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

Breast Cancer Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01872260
• Other study ID #: CLEE011X2107
• Secondary ID: 2013-001219-57
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: October 22, 2013
• Est. completion date: December 31, 2024

Study information

• Verified date: May 2024
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 255
• Est. completion date: December 31, 2024
• Est. primary completion date: December 31, 2024
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

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.
• Letrozole
Letrozole 2.5 mg/day
• BYL719
BYL719 - 28 days cycle (continuous) for Arm 2; 3 and 4

Locations

Country	Name	City	State
Australia	Novartis Investigative Site	Nedlands	Western Australia
Australia	Novartis Investigative Site	Parkville	Victoria
Australia	Novartis Investigative Site	Westmead	New South Wales
France	Novartis Investigative Site	Marseille
France	Novartis Investigative Site	Paris 10
France	Novartis Investigative Site	Saint Herblain
Italy	Novartis Investigative Site	Pisa	PI
Korea, Republic of	Novartis Investigative Site	Seoul
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Sevilla	Andalucia
Spain	Novartis Investigative Site	Valencia	Comunidad Valenciana
Switzerland	Novartis Investigative Site	Bellinzona
United Kingdom	Novartis Investigative Site	Glasgow
United Kingdom	Novartis Investigative Site	Manchester
United States	Massachusetts General Hospital SC-5	Boston	Massachusetts
United States	Texas Oncology Texas Oncology - Sammons	Dallas	Texas
United States	Sarah Cannon Research Institute SCRI SC	Nashville	Tennessee
United States	Vanderbilt University Medical Ctr Vanderbilt Thompson Ln	Nashville	Tennessee
United States	Mays Cancer Ctr Uthsa Mdacc Dept of Onc	San Antonio	Texas
United States	University of California at San Diego, Moores Cancer Ctr Dept of Moores Cancer Center	San Diego	California
United States	UCSF Medical Center .	San Francisco	California
United States	Northwest Medical Specialties Northwest Medical Specialties	Tacoma	Washington
United States	H Lee Moffitt Cancer Center and Research Institute H. Lee Moffitt Cancer Center	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Australia,  France,  Italy,  Korea, Republic of,  Spain,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of Dose limiting toxicities (DLTs) - Phase lb only		28 days
Primary	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
Primary	PK profiles of LEE011 and letrozole	To characterize PK profiles of LEE011 and Letrozole.	18 months
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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