| Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) | Progression-Free Survival (PFS) of BYL719 Administered in Combination With T-DM1 for All Patients Treated on Study. | Patients with Prior TDM1 Exposure | 6.2 Months |
Other Pre-specified
Best Response of BYL719 Administered in Combination With T-DM1 by Cohort
Best Response (BR) of patients treated with BYL719 and T-DM1 combination treatment is assessed every 9 weeks with physical exam and imaging and defined by Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0). BR 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. Complete Response (CR): Disappearance of all target lesions Partial Response (PR): \>=30% decrease in the sum of the longest diameter (LD) of target lesions Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum of LD recorded since the treatment started or the appearance of one or more new lesions
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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) | Best Response of BYL719 Administered in Combination With T-DM1 by Cohort | Complete Response | 0 participants |
| Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) | Best Response of BYL719 Administered in Combination With T-DM1 by Cohort | Partial Response | 4 participants |
| Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) | Best Response of BYL719 Administered in Combination With T-DM1 by Cohort | Stable Disease | 5 participants |
| Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) | Best Response of BYL719 Administered in Combination With T-DM1 by Cohort | Progressive Disease | 1 participants |
| Cohort 1 (300mg BYL719, 3.6mg/kg T-DM1) | Best Response of BYL719 Administered in Combination With T-DM1 by Cohort | Progressive Disease | 1 participants |
| Cohort 1 (300mg BYL719, 3.6mg/kg T-DM1) | Best Response of BYL719 Administered in Combination With T-DM1 by Cohort | Complete Response | 1 participants |
| Cohort 1 (300mg BYL719, 3.6mg/kg T-DM1) | Best Response of BYL719 Administered in Combination With T-DM1 by Cohort | Stable Disease | 1 participants |
| Cohort 1 (300mg BYL719, 3.6mg/kg T-DM1) | Best Response of BYL719 Administered in Combination With T-DM1 by Cohort | Partial Response | 1 participants |
Other Pre-specified
Clinical Benefit Rate (CBR) of BYL719 Administered in Combination With T-DM1 by Cohort
Clinical Benefit Rate (CBR) patients treated BYL719 and T-DM1 combination treatment is defined as the number of patients with Complete Response + Partial Response + Stable Disease for over 6 months documented as their best response, assessed every 3 cycles (every 9 weeks) with physical exam and imaging (CT chest/abdomen/pelvis and bone scan, or PET/CT) and defined by RECIST guidelines. 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 cycles (1 cycle =21 days) while on treatment where the median number of cycles is 11 and range is 3-19 cycles.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) | Clinical Benefit Rate (CBR) of BYL719 Administered in Combination With T-DM1 by Cohort | 7 participants |
| Cohort 1 (300mg BYL719, 3.6mg/kg T-DM1) | Clinical Benefit Rate (CBR) of BYL719 Administered in Combination With T-DM1 by Cohort | 3 participants |
Other Pre-specified
Number of Patients With Changes in PIK3CA Gene, PTEN Expression and Akt/mTOR Downstream Markers
Patients tumor tissue collected during biopsy will be evaluated by immunohitochemistry (IHC) and Next Generation Sequencing (NGS) to see if the study drugs are efficacious on patients who have this alteration.
Time frame: Baseline
Population: The sample size was so small for each cohort and due to the exploratory nature of outcome measure, there wouldn't any merit to separating out dose cohorts. Mutations were collected for patients combined, reported on and correlated with response descriptively. No data was collected/no analysis was completed on each dose cohort separately.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) | Number of Patients With Changes in PIK3CA Gene, PTEN Expression and Akt/mTOR Downstream Markers | PTEN Loss (IHC) | 2 Participants |
| Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) | Number of Patients With Changes in PIK3CA Gene, PTEN Expression and Akt/mTOR Downstream Markers | AKT Increased Expression (IHC) | 3 Participants |
| Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) | Number of Patients With Changes in PIK3CA Gene, PTEN Expression and Akt/mTOR Downstream Markers | PIK3CA Mutation (NGS) | 4 Participants |
| Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) | Number of Patients With Changes in PIK3CA Gene, PTEN Expression and Akt/mTOR Downstream Markers | PI3K Pathway Aberration | 9 Participants |
| Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) | Number of Patients With Changes in PIK3CA Gene, PTEN Expression and Akt/mTOR Downstream Markers | Patients with Response and PTEN Loss | 1 Participants |
| Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) | Number of Patients With Changes in PIK3CA Gene, PTEN Expression and Akt/mTOR Downstream Markers | Patient with Response and AKT Increased Expression | 1 Participants |
| Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) | Number of Patients With Changes in PIK3CA Gene, PTEN Expression and Akt/mTOR Downstream Markers | Patient with Response and P13K Pathway Aberration | 2 Participants |
| Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) | Number of Patients With Changes in PIK3CA Gene, PTEN Expression and Akt/mTOR Downstream Markers | Patients with SD and PTEN Loss | 1 Participants |
| Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) | Number of Patients With Changes in PIK3CA Gene, PTEN Expression and Akt/mTOR Downstream Markers | Patient with SD and AKT Increased Expression | 1 Participants |
| Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) | Number of Patients With Changes in PIK3CA Gene, PTEN Expression and Akt/mTOR Downstream Markers | Patients with SD and PIK3CA Mutation | 1 Participants |
| Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) | Number of Patients With Changes in PIK3CA Gene, PTEN Expression and Akt/mTOR Downstream Markers | Patients with SD and P13K Pathway Aberration | 5 Participants |
| Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) | Number of Patients With Changes in PIK3CA Gene, PTEN Expression and Akt/mTOR Downstream Markers | Patients with PD and PTEN Loss | 0 Participants |
| Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) | Number of Patients With Changes in PIK3CA Gene, PTEN Expression and Akt/mTOR Downstream Markers | Patients with PD and AKT Increased Expression | 0 Participants |
| Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) | Number of Patients With Changes in PIK3CA Gene, PTEN Expression and Akt/mTOR Downstream Markers | Patients with PD and PIK3CA Mutation | 1 Participants |
| Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) | Number of Patients With Changes in PIK3CA Gene, PTEN Expression and Akt/mTOR Downstream Markers | Patients with PD and P13K Pathway Aberration | 1 Participants |
Post Hoc
Toxicity of the Combination of BYL719 and T-DM1 Treatment by Cohort
Toxicity profile of BYL719 in combination with T-DM1 will be assessed using National Cancer Institute's Common Toxicity Criteria for Adverse Events version 4.0 (CTCAEv4.0). Toxicity is defined as an AE that is determined to be at least possibly related to at least one of the study drugs: BYL719 and T-DM1. 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: From the time of treatment initiation thoughout treatment until 30 days post last dose. Range of cycles completed =1 to 19 where 1 cycle =21 days
Population: Any patient that received a dose of study drug was evaluable for this outcome measure
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) | Toxicity of the Combination of BYL719 and T-DM1 Treatment by Cohort | Lymphocyte Count Decreased | 0 participants |
| Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) | Toxicity of the Combination of BYL719 and T-DM1 Treatment by Cohort | Anorexia | 2 participants |
| Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) | Toxicity of the Combination of BYL719 and T-DM1 Treatment by Cohort | Electrocardiogram QT corrected interval prolonged | 0 participants |
| Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) | Toxicity of the Combination of BYL719 and T-DM1 Treatment by Cohort | Hyperglycemia | 2 participants |
| Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) | Toxicity of the Combination of BYL719 and T-DM1 Treatment by Cohort | Platelet Count Decreased | 1 participants |
| Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) | Toxicity of the Combination of BYL719 and T-DM1 Treatment by Cohort | Abnormal Uterine Bleeding | 0 participants |
| Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) | Toxicity of the Combination of BYL719 and T-DM1 Treatment by Cohort | Pancreatitis | 0 participants |
| Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) | Toxicity of the Combination of BYL719 and T-DM1 Treatment by Cohort | Rash Maculo-papular | 3 participants |
| Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) | Toxicity of the Combination of BYL719 and T-DM1 Treatment by Cohort | Weight Loss | 1 participants |
| Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) | Toxicity of the Combination of BYL719 and T-DM1 Treatment by Cohort | Hypertension | 1 participants |
| Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) | Toxicity of the Combination of BYL719 and T-DM1 Treatment by Cohort | Anemia | 0 participants |
| Cohort 1 (300mg BYL719, 3.6mg/kg T-DM1) | Toxicity of the Combination of BYL719 and T-DM1 Treatment by Cohort | Hypertension | 1 participants |
| Cohort 1 (300mg BYL719, 3.6mg/kg T-DM1) | Toxicity of the Combination of BYL719 and T-DM1 Treatment by Cohort | Anemia | 1 participants |
| Cohort 1 (300mg BYL719, 3.6mg/kg T-DM1) | Toxicity of the Combination of BYL719 and T-DM1 Treatment by Cohort | Pancreatitis | 1 participants |
| Cohort 1 (300mg BYL719, 3.6mg/kg T-DM1) | Toxicity of the Combination of BYL719 and T-DM1 Treatment by Cohort | Electrocardiogram QT corrected interval prolonged | 1 participants |
| Cohort 1 (300mg BYL719, 3.6mg/kg T-DM1) | Toxicity of the Combination of BYL719 and T-DM1 Treatment by Cohort | Lymphocyte Count Decreased | 1 participants |
| Cohort 1 (300mg BYL719, 3.6mg/kg T-DM1) | Toxicity of the Combination of BYL719 and T-DM1 Treatment by Cohort | Platelet Count Decreased | 2 participants |
| Cohort 1 (300mg BYL719, 3.6mg/kg T-DM1) | Toxicity of the Combination of BYL719 and T-DM1 Treatment by Cohort | Weight Loss | 0 participants |
| Cohort 1 (300mg BYL719, 3.6mg/kg T-DM1) | Toxicity of the Combination of BYL719 and T-DM1 Treatment by Cohort | Anorexia | 0 participants |
| Cohort 1 (300mg BYL719, 3.6mg/kg T-DM1) | Toxicity of the Combination of BYL719 and T-DM1 Treatment by Cohort | Hyperglycemia | 2 participants |
| Cohort 1 (300mg BYL719, 3.6mg/kg T-DM1) | Toxicity of the Combination of BYL719 and T-DM1 Treatment by Cohort | Abnormal Uterine Bleeding | 1 participants |
| Cohort 1 (300mg BYL719, 3.6mg/kg T-DM1) | Toxicity of the Combination of BYL719 and T-DM1 Treatment by Cohort | Rash Maculo-papular | 4 participants |