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

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.

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

Study Overview

• Status: Completed
• Conditions: Advanced or Metastatic Breast Cancer
• Intervention / Treatment: Drug: LEE011; Drug: Buparlisib; Drug: Letrozole

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 1

Contacts and Locations

Study Locations

• Spain
  • Madrid, Spain, 28007
    • Novartis Investigative Site
• United States
  • California
    • Los Angeles, California, United States, 90095
      • University of California at Los Angeles UCLA SC
  • Indiana
    • Lafayette, Indiana, United States, 47905
      • Horizon Oncology Center SC
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina SC
  • Texas
    • San Antonio, Texas, United States, 78922
      • South Texas Accelerated Research Therapeutics SC
  • Utah
    • Salt Lake City, Utah, United States, 84103
      • University of Utah / Huntsman Cancer Institute SC-3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• Results for CLEE011A2112C can be found on the Novartis Clinical Trial Results Website

Study record dates

Study Major Dates

• Study Start (Actual): June 27, 2014
• Primary Completion (Actual): October 26, 2016
• Study Completion (Actual): October 26, 2016

Study Registration Dates

• First Submitted: May 28, 2014
• First Submitted That Met QC Criteria: May 30, 2014
• First Posted (Estimate): June 3, 2014

Study Record Updates

• Last Update Posted (Actual): December 19, 2020
• Last Update Submitted That Met QC Criteria: December 16, 2020
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Keywords: breast cancer,; PI3K,; MTD; LEE011,; buparlisib,; letrozole,; HR +,; HER2 - negative,; post-menopausal,; CDK 4/6,
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Letrozole
• Other Study ID Numbers: CLEE011A2112C

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No