Dose Escalation Study of LEE011 in Combination With Buparlisib and Letrozole in HR+, HER2-negative Post-menopausal Women With Advanced Breast Cancer.

Study Overview
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Brief Summary
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This is a multi-center, open-label, non-randomized, phase I study

Official Title
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A Phase 1 Dose Escalation Study of LEE011 in Combination With Buparlisib and Letrozole for the Treatment of HR+, HER2-negative Post-menopausal Women With Locally Advanced or Metastatic Breast Cancer.

Conditions
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Advanced or Metastatic Breast Cancer

Intervention / Treatment
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* Drug: LEE011
* Drug: Buparlisib
* Drug: Letrozole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women with advanced (recurrent or metastatic) breast cancer who received no prior therapy for advanced disease. Patient is postmenopausal. Patient may have received ≤ 2 lines of chemotherapy for metastatic or recurrent breast cancer in the dose-escalation phase. Patient has a histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer by local laboratory. Patient has HER2-negative breast cancer defined as a negative in situ hybridization test or an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required by local laboratory testing. Patient must have either: Measurable disease, i.e., at least one measurable lesion as per RECIST 1.1 criteria or at least one predominantly lytic bone lesion Exclusion Criteria: Patient who received any CDK4/6 or PI3K inhibitor. Patient has active cardiac disease or a history of cardiac dysfunction including any of the following: History of angina pectoris, symptomatic pericarditis, or myocardial infarction within 12 months prior to study entry History of documented congestive heart failure (New York Heart Association functional classification III-IV) Documented cardiomyopathy Patient has a Left Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO) History of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal arrhythmias, or conduction abnormality in the previous 12 months. On screening, any of the following cardiac parameters: bradycardia (heart rate < 50 at rest), tachycardia (heart rate > 90 at rest), PR interval > 220 msec, QRS interval >109 msec, or QTcF >450 msec. Systolic blood pressure >160 or <90 mmHg Patient is currently receiving any of the following medications: That are known strong inducers or inhibitors of CYP3A4. That have a known risk to prolong the QT interval or induce Torsades de Pointes. That have a narrow therapeutic window and are predominantly metabolized through CYP3A4. Certain scores on an anxiety and depression mood questionnaires

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LEE011 + buparlisib + letrozole<br>open label, dose escalation evaluating max tolerated dose of the triple combination | Drug: LEE011<br>* 3 weeks on and 1 week off<br>Drug: Buparlisib<br>* daily<br>Drug: Letrozole<br>* 2.5 mg daily;<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose-limiting toxicities (DLTs) | Dose Escalation Phase: Frequency of DLTs at each dose level associated with administration of LEE011, buparlisib, and letrozole in a 28 day cycle | 28 days | 
| Safety and tolerability of the combination of LEE011, buparlisib, and letrozole | Dose Expansion Phase: Incidence of AEs, SAEs (overal and severity), laboratory abnormalities, ECG, vital, dose interteruptions, dose reductions, and dose intensity as a measure of safety and tolerability. | approximately 25 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerabiity of the combination of LEE011, buparlisib, and letrozole | Dose Escalation Phase: Incidence of AEs, SAEs (overall and severity), laboratory abnormalities, ECG, vital, dose interterruptions, dose reductions, and dose intensity as a measure of safety and tolerability. | approximately 25 months | 
| Pharmacokinetic paramters such as AUClast and Cmax of LEE011, buparlisib, and letrozole in order to characterize the PK profiles | Dose Escalation Phase: When given in combination as well any other clinically significant metabolites that may be identified | approximately 25 months | 
| Pharmacokinetic paramters such as AUClast and Cmax of LEE011, buparlisib, and letrozole in order to characterize the PK profiles | Dose Expansion Phase: When given in combination as well as any other clinically significant metabolites that may be identified | approximately 25 months | 
| Disease control rate | Dose Expansion Phase: Proportion of patients with the best overall response of CR (complete response), PR (partial response), or SD (stable disease) | approximately 25 months | 
| PFS (progression free survival) | Dose Expansion Phase: Time from date of start of treatment to date of first documented progression or death due to any cause. | approximately 25 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LEE011,, buparlisib,, letrozole,, HR +,, HER2 - negative,, post-menopausal,, breast cancer,, CDK 4/6,, PI3K,, MTD