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

NCT02038010 | Completed Phase 1 Results DMC

• 4 other identifiers: NU 13B06NCI-2013-02224P30CA060553STU00087202
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 1

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.

Conditions

HER2-positive Breast Cancer; Recurrent Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer

Outcome Measures

Primary Outcomes (2)

• 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

  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.

  The 1st 21 days (Cycle 1) of treatment

Secondary Outcomes (3)

• 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.

• 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.

• 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.

Other Outcomes (3)

• Number of Patients With Changes in PIK3CA Gene, PTEN Expression and Akt/mTOR Downstream Markers

  Baseline

• 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.

• 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.

Study Arms (1)

Treatment (PI3K inhibitor BYL719, ado-trastuzumab emtansine)

EXPERIMENTAL

Patients receive PI3K inhibitor BYL719 PO daily on days 1-21 and ado-trastuzumab emtansine IV over 30-90 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Drug: PI3K inhibitor BYL719; Biological: ado-trastuzumab emtansine; Other: pharmacological study; Other: laboratory biomarker analysis

Interventions

PI3K inhibitor BYL719 DRUG

Given PO

Also known as: BYL719, phosphoinositide 3-kinase inhibitor BYL719

Treatment (PI3K inhibitor BYL719, ado-trastuzumab emtansine)

ado-trastuzumab emtansine BIOLOGICAL

Given IV

Also known as: Kadcyla, T-DM1, trastuzumab-DM1, trastuzumab-MCC-DM1, trastuzumab-MCC-DM1 antibody-drug conjugate

Treatment (PI3K inhibitor BYL719, ado-trastuzumab emtansine)

pharmacological study OTHER

Correlative studies

Also known as: pharmacological studies

Treatment (PI3K inhibitor BYL719, ado-trastuzumab emtansine)

laboratory biomarker analysis OTHER

Optional correlative studies

Treatment (PI3K inhibitor BYL719, ado-trastuzumab emtansine)

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Northwestern University: lead
• Novartis: collaborator
• National Cancer Institute (NCI): collaborator

Study Sites (1)

Northwestern University

Chicago, Illinois, 60611, United States

Location

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Alpelisib; Ado-Trastuzumab Emtansine

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Maytansine; Macrolides; Lactones; Organic Chemicals; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Trastuzumab; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: William Gradishar, MD
• Organization: Northwestern University

w-gradishar@northwestern.edu

312 695 4541

Study Officials

• Sarika Jain

  Northwestern University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: January 14, 2014
• First Posted: January 16, 2014
• Study Start: May 21, 2014
• Primary Completion: April 15, 2015
• Study Completion: May 20, 2017
• Last Updated: June 29, 2020
• Results First Posted: March 4, 2020

Record last verified: 2020-06

Locations

US (1)