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

Primary Purpose

Breast Cancer

Status
Active
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
LEE011
Letrozole
BYL719
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Breast Cancer focused on measuring Hormone-receptor positive

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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

Sites / Locations

  • University of California at San Diego, Moores Cancer Ctr Dept. of Moores Cancer Center
  • UCSF Medical Center .
  • H Lee Moffitt Cancer Center and Research Institute H. Lee Moffitt Cancer Center
  • Massachusetts General Hospital SC-5
  • Sarah Cannon Research Institute SCRI SC
  • Vanderbilt University Medical Center Vanderbilt - Thompson Ln
  • Texas Oncology Texas Oncology - Sammons
  • Mays Cancer Ctr Uthsa Mdacc Dept of Onc
  • Northwest Medical Specialties Northwest Medical Specialties
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

LEE011 + letrozole Arm 1

BYL719 + letrozole Arm 2

LEE011 + BYL719 + letrozole Arm 3

LEE011+ BYL719+letrozole Arm 4

Arm Description

LEE011 - 28 day cycles (21 days followed by a 7 day break - dose escalating), letrozole - 2.5 mg/day

BYL719 - daily (dose escalating) letrozole - 2.5 mg/day

LEE011 - 28 day cycles (21 days followed by a 7 day break -dose escalating), BYL719 - daily (dose escalating), letrozole 2.5 mg/day

LEE011-daily (dose escalating), BYL719 -daily (dose escalating), letrozole 2.5 mg/day

Outcomes

Primary Outcome Measures

Incidence of Dose limiting toxicities (DLTs) - Phase lb only
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.
PK profiles of LEE011 and letrozole
To characterize PK profiles of LEE011 and Letrozole.

Secondary Outcome Measures

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
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.
Overall Response Rate (ORR)
ORR is defined as the proportion of patients with a best overall response of complete response or partial response.
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.
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.
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.
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

Full Information

First Posted
May 30, 2013
Last Updated
October 16, 2023
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT01872260
Brief Title
Study of LEE011, BYL719 and Letrozole in Advanced ER+ Breast Cancer
Official Title
A Phase Ib/II, Multicenter Study of the Combination of LEE011 and BYL719 With Letrozole in Adult Patients With Advanced ER+ Breast Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
October 22, 2013 (Actual)
Primary Completion Date
November 29, 2024 (Anticipated)
Study Completion Date
December 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Breast Cancer
Keywords
Hormone-receptor positive

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
255 (Actual)

8. Arms, Groups, and Interventions

Arm Title
LEE011 + letrozole Arm 1
Arm Type
Experimental
Arm Description
LEE011 - 28 day cycles (21 days followed by a 7 day break - dose escalating), letrozole - 2.5 mg/day
Arm Title
BYL719 + letrozole Arm 2
Arm Type
Experimental
Arm Description
BYL719 - daily (dose escalating) letrozole - 2.5 mg/day
Arm Title
LEE011 + BYL719 + letrozole Arm 3
Arm Type
Experimental
Arm Description
LEE011 - 28 day cycles (21 days followed by a 7 day break -dose escalating), BYL719 - daily (dose escalating), letrozole 2.5 mg/day
Arm Title
LEE011+ BYL719+letrozole Arm 4
Arm Type
Experimental
Arm Description
LEE011-daily (dose escalating), BYL719 -daily (dose escalating), letrozole 2.5 mg/day
Intervention Type
Drug
Intervention Name(s)
LEE011
Intervention Description
LEE011 - 28 day cycles (21 days followed by a 7 day break) for Arms 1, 3. LEE011 28 days cycles (continuous) Arm 4.
Intervention Type
Drug
Intervention Name(s)
Letrozole
Intervention Description
Letrozole 2.5 mg/day
Intervention Type
Drug
Intervention Name(s)
BYL719
Intervention Description
BYL719 - 28 days cycle (continuous) for Arm 2; 3 and 4
Primary Outcome Measure Information:
Title
Incidence of Dose limiting toxicities (DLTs) - Phase lb only
Time Frame
28 days
Title
Safety and tolerability
Description
Adverse Events (AEs), serious AEs (SAEs), changes in hematology and chemistry values, vital signs, electrocardiograms (ECGs), dose interruptions, reductions and dose intensity.
Time Frame
Average 18 months
Title
PK profiles of LEE011 and letrozole
Description
To characterize PK profiles of LEE011 and Letrozole.
Time Frame
18 months
Secondary Outcome Measure Information:
Title
Safety and tolerability of LEE011 in combination with letrozole, BYL719 in combination with letrozole, and the triple combination of LEE011 +BYL719 with letrozole
Description
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
Time Frame
Average 24 months
Title
Plasma concentration-time profiles of LEE011, BYL719 and letrozole
Description
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.
Time Frame
Average 24 months
Title
Overall Response Rate (ORR)
Description
ORR is defined as the proportion of patients with a best overall response of complete response or partial response.
Time Frame
Average 24 months
Title
Duration of Response (DOR)
Description
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.
Time Frame
Average 24 months
Title
Progression Free Survival (PFS)
Description
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.
Time Frame
Average 24 months
Title
Pharmacokinetics (PK) parameters, including but not limited to AUCtau, Cmin, Cmax, Tmax, accumulation ratio (Racc)
Description
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.
Time Frame
Average 24 months
Title
Safety and tolerability of the triple combination of LEE011 +BYL719 with letrozole in patients previously treated with either doublet
Description
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
Time Frame
Average 24 months

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
University of California at San Diego, Moores Cancer Ctr Dept. of Moores Cancer Center
City
San Diego
State/Province
California
ZIP/Postal Code
92103
Country
United States
Facility Name
UCSF Medical Center .
City
San Francisco
State/Province
California
ZIP/Postal Code
94143
Country
United States
Facility Name
H Lee Moffitt Cancer Center and Research Institute H. Lee Moffitt Cancer Center
City
Tampa
State/Province
Florida
ZIP/Postal Code
33612
Country
United States
Facility Name
Massachusetts General Hospital SC-5
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Sarah Cannon Research Institute SCRI SC
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37203
Country
United States
Facility Name
Vanderbilt University Medical Center Vanderbilt - Thompson Ln
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States
Facility Name
Texas Oncology Texas Oncology - Sammons
City
Dallas
State/Province
Texas
ZIP/Postal Code
75246
Country
United States
Facility Name
Mays Cancer Ctr Uthsa Mdacc Dept of Onc
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229
Country
United States
Facility Name
Northwest Medical Specialties Northwest Medical Specialties
City
Tacoma
State/Province
Washington
ZIP/Postal Code
98405
Country
United States
Facility Name
Novartis Investigative Site
City
Westmead
State/Province
New South Wales
ZIP/Postal Code
2145
Country
Australia
Facility Name
Novartis Investigative Site
City
Parkville
State/Province
Victoria
ZIP/Postal Code
3050
Country
Australia
Facility Name
Novartis Investigative Site
City
Nedlands
State/Province
Western Australia
ZIP/Postal Code
6009
Country
Australia
Facility Name
Novartis Investigative Site
City
Marseille
ZIP/Postal Code
13273
Country
France
Facility Name
Novartis Investigative Site
City
Paris 10
ZIP/Postal Code
75475
Country
France
Facility Name
Novartis Investigative Site
City
Saint Herblain
ZIP/Postal Code
44805
Country
France
Facility Name
Novartis Investigative Site
City
Pisa
State/Province
PI
ZIP/Postal Code
56126
Country
Italy
Facility Name
Novartis Investigative Site
City
Seoul
ZIP/Postal Code
03080
Country
Korea, Republic of
Facility Name
Novartis Investigative Site
City
Sevilla
State/Province
Andalucia
ZIP/Postal Code
41013
Country
Spain
Facility Name
Novartis Investigative Site
City
Valencia
State/Province
Comunidad Valenciana
ZIP/Postal Code
46010
Country
Spain
Facility Name
Novartis Investigative Site
City
Madrid
ZIP/Postal Code
28009
Country
Spain
Facility Name
Novartis Investigative Site
City
Madrid
ZIP/Postal Code
28050
Country
Spain
Facility Name
Novartis Investigative Site
City
Bellinzona
ZIP/Postal Code
6500
Country
Switzerland
Facility Name
Novartis Investigative Site
City
Glasgow
State/Province
Scotland
ZIP/Postal Code
G12 0YN
Country
United Kingdom
Facility Name
Novartis Investigative Site
City
Manchester
ZIP/Postal Code
M20 4BX
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

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

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