Ribociclib vs. Palbociclib in Patients With Advanced Breast Cancer Within the HER2-Enriched Intrinsic Subtype

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Metastatic Breast Cancer

Intervention / Treatment
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* Drug: Ribociclib + Letrozole OR Fulvestrant
* Drug: Palbociclib + Letrozole OR Fulvestrant
* Drug: Paclitaxel +/- Tislelizumab


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ribociclib + Endocrine Therapy<br>Ribociclib + Fulvestrant or Letrozole | Drug: Ribociclib + Letrozole OR Fulvestrant<br>* Endocrine Therapy will be selected by the investigator. For premenopausal women and men: LHRH agonist once every 4 weeks<br>|
| Experimental: Palbociclib + Endocrine Therapy<br>Palbociclib + Fulvestrant or Letrozole | Drug: Palbociclib + Letrozole OR Fulvestrant<br>* Endocrine Therapy will be selected by the investigator. For premenopausal women and men: LHRH agonist once every 4 weeks<br>|
| Experimental: Paclitaxel +/- Tislelizumab - Exploratory cohort<br>Additional experimental Cohort that includes patients with Basal-Like intrinsic subtype. | Drug: Paclitaxel +/- Tislelizumab<br>* Patients in this arm could receive as the first line of therapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival | using RECIST 1.1 criteria, as assessed by local radiologists/investigators | From date of randomization until the date of first documented progression, death, lost of follow-up, withdraw consent or the study is terminated by SOLTI, whichever occurs first, assessed up to approximately 62 months after the first patient enrolled | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival 2 | defined as the time from randomization to first documented progression on next-line therapy or death, whichever occurs first | From randomization until documented progression to second line of therapy, death, lost of follow-up, withdraw consent or the study is terminated by SOLTI, whichever occurs first, assessed up to approximately 62 months after the first patient enrolled | 
| Overall Survival | the proportion of exitus patients | until patient death, assessed up to approximately 62 months after the first patient enrolled | 
| Overall response and clinical benefit | defined as percentage of patients with CR, PR per RECIST 1.1 or SD lasting 24 weeks or longer, as defined by RECIST 1.1. | until disease progression or 24 weeks from treatment start. | 
| Time to response and duration of response | defined per RECIST 1.1 | time from treatment start to response and time from response to disease progression, assessed up to approximately 62 months after the first patient enrolled | 
| Adverse events (safety) | Occurrence /severity of AEs, laboratory abnormalities, discontinuation rates, dose reductions/interruptions | from randomization/enrollment to end of study assessed up to approximately 62 months after the first patient enrolled | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PAM50, intrinsic subtype, HER2-Enriched