A Phase III, multicenter, open-label study of ribociclib vs. palbociclib in patients with advanced hormone receptor-positive/HER2-negative/HER2-Enriched breast cancer - HARMONIA trial

HARMONIA is an international, multicenter, randomized, open-label and phase III study.
The primary objective of this study is to demonstrate that the combination of ribociclib
with endocrine therapy (letrozole or fulvestrant) is superior to palbociclib with
endocrine therapy (letrozole or fulvestrant) in prolonging progression-free survival in
patients with advanced HR+/HER2- and HER2-E breast cancer. The study will enroll
approximately 456 patients with HER2-E disease from approximately 95 sites worldwide.

In addition, the HARMONIA trial will include an exploratory cohort of patients with
HR+/HER2- and Basal-like disease treated with paclitaxel +/- Tislelizumab. This cohort
does not have a predefined sample size and the objective is only exploratory, given the
suggested lack of efficacy of the combinations of hormone therapy and CDK4/6 inhibitors
in this subgroup of patients. Enrolment into the basal-like cohort will stop once the
HER2-E disease cohort is fully enrolled.

Main Inclusion Criteria:

- Histologically documented HR-positive and HER2-negative breast cancer by local
testing

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

- advanced (loco regionally recurrent not amenable to curative therapy or metastatic)
breast cancer.

- Availability of FFPE tumor block for biomarker analysis, obtained during metastatic
period.

- HER2-E or Basal-like subtype as per central PAM50 analysis.

- Measurable disease or non-measurable disease, as defined by RECIST v1.1

- Adequate hematologic and end-organ function

- Patient must be willing and able to comply with scheduled visits, treatment plans,
laboratory tests, and other trial procedures.

- Women of childbearing potential must have confirmed negative serum pregnancy test
within 7 days prior to randomization.

- Women of CBP must be willing to use highly effective methods of contraception.

- Patient must have a 6-lead or 12-lead ECG with ALL of the following parameters at
screening:

- QTcF interval (QT interval using Fridericia's correction) at screening < 450
msec.

- Resting heart rate 50-90 beats per minute (determined from the ECG).

Main Exclusion Criteria:

- Prior therapy with any CDK4/6 inhibitors.

- Patient has received prior treatment with chemotherapy for advanced/metastatic
breast cancer