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

Phase 2Active Not RecruitingNCT01872260

Novartis Pharmaceuticals259 enrolled

Overview

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

259

Conditions

Breast Cancer

Interventions

Eligibility

Sex: FEMALEMin age: 18 YearsMax age: 100 Years

Medical Language ↔ Plain English

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

Locations (25)

Univ of California at San Diego Moores Cancer Ctr

San Diego, California, United States

UCSF Medical Center

San Francisco, California, United States

H Lee Moffitt Cancer Center and Research Institute

Tampa, Florida, United States

Massachusetts General Hospital SC-5

Boston, Massachusetts, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Tennessee Oncology

Nashville, Tennessee, United States

Vanderbilt University Medical Ctr

Nashville, Tennessee, United States

Texas Oncology

Amarillo, Texas, United States

Mays Cancer Ctr Uthsa Mdacc

San Antonio, Texas, United States

Northwest Medical Specialties

Tacoma, Washington, United States

...and 15 more locations

Outcomes

Primary Outcomes

Incidence of Dose limiting toxicities (DLTs) - Phase lb only

Time frame: 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.

Time frame: Average 18 months

PK profiles of LEE011 and letrozole

To characterize PK profiles of LEE011 and Letrozole.

Time frame: 18 months

Secondary Outcomes

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

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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

Time frame: Average 24 months