A Phase Ib Dose Escalation Study of the Combination of LEE011 With Letrozole and Dose Expansion of LEE011 With Hormonal Therapy for the Treatment of Pre-(With Goserelin) and Postmenopausal Women With Hormone Receptor Positive, HER2-negative, Advanced Breast Cancer

Study Overview
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Brief Summary
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The purpose of the Phase Ib is to: determine the recommended dose of LEE011 in combination with a standard dose of letrozole as well as to provide additional safety and anti-tumor activity data in Asian non-Japanese patients determine the recommended dose of LEE011 in combination with a standard dose of letrozole as well as to provide additional safety and activity data in Japanese patients evaluate the safety and anti-tumor activity of LEE011 at the RP2D established in the dose escalation part in combination with a standard dose of letrozole, fulvestrant or tamoxifen plus goserelin in Japanese patients.

Official Title
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A Phase Ib Dose Escalation Study of the Combination of LEE011 With Letrozole and Dose Expansion of LEE011 With Hormonal Therapy for the Treatment of Pre-(With Goserelin) and Postmenopausal Women With Hormone Receptor Positive, HER2-negative, Advanced Breast Cancer

Conditions
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Hormone Receptor Positive, HER2-negative, Advanced Breast Cancer

Intervention / Treatment
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* Drug: LEE011
* Drug: Letrozole
* Drug: Tamoxifen
* Drug: Fulvestrant
* Drug: goserelin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women with advanced (locoregionally recurrent or metastatic) breast cancer not amenable to curative therapy (surgery and/or radiotherapy). Patient has a histologically and/or cytologically confirmed diagnosis of estrogen receptor positive and/or progesterone receptor positive breast cancer Patient has HER2-negative breast cancer Patient has adequate bone marrow and organ function Exclusion Criteria: Patient who received any CDK4/6 inhibitor. Patient has a known hypersensitivity to any of the excipients of LEE011 or letrozole Patients with inflammatory breast cancer. Patient who received any prior systemic anti-cancer therapy (including hormonal therapy and chemotherapy) for advanced breast cancer Patient is currently using other anti-cancer therapy Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major side effects. Patient who has received radiotherapy ≤ 4 weeks Patient has a concurrent malignancy or malignancy within 3 years Patient has metastases to the central nervous system (CNS). Patient has a known history of HIV infection 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LEE011 +Letrozole<br>LEE011 - 3 weeks on 1 week off Letrozole 2.5mg - Once daily | Drug: LEE011<br>* LEE011 as 50 mg and 200 mg hard gelatin oral capsules as individual patient supply packaged in bottles. LEE011 will be taken QD - days 1-21 of each 28 days cycle.<br>Drug: Letrozole<br>* 25mg<br>|
| Experimental: LEE011 + Tamoxifen<br>LEE011 - 3 weeks on 1 week off Tamoxifen 20mg - Once daily | Drug: Tamoxifen<br>* 20 mg<br>Drug: goserelin<br> <br> |
| Experimental: LEE011 + Fulvestrant<br>LEE011 - 3 weeks on 1 week off Fulvestrant 500 mg - Dosed every 28 days (Day 1 for each cycle) with 1 additional dose on Day 15 of Cycle 1 | Drug: Fulvestrant<br>* 500 mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase Ib Dose escalation - Frequency of dose limiting toxicities (DLTs) | DLTs at each dose level associated with administration of LEE011 and letrozole | first cycle (28 days) | 
| Phase Ib Dose Expansion: Number of participants with adverse events (AEs) | This will be defined by changes in hematology and chemistry values, vital signs and ECGs, frequency and duration of AEs, lab abnormalities and other safety parameters. For LEE011 and letrozole or tamoxifen or fulvestrant | 18 months | 
| Phase Ib Dose Expansion: Number of participants with serious adverse events (SAEs) | This will be defined by changes in hematology and chemistry values, vital signs and ECGs, frequency and duration of SAEs, lab abnormalities and other safety parameters. For LEE011 and letrozole or tamoxifen or fulvestrant | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events (AEs) - Phase Ib dose escalation | This will be defined by changes in hematology and chemistry values, vital signs and ECGs, frequency and duration of AEs, lab abnormalities and other safety parameters. For LEE011 and letrozole or tamoxifen or fulvestrant | 18 months | 
| Number of participants with serious adverse events (SAEs) - Phase Ib dose escalation | This will be defined by changes in hematology and chemistry values, vital signs and ECGs, frequency and duration of SAEs, lab abnormalities and other safety parameters. For LEE011 and letrozole or tamoxifen or fulvestrant | 18 months | 
| Overall Response Rate (ORR) - Phase Ib dose expansion | Anti-tumor activity for LEE011 and letrozole or tamoxifen or fulvestrant | 18 months | 
| Clinical Benefit Rate (CBR) - Phase Ib dose expansion | Anti-tumor activity for LEE011 and letrozole or tamoxifen or fulvestrant | 18 months | 
| Composite Plasma pharmacokinetics (PK) parameters of LEE011 (and relevant metabolites) and letrozole - Phase Ib | As assessed by PK parameters such as Cmax, Tmax, AUC0-24hours, accumulation ratio and Ctrough for LEE011 (and relevant metabolites) and letrozole, tamoxifen and fulvestrant | C1D1, C1D2, C1D8, C1D15, C1D21, C1D22, C2D15, C3D15 | 
| Progression Free Survival (PFS) as per RECIST v1.1- phase Ib dose expansion | Anti-tumor activity for LEE011 and letrozole or tamoxifen or fulvestrant | 18 months | 
| Overall Survival (OS) - Phase Ib dose expansion | Anti-tumor activity for LEE011 and letrozole or tamoxifen or fulvestrant | 18 months | 
| Disease Control Rate (DCR) - Phase Ib dose expansion | Anti-tumor activity for LEE011 and letrozole or tamoxifen or fulvestrant | 18 months | 
| Duration of Response (DOR) - Phase Ib dose expansion | Anti-tumor activity for LEE011 and letrozole or tamoxifen or fulvestrant | 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LEE011,, Letrozole, Advanced breast cancer, Hormone receptor positive, HER2-negative, Tamoxifen, Fulvestrant, Postmenopausal Asian women, Pre and Postmenopausal Japanese women