Clinical trial NCT01872260: 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
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Breast Cancer
Keywords: Hormone-receptor positive
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2013-06-07
Enrollment: 255
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Incidence of Dose limiting toxicities (DLTs) - Phase lb only
timeFrame: 28 days
measure: Safety and tolerability
timeFrame: Average 18 months
measure: PK profiles of LEE011 and letrozole
timeFrame: 18 months
Secondary outcomes:
measure: Safety and tolerability of LEE011 in combination with letrozole, BYL719 in combination with letrozole, and the triple combination of LEE011 +BYL719 with letrozole
timeFrame: Average 24 months
measure: Plasma concentration-time profiles of LEE011, BYL719 and letrozole
timeFrame: Average 24 months
measure: Overall Response Rate (ORR)
timeFrame: Average 24 months
measure: Duration of Response (DOR)
timeFrame: Average 24 months
measure: Progression Free Survival (PFS)
timeFrame: Average 24 months
measure: Pharmacokinetics (PK) parameters, including but not limited to AUCtau, Cmin, Cmax, Tmax, accumulation ratio (Racc)
timeFrame: Average 24 months
measure: Safety and tolerability of the triple combination of LEE011 +BYL719 with letrozole in patients previously treated with either doublet
timeFrame: Average 24 months
Other outcomes:
Locations:
city: San Diego
country: United States
facility: Univ of California at San Diego Moores Cancer Ctr
state: California
city: San Francisco
country: United States
facility: UCSF Medical Center
state: California
city: Tampa
country: United States
facility: H Lee Moffitt Cancer Center and Research Institute
state: Florida
city: Boston
country: United States
facility: Massachusetts General Hospital SC-5
state: Massachusetts
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University Medical Ctr
state: Tennessee
city: Dallas
country: United States
facility: Texas Oncology
state: Texas
city: San Antonio
country: United States
facility: Mays Cancer Ctr Uthsa Mdacc
state: Texas
city: Tacoma
country: United States
facility: Northwest Medical Specialties
state: Washington
city: Westmead
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Parkville
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Nedlands
country: Australia
facility: Novartis Investigative Site
state: Western Australia
city: Marseille
country: France
facility: Novartis Investigative Site
city: Paris 10
country: France
facility: Novartis Investigative Site
city: Saint Herblain
country: France
facility: Novartis Investigative Site
city: Pisa
country: Italy
facility: Novartis Investigative Site
state: PI
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Sevilla
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Valencia
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Bellinzona
country: Switzerland
facility: Novartis Investigative Site
city: Glasgow
country: United Kingdom
facility: Novartis Investigative Site
city: Manchester
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: