Study of LEE011 With Fulvestrant and BYL719 or BKM120 in Advanced Breast Cancer

Study Overview
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Brief Summary
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The purpose of this trial is to explore the clinical utility of the three investigational agents in HR+, HER2- breast cancer. LEE011 (CDK4/6 inhibitor), BKM120 (PI3K-pan class I-inhibitor) and BYL719 (PI3K-alpha specific class I inhibitor) in combination with fulvestrant. This is a multi-center, open-label Phase Ib/II study. The Phase Ib portion of the study is a dose escalation to estimate the MTD and/or RP2D for three regimens: LEE011 with fulvestrant; LEE011 and BKM120 with fulvestrant; LEE011and BYL719 with fulvestrant. The Phase II portion of the study was planned to be a randomized study to assess the anti-tumor activity as well as safety and tolerability of LEE011 with fulvestrant to LEE011 and BKM120 with fulvestrant, and LEE011 and BYL719 with fulvestrant in patients with ER+/HER2- locally advanced or metastatic breast cancer. Approximately 216 adult women with ER+/HER2- locally advanced or metastatic breast cancer were planned to be enrolled.

Detailed Description
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On 31-May-2016 Novartis's made the decision decision to not open the Phase II portion of the study, for business reasons. Sufficient data had already been collected and no additional data for the triplet combinations was needed. As a result, the Phase II portion of the trial was not opened.

Official Title
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A Phase Ib/II Study of LEE011 in Combination With Fulvestrant and BYL719 or BKM120 in the Treatment of Postmenopausal Women With Hormone Receptor Positive, HER2 Negative Locally Recurrent or Advanced Metastatic Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: LEE011
* Drug: BYL719
* Drug: fulvestrant
* Drug: BKM120


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Postmenopausal, Hormone receptor positive (HR+), HER2 negative breast cancer Unlimited number of lines of endocrine therapy and up to two lines of cytotoxic chemotherapy in the metastatic setting (Phase Ib) Unlimited number of lines of endocrine therapy and one line of cytotoxic chemotherapy in the metastatic setting (Phase II) Exclusion Criteria: HER2-overexpression in the patient's tumor tissue Inadequate bone marrow function or evidence of end-organ damage Severe or uncontrolled medical issues 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LEE011 + BKM120 + fulvestrant<br>LEE011 - 28 day cycles (21 days followed by a 7 day break - dose escalating) BKM120 - daily (dose escalating) fulvestrant - i.m. - 500 mg given on day 1 and day 15 of Cycle 1, then on Day 1 of each subsequent cycle. | Drug: LEE011<br>* LEE011: supplied as capsules of dosage strength of 50 mg or 200 mg. The capsules will be differentiated through different sizes<br>Drug: fulvestrant<br>* Fulvestrant will be supplied according to local practice and regulation. Fulvestrant is a commercially available product, comes in 500 mg dose and is an injection for intramuscular (i.m.) administration.<br>Drug: BKM120<br>* BKM120: supplied as 10 mg or 50 mg capsules. The capsules will be differentiated through different sizes.<br>|
| Experimental: LEE011 + BYL719 + fulvestrant<br>LEE011 - 28 day cycles (21 days followed by a 7 day break - dose escalating) BYL719 - daily (dose escalating) fulvestrant - i.m. - 500 mg given on day 1 and day 15 of Cycle 1, then on Day 1 of each subsequent cycle. | Drug: LEE011<br>* LEE011: supplied as capsules of dosage strength of 50 mg or 200 mg. The capsules will be differentiated through different sizes<br>Drug: BYL719<br>* BYL719: supplied as tablets of dosage strength of 10 mg, 50 mg or 200 mg. Tablets will be differentiated through different sizes and/or colors.<br>Drug: fulvestrant<br>* Fulvestrant will be supplied according to local practice and regulation. Fulvestrant is a commercially available product, comes in 500 mg dose and is an injection for intramuscular (i.m.) administration.<br>|
| Experimental: LEE011 + fulvestrant<br>LEE011 - 28 day cycles (3 weeks on, 1 week off) or (continuous daily dosing - dose escalating) fulvestrant - 500 mg i.m. given on Day 1 and Day 15 of Cycle 1, then on Day 1 of each subsequent cycle. | Drug: LEE011<br>* LEE011: supplied as capsules of dosage strength of 50 mg or 200 mg. The capsules will be differentiated through different sizes<br>Drug: fulvestrant<br>* Fulvestrant will be supplied according to local practice and regulation. Fulvestrant is a commercially available product, comes in 500 mg dose and is an injection for intramuscular (i.m.) administration.<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 | Dose limiting toxicities | 28 days | 
| Progression free survival (PFS) - Phase ll only | Progression Free Survival per RECIST v 1.1 by local investigator assessment | 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability of the combinations of LEE011 with fulvestrant, LEE011 + BKM120 with fulvestrant and LEE011 + BYL719 with fulvestrant | Adverse Events (AEs), serious AEs (SAEs), changes in hematology and chemistry values, vital signs, electrocardiograms (ECGs), dose interruptions, reductions and dose intensity | 36 months | 
| Plasma concentration-time profiles of LEE011, BKM120, BYL719 and fulvestrant. | To characterize the PK profiles of LEE011, BKM120, BYL719, and fulvestrant when used in combination as well as to evaluate any other clinically significant metabolites that may be identified. PK parameters for LEE011, BKM120 and BYL719, including but not limited to Cmax, Cmin, Tmax, AUCtau, accumulation ratio (Racc),and Ctrough values for fulvestrant. | 36 months | 
| Overall Response Rate (ORR) | ORR is defined as the proportion of patients with a best overall response of complete response or partial response. | 36 months | 
| Duration of Response (DOR) | Duration of Response 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. | 36 months | 
| Progression Free Survival (PFS) (phase l only) | 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. | 36 months | 
| Overall Survival (OS) - Phase II only | OS is defined as the time from date of randomization/start of treatment to date of death due to any cause. If a patient is not known to have died, survival will be censored at the date of last known date patient alive. | 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hormone receptor positive, HER2 negative