Study of LEE011, BYL719 and Letrozole in Advanced ER+ Breast Cancer

A Phase Ib/II, Multicenter Study of the Combination of LEE011 and BYL719 With Letrozole in Adult Patients With Advanced ER+ Breast Cancer

The purpose of this trial is to inform the future clinical development of the two investigational agents in ER+ breast cancer, LEE011 (CDK4/6 inhibitor) and BYL719 (PI3K-alpha inhibitor).

This is a multi-center, open-label Phase Ib study. The Phase Ib dose escalation will estimate the MTD and/or RP2D for three regimens: two double combinations, LEE011 with letrozole and BYL719 with letrozole, followed by triple combinations of LEE011 + BYL719 with letrozole (Arms 3 and 4).

The Phase Ib dose escalation part will be followed by Phase Ib dose expansions to further characterize the safety, tolerability, PK and preliminary clinical anti-tumor activity of the combinations. Optional crossover for patients who have progressed while on dose escalation or dose expansion with doublet treatment on Arms 1 or 2 to be treated with the triplet combination (Arm 3) after the determination of the RP2D for Arm 3; is no longer permitted after protocol amendment 6.

Approximately 270 adult women with ER+/HER2- locally advanced or metastatic breast cancer will be enrolled.

Study Overview

• Status: Active, not recruiting
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: LEE011; Drug: Letrozole; Drug: BYL719

• Study Type: Interventional
• Enrollment (Actual): 255
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Westmead, New South Wales, Australia, 2145
      • Novartis Investigative Site
  • Victoria
    • Parkville, Victoria, Australia, 3050
      • Novartis Investigative Site
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Novartis Investigative Site
• France
  • Marseille, France, 13273
    • Novartis Investigative Site
  • Paris 10, France, 75475
    • Novartis Investigative Site
  • Saint Herblain, France, 44805
    • Novartis Investigative Site
• Italy
  • PI
    • Pisa, PI, Italy, 56126
      • Novartis Investigative Site
• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28050
    • Novartis Investigative Site
  • Madrid, Spain, 28009
    • Novartis Investigative Site
  • Andalucia
    • Sevilla, Andalucia, Spain, 41013
      • Novartis Investigative Site
  • Comunidad Valenciana
    • Valencia, Comunidad Valenciana, Spain, 46010
      • Novartis Investigative Site
• Switzerland
  • Bellinzona, Switzerland, 6500
    • Novartis Investigative Site
• United Kingdom
  • Glasgow, United Kingdom, G12 0YN
    • Novartis Investigative Site
  • Manchester, United Kingdom, M20 4BX
    • Novartis Investigative Site
• United States
  • California
    • San Diego, California, United States, 92103
      • University of California at San Diego, Moores Cancer Ctr Dept. of Moores Cancer Center
    • San Francisco, California, United States, 94143
      • UCSF Medical Center .
  • Florida
    • Tampa, Florida, United States, 33612
      • H Lee Moffitt Cancer Center and Research Institute H. Lee Moffitt Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital SC-5
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute SCRI SC
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Ctr Vanderbilt - Thompson Ln
  • Texas
    • Dallas, Texas, United States, 75246
      • Texas Oncology Texas Oncology - Sammons
    • San Antonio, Texas, United States, 78229
      • Mays Cancer Ctr Uthsa Mdacc Dept of Onc
  • Washington
    • Tacoma, Washington, United States, 98405
      • Northwest Medical Specialties Northwest Medical Specialties

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Postmenopausal, Estrogen-receptor positive and/or Progesterone-receptor positive breast cancer
• Phase Ib dose escalation only: Any number of prior lines of endocrine therapy is allowed with the exception of cytotoxic therapy which is limited to one prior line administered in the advanced (metastatic or locally advanced) setting.
• Phase Ib dose expansions Arms 1, 2 and 3
• No prior systemic treatment in the advanced (metastatic or locally advanced) setting with the exception of treatment with letrozole for a maximum of one month prior to starting study treatment.
• Patients who received (neo)adjuvant therapy for breast cancer are eligible. Prior therapy with letrozole or anastrozole in the (neo)adjuvant setting is permitted if the disease-free interval is greater than 12 months from the completion of treatment.

Exclusion Criteria:

• HER2-overexpression in the patient's tumor tissue
• Patients with active CNS or other brain metastases
• Major surgery within 2 weeks
• Acute or chronic pancreatitis
• Bilateral diffuse lymphangitic carcinomatosis
• Another malignancy within 3 years
• Receiving hormone replacement therapy that cannot be discontinued
• Impaired cardiac function
• Patients with clinically manifest diabetes mellitus (treated and/or clinical signs or with fasting glucose ≥ 126 mg/dL / 7.0 mmol/L or hemoglobin A1c >6.5%), history of gestational diabetes mellitus or documented steroid-induced diabetes mellitus.
• Other protocol-defined inclusion/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LEE011 + letrozole Arm 1; LEE011 - 28 day cycles (21 days followed by a 7 day break - dose escalating), letrozole - 2.5 mg/day	Drug: LEE011; LEE011 - 28 day cycles (21 days followed by a 7 day break) for Arms 1, 3. LEE011 28 days cycles (continuous) Arm 4.; Drug: Letrozole; Letrozole 2.5 mg/day
Experimental: BYL719 + letrozole Arm 2; BYL719 - daily (dose escalating) letrozole - 2.5 mg/day	Drug: Letrozole; Letrozole 2.5 mg/day; Drug: BYL719; BYL719 - 28 days cycle (continuous) for Arm 2; 3 and 4
Experimental: LEE011 + BYL719 + letrozole Arm 3; LEE011 - 28 day cycles (21 days followed by a 7 day break -dose escalating), BYL719 - daily (dose escalating), letrozole 2.5 mg/day	Drug: LEE011; LEE011 - 28 day cycles (21 days followed by a 7 day break) for Arms 1, 3. LEE011 28 days cycles (continuous) Arm 4.; Drug: Letrozole; Letrozole 2.5 mg/day; Drug: BYL719; BYL719 - 28 days cycle (continuous) for Arm 2; 3 and 4
Experimental: LEE011+ BYL719+letrozole Arm 4; LEE011-daily (dose escalating), BYL719 -daily (dose escalating), letrozole 2.5 mg/day	Drug: LEE011; LEE011 - 28 day cycles (21 days followed by a 7 day break) for Arms 1, 3. LEE011 28 days cycles (continuous) Arm 4.; Drug: Letrozole; Letrozole 2.5 mg/day; Drug: BYL719; BYL719 - 28 days cycle (continuous) for Arm 2; 3 and 4

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Dose limiting toxicities (DLTs) - Phase lb only		28 days
Safety and tolerability	Adverse Events (AEs), serious AEs (SAEs), changes in hematology and chemistry values, vital signs, electrocardiograms (ECGs), dose interruptions, reductions and dose intensity.	Average 18 months
PK profiles of LEE011 and letrozole	To characterize PK profiles of LEE011 and Letrozole.	18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and tolerability of LEE011 in combination with letrozole, BYL719 in combination with letrozole, and the triple combination of LEE011 +BYL719 with letrozole	Safety and tolerability will be determined by type, frequency and severity of adverse events and laboratory abnormalities per Common Terminology Criteria for Adverse Events (CTCAE) version 4.03	Average 24 months
Plasma concentration-time profiles of LEE011, BYL719 and letrozole	To characterize the PK profiles of LEE011, BYL719, and letrozole when used in combination as well as to evaluate any other clinically significant metabolites that may be identified.	Average 24 months
Overall Response Rate (ORR)	ORR is defined as the proportion of patients with a best overall response of complete response or partial response.	Average 24 months
Duration of Response (DOR)	DOR is calculated as the time from the date of first documented response (complete response (CR) or partial response (PR)) to the first documented date of progression or death due to underlying cancer.	Average 24 months
Progression Free Survival (PFS)	PFS is the time from date of randomization/start of treatment to the date of event defined as the first documented progression or death due to any cause.	Average 24 months
Pharmacokinetics (PK) parameters, including but not limited to AUCtau, Cmin, Cmax, Tmax, accumulation ratio (Racc)	To characterize the PK profiles of LEE011, BYL719, and letrozole when used in combination as well as to evaluate any other clinically significant metabolites that may be identified.	Average 24 months
Safety and tolerability of the triple combination of LEE011 +BYL719 with letrozole in patients previously treated with either doublet	Safety and tolerability will be determined by type, frequency and severity of adverse events and laboratory abnormalities per Common Terminology Criteria for Adverse Events (CTCAE) version 4.03	Average 24 months

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): October 22, 2013
• Primary Completion (Estimated): November 29, 2024
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: May 30, 2013
• First Submitted That Met QC Criteria: June 4, 2013
• First Posted (Estimated): June 7, 2013

Study Record Updates

• Last Update Posted (Actual): February 12, 2024
• Last Update Submitted That Met QC Criteria: February 9, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Hormone-receptor positive
• 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: CLEE011X2107; 2013-001219-57 (EudraCT Number)

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