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

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT01872260

Collaborator

(none)

255

Enrollment

Locations

Arms

110.3

Anticipated Duration (Months)

10.6

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: LEE011 Drug: Letrozole Drug: BYL719	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

255 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Oct 22, 2013

Anticipated Primary Completion Date :

Nov 30, 2022

Anticipated Study Completion Date :

Dec 31, 2022

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

Incidence of Dose limiting toxicities (DLTs) - Phase lb only [28 days]
Safety and tolerability [Average 18 months]
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 [18 months]
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 [Average 24 months]
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 [Average 24 months]
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) [Average 24 months]
ORR is defined as the proportion of patients with a best overall response of complete response or partial response.
Duration of Response (DOR) [Average 24 months]
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) [Average 24 months]
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) [Average 24 months]
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 [Average 24 months]
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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California at San Diego, Moores Cancer Ctr Dept. of Moores Cancer Center	San Diego	California	United States	92103
2	UCSF Medical Center	San Francisco	California	United States	94143
3	H Lee Moffitt Cancer Center and Research Institute H. Lee Moffitt Cancer Center	Tampa	Florida	United States	33612
4	Massachusetts General Hospital SC-5	Boston	Massachusetts	United States	02114
5	Sarah Cannon Research Institute SCRI SC	Nashville	Tennessee	United States	37203
6	Vanderbilt University Medical Center Vanderbilt - Thompson Ln	Nashville	Tennessee	United States	37232
7	Texas Oncology Texas Oncology - Sammons	Dallas	Texas	United States	75246
8	Cancer Therapy and Research Center UT Health Science Center Dept of Onc	San Antonio	Texas	United States	78229
9	Northwest Medical Specialties Northwest Medical Specialties	Tacoma	Washington	United States	98405
10	Novartis Investigative Site	Westmead	New South Wales	Australia	2145
11	Novartis Investigative Site	Parkville	Victoria	Australia	3050
12	Novartis Investigative Site	Nedlands	Western Australia	Australia	6009
13	Novartis Investigative Site	Marseille		France	13273
14	Novartis Investigative Site	Paris Cedex 10		France	75475
15	Novartis Investigative Site	Saint Herblain cedex		France	44805
16	Novartis Investigative Site	Pisa	PI	Italy	56126
17	Novartis Investigative Site	Seoul		Korea, Republic of	03080
18	Novartis Investigative Site	Sevilla	Andalucia	Spain	41013
19	Novartis Investigative Site	Valencia	Comunidad Valenciana	Spain	46010
20	Novartis Investigative Site	Madrid		Spain	28009
21	Novartis Investigative Site	Madrid		Spain	28050
22	Novartis Investigative Site	Bellinzona		Switzerland	6500
23	Novartis Investigative Site	Glasgow	Scotland	United Kingdom	G12 0YN
24	Novartis Investigative Site	Manchester		United Kingdom	M20 4BX

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Novartis Pharmaceuticals

ClinicalTrials.gov Identifier:

NCT01872260

Other Study ID Numbers:

CLEE011X2107
2013-001219-57

First Posted:

Jun 7, 2013

Last Update Posted:

Feb 18, 2022

Last Verified:

Feb 1, 2022

Individual Participant Data (IPD) Sharing Statement:

Plan to Share IPD:

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Keywords provided by Novartis Pharmaceuticals

Hormone-receptor positive

Additional relevant MeSH terms:

Breast Neoplasms

Letrozole

Study Results

No Results Posted as of Feb 18, 2022