Title
A Phase III, Multicenter, Open-Label Study of Ribociclib vs. Palbociclib in Patients With Advanced Hormone Receptor-Positive/HER2-Negative/HER2-Enriched Breast Cancer.

Description
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.

Objective
Primary Objective:
1. Compare PFS of ribociclib plus endocrine therapy over palbociclib plus endocrine therapy in patients w/advanced hormone receptor-positive, HER2-negative and HER2-E breast cancer.

Secondary Objectives:
1. Compare the two treatment arms with respect to Progression on nextline therapy (PFS2) in the HER2-E cohort
2. Compare the two treatment arms with respect to overall survival in the HER2-E cohort
3. Evaluate the two treatment arms with respect to overall response rate (ORR) and clinical benefit rate (CBR) in the HER2-E cohort.
4. Describe time to response and duration of response in each treatment arm in the HER2-E cohort.
5. Evaluate the safety and tolerability of ribociclib and palbociclib in combination with endocrine therapy in the HER2-E cohort
6. Evaluate patient reported outcomes for health-related quality of life in the two treatment arms of the HER2-E cohort.

Exploratory Objectives:
1. Describe the progression-free survival in the Basal-like cohort.
2. Describe the overall survival in the Basal-like cohort.
3. Describe the ORR and CBR in the Basal-like cohort.
4. Explore molecular alterations in circulating tumor DNA.
5. Compare subtype in primary vs metastatic tumor samples.
6. Study changes in the intrinsic subtype during and after study treatment

Treatment Experimental: Ribociclib + Endocrine Therapy
Ribociclib + Fulvestrant or Letrozole
Drug: Ribociclib + Letrozole OR Fulvestrant
Endocrine Therapy will be selected by the investigator. For premenopausal women and men: LHRH agonist once every 4 weeks

Experimental: Palbociclib + Endocrine Therapy
Palbociclib + Fulvestrant or Letrozole
Drug: Palbociclib + Letrozole OR Fulvestrant
Endocrine Therapy will be selected by the investigator. For premenopausal women and men: LHRH agonist once every 4 weeks

Experimental: Paclitaxel +/- Tislelizumab - Exploratory cohort
Additional experimental Cohort that includes patients with Basal-Like intrinsic subtype.
Drug: Paclitaxel +/- Tislelizumab
Patients in this arm could receive as the first line of therapy

Key Eligibility 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).

Applicable Disease Sites
Breast

Participating Institutions
UW Health 1 S. Park Medical Center; UW Health Eastpark Medical Center; UW Health University Hospital