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 prior therapy for advanced disease


This is a randomized two-arm study in patients who are naive to prior antineoplastic therapy in the advanced setting to evaluate the effect of adding Lee011 to letrozole, the approved first-line treatment for advanced hormone receptor+ breast cancer. The two-arm, double blind and randomized design minimizes allocation bias, balancing both known and unknown prognostic factors in the assignment of treatments.

The trial utilizes a randomized, double-blind, placebo-controlled, multicenter, parallel group, design. This is the gold standard design for phase iii trials. The stratification factor (lung or liver involvement: yes versus no) was selected because of its well-recognized prognostic value.

This is an international, multi-center, randomized, double-blind, placebo controlled phase iii trial to determine the efficacy and safety of treatment with Lee011 plus letrozole versus placebo plus letrozole in postmenopausal women with HR+, HeR2-negative advanced (recurrent or metastatic) breast cancer who received no prior therapy for advanced disease.

approximately 500 patients will be randomly assigned to one of the below treatment arms in 1:1 ratio:
a. Letrozole (2.5 mg once daily) + Lee011 600 mg (day 1 to 21 in a 28 day cycle); oR
b. Letrozole (2.5 mg once daily) + placebo (day 1 to 21 in a 28 day cycle).

Randomization will be stratified by the presence of liver and/or lung metastases (yes versus no).

Progression-free survival, as assessed by the local radiologists/investigators and using ReCiST 1.1 criteria, will be the primary endpoint. PFS as assessed through blinded independent central review will be used for supportive evidence of the primary efficacy endpoint.

When available, the collection of archival tumor tissue is mandatory for all patients to assess the molecular characteristic relevant to breast cancer and cell cycle.

Participant Eligibility

* Patient is an adult, female >= 18 years old at the time of informed consent and has signed informed consent before any trial related activities and according to local guidelines.

* Women with advanced (locoregionally recurrent or metastatic) breast cancer not amenable to curative therapy

* Patient is postmenopausal. Postmenopausal status is defined either by:
a. Prior bilateral oophorectomy
b. Age >=60
c. Age <60 and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifen, or ovarian suppression) and FSH and estradiol in the postmenopausal range per local normal range
Note: For women with therapy-induced amenorrhea, serial measurements of FSH and/or estradiol are needed to ensure postmenopausal status. Ovarian radiation or treatment with a luteinizing hormone-releasing hormone agonist (LH-RHa) (goserelin acetate or leuprolide acetate) is not permitted for induction of ovarian suppression in this trial.

* Patient has a histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer by local laboratory.

* Patient has HER2-negative breast cancer defined as a negative in situ hybridization test or an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required by local laboratory testing.

* Patient must have either:
Measurable disease, i.e., at least one measurable lesion as per RECIST
1.1 criteria

* (Tumor lesions previously irradiated or subjected to other locoregional therapy will only be considered measurable if disease progression at the treated site after completion of therapy is clearly documented).

* If no measurable disease is present, then at least one predominantly lytic bone lesion must be present (Patients with no measurable disease and only one predominantly lytic bone lesion that has been previously irradiated are eligible if there is documented evidence of disease progression of the bone lesion after irradiation)

* Patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1