BYL719 and Letrozole in Post-Menopausal Patients With Hormone Receptor-Positive Metastatic Breast Cancer
|ClinicalTrials.gov Identifier: NCT01791478|
Recruitment Status : Active, not recruiting
First Posted : February 15, 2013
Last Update Posted : March 1, 2018
|Condition or disease||Intervention/treatment||Phase|
|Estrogen Receptor-positive Breast Cancer HER2-negative Breast Cancer Invasive Ductal Breast Carcinoma Progesterone Receptor-positive Breast Cancer Recurrent Breast Cancer Stage IV Breast Cancer||Drug: PI3K inhibitor BYL719 Drug: letrozole Other: laboratory biomarker analysis Other: pharmacological studies||Phase 1|
PRIMARY OBJECTIVE: To determine the safety and tolerability of BYL719 given in combination with endocrine therapy in post-menopausal patients with hormone receptor-positive metastatic breast cancer by determining:
I. Dose limiting toxicities (DLTs) during the first 4 weeks of treatment (cycle 1).
II. Maximum tolerated dose (MTD) of BYL719 (PI3K inhibitor BYL719) given in combination with letrozole.
III. Highest tolerated dose - ability to tolerate BYL719 with letrozole for a total of 8 weeks without development of:
- Hyperglycemia (fasting glucose > 200 mg/dL) for more than 2 weeks in a row despite optimal medical treatment
- CTC Grade 3 or > rash for more than 2 weeks in a row despite optimal medical treatment
- CTC Grade 2 or > GI toxicity for more than 2 weeks in a row despite optimal medical treatment
- CTC Grade 2 or > serum creatinine, bilirubin, AST, ALT elevation from baseline for more than 2 weeks in a row despite optimal medical treatment
SECONDARY OBJECTIVES: To determine the anti-tumor effect of the combinations of endocrine therapy with BYL719 in post-menopausal patients with hormone receptor-positive metastatic breast cancer by assessing:
I. Progression free survival (PFS). II. Objective response rate (ORR). III. Clinical benefit rate (complete response [CR]+partial response [PR]+stable disease [SD] >= 6 months).
I. Pharmacokinetics of BYL719 in combination with letrozole: Plasma concentration-time profiles and derived basic pharmacokinetic (PK) parameters of BYL719 and letrozole, including but not limited to area under the plasma concentration-time curve from time zero to the last measurable concentration (AUC0-tlast), AUC curve to infinite time (AUC0-inf), maximum observed concentration (Cmax), time to peak concentration (Tmax), clearance over bioavailability (CL/F), apparent volume of distribution (Vz/F) and the terminal half-life (t1/2) and other PK parameters if deemed appropriate.
II. Correlation of response with alterations of the PI3K pathway: Mutational analysis of PIK3CA (exons 9 and 20), phosphatase and tensin homolog (PTEN), and AKT1 in formalin-fixed paraffin blocks (FFPB) from previous surgeries or fresh-frozen biopsies (if available) on all patients enrolled in the trial.
OUTLINE: This is an open-label phase Ib dose-escalation study of the PI3K inhibitor BYL719 in combination with letrozole in post-menopausal patients with ER+ metastatic breast cancer.
Patients receive BYL719 orally (PO) once daily (QD) and letrozole PO QD. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 4 weeks.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||46 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase Ib Trial of BYL719 (an α-Specific PI3K Inhibitor) in Combination With Endocrine Therapy in Post-Menopausal Patients With Hormone Receptor-Positive Metastatic Breast Cancer|
|Study Start Date :||April 2013|
|Primary Completion Date :||December 2014|
|Estimated Study Completion Date :||September 2018|
Experimental: Treatment (PI3K inhibitor BYL719, letrozole)
Patients receive PI3K inhibitor BYL719 PO QD and letrozole PO QD. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
Drug: PI3K inhibitor BYL719
Other Name: BYL719, a-specific phosphoinositide 3-kinase inhibitor BYL719Drug: letrozole
Other Names:Other: laboratory biomarker analysis
Correlative studiesOther: pharmacological studies
- Maximum tolerated dose of BYL719 in combination with letrozole [ Time Frame: 4 weeks ]Highest dose of BYL719 tested in which a DLT is experienced by 0 out of 3 or 1 of 6 patients, based on the NCI Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0
- Highest tolerated dose of BYL719 in combination with letrozole [ Time Frame: 8 weeks ]Highest dose of BYL719 without CTC Grade > 2 hyperglycemia(fasting glucose > 200 mg/dL) for > 2 weeks, Grade > 3 rash for > 2 weeks , Grade > 2 gastrointestinal toxicity for > 2 weeks and Grade > 2 creatinine, bilirubin, AST, ALT for > 2 weeks.
- Clinical benefit rate [ Time Frame: At 6 months of study treatment ]Per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1; percentage of patients with complete response (CR) + partial response (PR) + stable disease (SD) for more than 6 months.
- Overall progression-free survival [ Time Frame: Up to 4 weeks after interruption of study treatment ]Duration from on-study date to date of progressive disease.
- Overall response [ Time Frame: Every 8 weeks to interruption of treatment ]Per RECIST version 1.1. number of patients each with CR, PR, SD, and progressive disease (PD) as their best response.
- Worst grade toxicities [ Time Frame: Up to 4 weeks after interruption of study treatment ]Number of patients with worst-grade toxicity at each of five grades (grade 1, least severe; to grade 5, most severe) following NCI Common Toxicity Criteria 4.0.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01791478
|United States, Massachusetts|
|Massachusetts General Hospital, Dana-Farber Cancer Institute|
|Boston, Massachusetts, United States, 02114|
|United States, Tennessee|
|Vanderbilt-Ingram Cancer Center|
|Nashville, Tennessee, United States, 37232-6838|
|Principal Investigator:||Ingrid Mayer||Vanderbilt-Ingram Cancer Center|