Purpose

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

Eligibility

Eligible Ages
Over 18 Years
Eligible Genders
Female
Accepts Healthy Volunteers
No

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

Study Design

Phase
Phase 1/Phase 2
Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel Assignment
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
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

More Details

Status
Active, not recruiting
Sponsor
Novartis Pharmaceuticals

Study Contact

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.