Trial Outcomes & Findings for BYL719 + T-DM1 in HER2(+) Metastatic Breast Cancer Pts Who Progress on Prior Trastuzumab & Taxane Tx (NCT NCT02038010)

NCT ID: NCT02038010

Last Updated: 2020-06-29

Results Overview

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

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

17 participants

Primary outcome timeframe

The 1st 21 days (Cycle 1) of treatment

Results posted on

2020-06-29

Participant Flow

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.

Participant milestones

Participant milestones
Measure	Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) 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	Cohort 1 (300mg BYL719, 3.6mg/kg T-DM1) 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
Completed 1st Cycle and Started Cycle 2 STARTED	11	6
Completed 1st Cycle and Started Cycle 2 Completed 1st Cycle	11	5
Completed 1st Cycle and Started Cycle 2 Continued on to Cycle 2	10	4
Completed 1st Cycle and Started Cycle 2 COMPLETED	10	4
Completed 1st Cycle and Started Cycle 2 NOT COMPLETED	1	2
Completed 3 Cycles/Reached 1st Response STARTED	10	4
Completed 3 Cycles/Reached 1st Response Completed 3 Cycles	10	4
Completed 3 Cycles/Reached 1st Response Continued to Cycle 4	9	3
Completed 3 Cycles/Reached 1st Response COMPLETED	9	3
Completed 3 Cycles/Reached 1st Response NOT COMPLETED	1	1
Follow Up STARTED	11	6
Follow Up COMPLETED	4	3
Follow Up NOT COMPLETED	7	3

Reasons for withdrawal

Reasons for withdrawal
Measure	Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) 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	Cohort 1 (300mg BYL719, 3.6mg/kg T-DM1) 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
Completed 1st Cycle and Started Cycle 2 Progressive Disease	0	1
Completed 1st Cycle and Started Cycle 2 Patient Non Compliance	1	0
Completed 1st Cycle and Started Cycle 2 Withdrawal by Subject	0	1
Completed 3 Cycles/Reached 1st Response Progressive Disease	1	1
Follow Up Death	4	3
Follow Up Other	3	0

Baseline Characteristics

BYL719 + T-DM1 in HER2(+) Metastatic Breast Cancer Pts Who Progress on Prior Trastuzumab & Taxane Tx

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	BYL719 and T-DM1 Treatment n=17 Participants 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
Age, Categorical <=18 years	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	14 Participants n=5 Participants
Age, Categorical >=65 years	3 Participants n=5 Participants
Sex: Female, Male Female	17 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	14 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants
Race (NIH/OMB) White	17 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Region of Enrollment United States	17 Participants n=5 Participants
T-DM1 Systemic Therapy in Metastatic Setting Patients had prior T-DM1 therapy	10 Participants n=5 Participants
T-DM1 Systemic Therapy in Metastatic Setting Patients had not had prior TDM1 therapy	7 Participants n=5 Participants
Hormone Receptor Status Positive	8 Participants n=5 Participants
Hormone Receptor Status Negative	9 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) n=3 Participants 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	Cohort 1 (300mg BYL719, 3.6mg/kg T-DM1) n=5 Participants 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
Dose Limiting Toxicity (DLT) of Dose-escalating BYL719 in Combination With T-DM1 Thrombocytopenia	0 Participants	1 Participants
Dose Limiting Toxicity (DLT) of Dose-escalating BYL719 in Combination With T-DM1 Rash Maculopapular	0 Participants	2 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) n=8 Participants 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	Cohort 1 (300mg BYL719, 3.6mg/kg T-DM1) 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
Maximum Tolerated Dose (MTD) of BYL719 in Combination With T-DM1.	250 mg per day	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) n=14 Participants 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	Cohort 1 (300mg BYL719, 3.6mg/kg T-DM1) 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
Progression-Free Survival (PFS) of BYL719 Administered in Combination With T-DM1 for All Patients Treated on Study. All Patients	8.1 Months Interval 3.9 to 10.8	—
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 Interval 8.1 to 12.5	—
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 Interval 1.6 to 10.5	—

SECONDARY outcome

Timeframe: 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)

Outcome measures

Outcome measures
Measure	Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) n=10 Participants 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	Cohort 1 (300mg BYL719, 3.6mg/kg T-DM1) n=4 Participants 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
Objective Response Rate (ORR) of BYL719 Administered in Combination With T-DM1 by Cohort	4 participants	2 participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) n=11 Participants 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	Cohort 1 (300mg BYL719, 3.6mg/kg T-DM1) 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
Number of Patients With Changes in PIK3CA Gene, PTEN Expression and Akt/mTOR Downstream Markers PTEN Loss (IHC)	2 Participants	—
Number of Patients With Changes in PIK3CA Gene, PTEN Expression and Akt/mTOR Downstream Markers AKT Increased Expression (IHC)	3 Participants	—
Number of Patients With Changes in PIK3CA Gene, PTEN Expression and Akt/mTOR Downstream Markers PIK3CA Mutation (NGS)	4 Participants	—
Number of Patients With Changes in PIK3CA Gene, PTEN Expression and Akt/mTOR Downstream Markers PI3K Pathway Aberration	9 Participants	—
Number of Patients With Changes in PIK3CA Gene, PTEN Expression and Akt/mTOR Downstream Markers Patients with Response and PTEN Loss	1 Participants	—
Number of Patients With Changes in PIK3CA Gene, PTEN Expression and Akt/mTOR Downstream Markers Patient with Response and AKT Increased Expression	1 Participants	—
Number of Patients With Changes in PIK3CA Gene, PTEN Expression and Akt/mTOR Downstream Markers Patient with Response and P13K Pathway Aberration	2 Participants	—
Number of Patients With Changes in PIK3CA Gene, PTEN Expression and Akt/mTOR Downstream Markers Patients with SD and PTEN Loss	1 Participants	—
Number of Patients With Changes in PIK3CA Gene, PTEN Expression and Akt/mTOR Downstream Markers Patient with SD and AKT Increased Expression	1 Participants	—
Number of Patients With Changes in PIK3CA Gene, PTEN Expression and Akt/mTOR Downstream Markers Patients with SD and PIK3CA Mutation	1 Participants	—
Number of Patients With Changes in PIK3CA Gene, PTEN Expression and Akt/mTOR Downstream Markers Patients with SD and P13K Pathway Aberration	5 Participants	—
Number of Patients With Changes in PIK3CA Gene, PTEN Expression and Akt/mTOR Downstream Markers Patients with PD and PTEN Loss	0 Participants	—
Number of Patients With Changes in PIK3CA Gene, PTEN Expression and Akt/mTOR Downstream Markers Patients with PD and AKT Increased Expression	0 Participants	—
Number of Patients With Changes in PIK3CA Gene, PTEN Expression and Akt/mTOR Downstream Markers Patients with PD and PIK3CA Mutation	1 Participants	—
Number of Patients With Changes in PIK3CA Gene, PTEN Expression and Akt/mTOR Downstream Markers Patients with PD and P13K Pathway Aberration	1 Participants	—

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) n=10 Participants 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	Cohort 1 (300mg BYL719, 3.6mg/kg T-DM1) n=4 Participants 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
Clinical Benefit Rate (CBR) of BYL719 Administered in Combination With T-DM1 by Cohort	7 participants	3 participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) n=10 Participants 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	Cohort 1 (300mg BYL719, 3.6mg/kg T-DM1) n=4 Participants 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
Best Response of BYL719 Administered in Combination With T-DM1 by Cohort Complete Response	0 participants	1 participants
Best Response of BYL719 Administered in Combination With T-DM1 by Cohort Partial Response	4 participants	1 participants
Best Response of BYL719 Administered in Combination With T-DM1 by Cohort Stable Disease	5 participants	1 participants
Best Response of BYL719 Administered in Combination With T-DM1 by Cohort Progressive Disease	1 participants	1 participants

POST_HOC outcome

Timeframe: 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

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

Outcome measures

Outcome measures
Measure	Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) n=11 Participants 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	Cohort 1 (300mg BYL719, 3.6mg/kg T-DM1) n=6 Participants 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
Toxicity of the Combination of BYL719 and T-DM1 Treatment by Cohort Anemia	0 participants	1 participants
Toxicity of the Combination of BYL719 and T-DM1 Treatment by Cohort Pancreatitis	0 participants	1 participants
Toxicity of the Combination of BYL719 and T-DM1 Treatment by Cohort Electrocardiogram QT corrected interval prolonged	0 participants	1 participants
Toxicity of the Combination of BYL719 and T-DM1 Treatment by Cohort Lymphocyte Count Decreased	0 participants	1 participants
Toxicity of the Combination of BYL719 and T-DM1 Treatment by Cohort Platelet Count Decreased	1 participants	2 participants
Toxicity of the Combination of BYL719 and T-DM1 Treatment by Cohort Weight Loss	1 participants	0 participants
Toxicity of the Combination of BYL719 and T-DM1 Treatment by Cohort Anorexia	2 participants	0 participants
Toxicity of the Combination of BYL719 and T-DM1 Treatment by Cohort Hyperglycemia	2 participants	2 participants
Toxicity of the Combination of BYL719 and T-DM1 Treatment by Cohort Abnormal Uterine Bleeding	0 participants	1 participants
Toxicity of the Combination of BYL719 and T-DM1 Treatment by Cohort Rash Maculo-papular	3 participants	4 participants
Toxicity of the Combination of BYL719 and T-DM1 Treatment by Cohort Hypertension	1 participants	1 participants

Adverse Events

Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1)

Serious events: 3 serious events

Other events: 11 other events

Deaths: 4 deaths

Cohort 1 (300mg BYL719, 3.6mg/kg T-DM1)

Serious events: 3 serious events

Other events: 6 other events

Deaths: 3 deaths

Serious adverse events

Serious adverse events
Measure	Cohort -1 (250mg BYL719, 3.6mg/kg T-DM1) n=11 participants at risk 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	Cohort 1 (300mg BYL719, 3.6mg/kg T-DM1) n=6 participants at risk 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
Respiratory, thoracic and mediastinal disorders Death due to Respiratory Failure	0.00% 0/11 • Adverse Events (AEs) were collected over 2 and half year period for all patients. Each patient was followed from the time of consent, during treatment at the beginning of each cycle through 30 days post last treatment, where 1 Cycle = 21 days the range of cycles attempted was 1-19.	16.7% 1/6 • Adverse Events (AEs) were collected over 2 and half year period for all patients. Each patient was followed from the time of consent, during treatment at the beginning of each cycle through 30 days post last treatment, where 1 Cycle = 21 days the range of cycles attempted was 1-19.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumor pain	0.00% 0/11 • Adverse Events (AEs) were collected over 2 and half year period for all patients. Each patient was followed from the time of consent, during treatment at the beginning of each cycle through 30 days post last treatment, where 1 Cycle = 21 days the range of cycles attempted was 1-19.	16.7% 1/6 • Adverse Events (AEs) were collected over 2 and half year period for all patients. Each patient was followed from the time of consent, during treatment at the beginning of each cycle through 30 days post last treatment, where 1 Cycle = 21 days the range of cycles attempted was 1-19.
Psychiatric disorders Delirium	0.00% 0/11 • Adverse Events (AEs) were collected over 2 and half year period for all patients. Each patient was followed from the time of consent, during treatment at the beginning of each cycle through 30 days post last treatment, where 1 Cycle = 21 days the range of cycles attempted was 1-19.	16.7% 1/6 • Adverse Events (AEs) were collected over 2 and half year period for all patients. Each patient was followed from the time of consent, during treatment at the beginning of each cycle through 30 days post last treatment, where 1 Cycle = 21 days the range of cycles attempted was 1-19.
Respiratory, thoracic and mediastinal disorders Epistaxis	9.1% 1/11 • Adverse Events (AEs) were collected over 2 and half year period for all patients. Each patient was followed from the time of consent, during treatment at the beginning of each cycle through 30 days post last treatment, where 1 Cycle = 21 days the range of cycles attempted was 1-19.	0.00% 0/6 • Adverse Events (AEs) were collected over 2 and half year period for all patients. Each patient was followed from the time of consent, during treatment at the beginning of each cycle through 30 days post last treatment, where 1 Cycle = 21 days the range of cycles attempted was 1-19.
Respiratory, thoracic and mediastinal disorders Hypoxemia	9.1% 1/11 • Adverse Events (AEs) were collected over 2 and half year period for all patients. Each patient was followed from the time of consent, during treatment at the beginning of each cycle through 30 days post last treatment, where 1 Cycle = 21 days the range of cycles attempted was 1-19.	0.00% 0/6 • Adverse Events (AEs) were collected over 2 and half year period for all patients. Each patient was followed from the time of consent, during treatment at the beginning of each cycle through 30 days post last treatment, where 1 Cycle = 21 days the range of cycles attempted was 1-19.
Gastrointestinal disorders Acute pancreatitis	9.1% 1/11 • Adverse Events (AEs) were collected over 2 and half year period for all patients. Each patient was followed from the time of consent, during treatment at the beginning of each cycle through 30 days post last treatment, where 1 Cycle = 21 days the range of cycles attempted was 1-19.	0.00% 0/6 • Adverse Events (AEs) were collected over 2 and half year period for all patients. Each patient was followed from the time of consent, during treatment at the beginning of each cycle through 30 days post last treatment, where 1 Cycle = 21 days the range of cycles attempted was 1-19.
Metabolism and nutrition disorders Elevated Fasting Plasma	9.1% 1/11 • Adverse Events (AEs) were collected over 2 and half year period for all patients. Each patient was followed from the time of consent, during treatment at the beginning of each cycle through 30 days post last treatment, where 1 Cycle = 21 days the range of cycles attempted was 1-19.	0.00% 0/6 • Adverse Events (AEs) were collected over 2 and half year period for all patients. Each patient was followed from the time of consent, during treatment at the beginning of each cycle through 30 days post last treatment, where 1 Cycle = 21 days the range of cycles attempted was 1-19.
Skin and subcutaneous tissue disorders Pain of skin	0.00% 0/11 • Adverse Events (AEs) were collected over 2 and half year period for all patients. Each patient was followed from the time of consent, during treatment at the beginning of each cycle through 30 days post last treatment, where 1 Cycle = 21 days the range of cycles attempted was 1-19.	16.7% 1/6 • Adverse Events (AEs) were collected over 2 and half year period for all patients. Each patient was followed from the time of consent, during treatment at the beginning of each cycle through 30 days post last treatment, where 1 Cycle = 21 days the range of cycles attempted was 1-19.
Infections and infestations Wound Infection	0.00% 0/11 • Adverse Events (AEs) were collected over 2 and half year period for all patients. Each patient was followed from the time of consent, during treatment at the beginning of each cycle through 30 days post last treatment, where 1 Cycle = 21 days the range of cycles attempted was 1-19.	16.7% 1/6 • Adverse Events (AEs) were collected over 2 and half year period for all patients. Each patient was followed from the time of consent, during treatment at the beginning of each cycle through 30 days post last treatment, where 1 Cycle = 21 days the range of cycles attempted was 1-19.

Other adverse events

Additional Information

William Gradishar, MD

Northwestern University

Phone: 312 695 4541

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place