A randomized pre-surgical pharmacodynamics study to assess the biological activity of LEE011 plus letrozole versus single agent letrozole in primary breast cancer (CLEE011A 2201)

The purpose of this study is to characterize the difference in
anti-proliferative activity of LEE011 600 mg QD and LEE011 400 mg QD in
combination with letrozole 2.5 mg QD versus (vs) single agent letrozole 2.5 mg
QD in postmenopausal women with HR+, HER2-negative, newly diagnosed, resectable
breast cancer who received no prior antineoplastic therapy. The collection of
data from the two experimental arms will help to better evaluate the safety and
biological activity of treatment with LEE011 plus letrozole.
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 and several
trials have demonstrated that in terms of cell cycle response, the main
biologic effect occurs as early as two weeks after starting therapy. 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. The preoperative setting is increasingly
used to assess new drugs in shorter-term window-of-opportunity studies for
early evidence of clinical efficacy. The establishment of Ki67 as an
intermediate marker of treatment benefit and of long-term outcome, with
endocrine drugs, provides the opportunity for new trial designs with Ki67 as
the primary endpoint. Also, change in proliferation early on in the treatment
was reported to mirror the recurrence-free survival in the adjuvant setting.
The effects of letrozole treatment could be improved by combining it with a
targeted therapy.
Recent clinical data indicate that inhibitors of CDK4/6 are active in advanced
ER+ breast cancer. PD0332991 is a selective inhibitor of CDK4/6 that, when used
in combination with letrozole, significantly prolonged progression free
survival in postmenopausal women with ER+, Her2- advanced breast cancer in a
randomized phase II trial.

Primary objective: To estimate the difference in anti-proliferative activity of
LEE011 600 mg QD and LEE011 400 mg QD in combination with letrozole 2.5 mg QD
vs single agent letrozole 2.5 mg QD as measured by changes in Ki-67 levels from
baseline to time day 15 as determined by cell cycle response rate. See protocol
for further details.
Secondary objectives: Safety and tolerability, ECG effects, pharmacodynamic
markers, pharmacokinetics.

Open-label randomized pre-surgical pharmacodynamics study. Approximately 120
patients.
Randomization (1:1:1) to treatment with
• LEE011 600 mg QD plus letrozole 2.5 mg QD
• LEE011 400 mg QD plus letrozole 2.5 mg QD
• letrozole 2.5 mg QD.
Treatment duration 14 days.
Surgery from day 15.

Treatment with letrozole with or without LEE.

Risk: Adverse events of study medication.
Burden:
6 visits. Duration 2-8 h.
Fasting blood draws during 6 visits (max. 20 mL/visit). During 3 visits 4 blood
draws for PK during 6 h.
ECG monitoring during 4 visits. During 3 visits 3-4 ECGs during 8 h.
2 times 24 h Holter monitoring.
2 times tumor biopsy (during screening and on day 15). In case there is tumor
tissue available from prior biopsy or surgery, no biopsy is required during
screening. On the day 15 a biopsy is required.