A randomized double-blind, placebo-controlled study of LEE011 in combination with letrozole for the treatment of postmenopausal women with hormone receptor positive, HER2-negative, advanced breast cancer who received no prior therapy for advanced disease (CLEE011A2301)

The purpose of this study is to characterize the anti-proliferative activity of
LEE011 600 mg when combined with letrozole 2.5 mg in postmenopausal women with
advanced HR+, HER2-negative breast cancer.
Hormone dependence is a fundamental hallmark of the majority of breast cancers,
and tumor growth can be inhibited either by deprivation of circulating
estrogens or by antagonising the effect of these hormones on their receptors.
For postmenopausal women with breast cancer, aromatase inhibitors are an
important treatment option. Letrozole is an aromatase inhibitor. In breast
cancer, genetic alterations such as amplifications and deletions occur at high
frequencies, and are closely related to poor clinical outcome. One such region
of amplification is with Cyclin D1, which plays a crucial role as a cell cycle
regulator, promoting progression through the G1-S phase, following complex
formation with CDK4/6 and phosphorylation of the retinoblastoma (rb) protein.
LEE011 is a highly soluble, potent, selective inhibitor of CDK4/6 kinases.
LEE011 inhibits CDK4/6 specific phosphorylation of pRb, thereby halting cell
cycle progression in the G1 phase.

Primary objective: Progression free survival (PFS) of treatment with letrozole
plus LEE011 compared to treatment with letrozole plus placebo .
Secondary objectives: Overall survival (OS), overall response rate (OR),
overall clinical benefit rate, time to deterioration of ECOG performance
status, safety and tolerability, quality of life.

Randomized double blind placebo controlled phase III study. Approximately 650
patients.
Randomization (1:1) to treatment in cycles of 4 weeks with
• letrozole 2.5 mg QD continuously plus LEE011 600 mg QD during the 1st 3 weeks
of a cycle
• letrozole 2.5 mg QD continuously plus placebo during the 1st 3 weeks of a
cycle
Treatment duration until disease progression or unacceptable side-effects.
Follow-up for survival.

Treatment with letrozole with or without LEE.

Risk: Adverse events of study medication.
Burden:
Visits cycle 1 day 1 and 15, next cycles day 1 only. Duration approx. 2-4 h.
Each visit fasting blood draw(s) 15-30 mL/occasion and collection of urine
Optional Blood draw for PK during cycle 1 day 15, pre-dose and 2 h post-dose
and optional blood draw for biomarker research during screening and day 15
ECG cycle 1 day 15, cycle 2 day 1, cycel 3 day 1, cycle 6 day 1, cycle 9 day 1
and end of study pre-dose and 2 hrs post-dose. Pre dose during cycle 4 day 1,
cycle 5 day 1, cycle 7 day 1 and cycle 8 day 1
MUGA-scan of echocardiogram during screening
Quality of life questionnaires (3x)(every 8-12 weeks)
Daily completion of diary
Tumor measurements (CT- or MRI-scans during the first 18 months every 8 weeks
and thereafter conform standard treatment (every 12 weeks).
Optional tumor biopsy at screening and disease progression.
In case the subjects discontinues the study medication prior to disease
progression: follow-up until progression with tumor measurements every 8-12
weeks.