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

Study Overview
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Brief Summary
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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.

Official Title
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A Phase Ib/II, Multicenter Study of the Combination of LEE011 and BYL719 With Letrozole in Adult Patients With Advanced ER+ Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: LEE011
* Drug: Letrozole
* Drug: BYL719


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LEE011 + letrozole Arm 1<br>LEE011 - 28 day cycles (21 days followed by a 7 day break - dose escalating), letrozole - 2.5 mg/day | Drug: LEE011<br>* LEE011 - 28 day cycles (21 days followed by a 7 day break) for Arms 1, 3. LEE011 28 days cycles (continuous) Arm 4.<br>Drug: Letrozole<br>* Letrozole 2.5 mg/day<br>|
| Experimental: BYL719 + letrozole Arm 2<br>BYL719 - daily (dose escalating) letrozole - 2.5 mg/day | Drug: Letrozole<br>* Letrozole 2.5 mg/day<br>Drug: BYL719<br>* BYL719 - 28 days cycle (continuous) for Arm 2; 3 and 4<br>|
| Experimental: LEE011 + BYL719 + letrozole Arm 3<br>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<br>* LEE011 - 28 day cycles (21 days followed by a 7 day break) for Arms 1, 3. LEE011 28 days cycles (continuous) Arm 4.<br>Drug: Letrozole<br>* Letrozole 2.5 mg/day<br>Drug: BYL719<br>* BYL719 - 28 days cycle (continuous) for Arm 2; 3 and 4<br>|
| Experimental: LEE011+ BYL719+letrozole Arm 4<br>LEE011-daily (dose escalating), BYL719 -daily (dose escalating), letrozole 2.5 mg/day | Drug: LEE011<br>* LEE011 - 28 day cycles (21 days followed by a 7 day break) for Arms 1, 3. LEE011 28 days cycles (continuous) Arm 4.<br>Drug: Letrozole<br>* Letrozole 2.5 mg/day<br>Drug: BYL719<br>* BYL719 - 28 days cycle (continuous) for Arm 2; 3 and 4<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Dose limiting toxicities (DLTs) - Phase lb only |  | 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. | Average 18 months | 
| PK profiles of LEE011 and letrozole | To characterize PK profiles of LEE011 and Letrozole. | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hormone-receptor positive