BYL719 and Letrozole in Post-Menopausal Patients With Hormone Receptor-Positive Metastatic Breast Cancer
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|ClinicalTrials.gov Identifier: NCT01791478|
Recruitment Status : Active, not recruiting
First Posted : February 15, 2013
Last Update Posted : October 2, 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|
|Actual Primary Completion Date :||December 2014|
|Estimated Study Completion Date :||September 2019|
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 BYL719
Other: laboratory biomarker analysis
Other: 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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
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|