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

Phase 1

Completed

• Conditions: Advanced or Metastatic Breast Cancer
• Interventions: Drug: LEE011; Drug: Buparlisib; Drug: Letrozole

• Registration Number: NCT02154776
• Lead Sponsor: Novartis Pharmaceuticals

Brief Summary

This is a multi-center, open-label, non-randomized, phase I study

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2014-05-28
• Study First Submitted QC: 2014-05-30
• Study First Posted: 2014-06-03
• Study Start: 2014-06-27
• Primary Completion: 2016-10-26
• Study Completion: 2016-10-26
• Status Verified: 2018-07
• Last Update Submitted: 2020-12-16
• Last Update Posted: 2020-12-19

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 13

Inclusion Criteria

1. Women with advanced (recurrent or metastatic) breast cancer who received no prior therapy for advanced disease.

2. Patient is postmenopausal.

3. Patient may have received ≤ 2 lines of chemotherapy for metastatic or recurrent breast cancer in the dose-escalation phase.

4. Patient has a histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer by local laboratory.

5. 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.

6. 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

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Exclusion Criteria

1. Patient who received any CDK4/6 or PI3K inhibitor.

2. 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

3. 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.

4. Certain scores on an anxiety and depression mood questionnaires

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
LEE011 + buparlisib + letrozole	LEE011	open label, dose escalation evaluating max tolerated dose of the triple combination
LEE011 + buparlisib + letrozole	Buparlisib	open label, dose escalation evaluating max tolerated dose of the triple combination
LEE011 + buparlisib + letrozole	Letrozole	open label, dose escalation evaluating max tolerated dose of the triple combination

Primary Outcome Measures

Name	Time	Method
Incidence of dose-limiting toxicities (DLTs)	28 days	Dose Escalation Phase: Frequency of DLTs at each dose level associated with administration of LEE011, buparlisib, and letrozole in a 28 day cycle
Safety and tolerability of the combination of LEE011, buparlisib, and letrozole	approximately 25 months	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.

Secondary Outcome Measures

Name	Time	Method
Safety and tolerabiity of the combination of LEE011, buparlisib, and letrozole	approximately 25 months	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.
Pharmacokinetic paramters such as AUClast and Cmax of LEE011, buparlisib, and letrozole in order to characterize the PK profiles	approximately 25 months	Dose Expansion Phase: When given in combination as well as any other clinically significant metabolites that may be identified
Disease control rate	approximately 25 months	Dose Expansion Phase: Proportion of patients with the best overall response of CR (complete response), PR (partial response), or SD (stable disease)
PFS (progression free survival)	approximately 25 months	Dose Expansion Phase: Time from date of start of treatment to date of first documented progression or death due to any cause.

Trial Locations

Locations (6)

Horizon Oncology Center SC; 🇺🇸 Lafayette, Indiana, United States

Medical University of South Carolina SC; 🇺🇸 Charleston, South Carolina, United States

South Texas Accelerated Research Therapeutics SC; 🇺🇸 San Antonio, Texas, United States

University of California at Los Angeles UCLA SC; 🇺🇸 Los Angeles, California, United States

University of Utah / Huntsman Cancer Institute SC-3; 🇺🇸 Salt Lake City, Utah, United States

Novartis Investigative Site; 🇪🇸 Madrid, Spain