Study to Compare the Combination of Ribociclib Plus Goserelin Acetate With Hormonal Therapy Versus Combination Chemotherapy in Premenopausal or Perimenopausal Patients With Advanced or Metastatic Breast Cancer

Study Overview
=================
Brief Summary
-----------------
To compare the combination of Ribociclib plus goserelin acetate with hormonal therapy versus combination chemotherapy in premenopausal or perimenopausal patients with advanced or metastatic breast cancer

Detailed Description
-----------------
A phase II randomized study of the combination of Ribociclib plus goserelin acetate with Hormonal Therapy versus physician choice chemotherapy in premenopausal or perimenopausal patients with hormone receptor-positive/ HER2-negative inoperable locally advanced or metastatic breast cancer - RIGHT Choice Study

Official Title
-----------------
A Phase II Randomized Study of the Combination of Ribociclib Plus Goserelin Acetate With Hormonal Therapy Versus Physician Choice Chemotherapy in Premenopausal or Perimenopausal Patients With Hormone Receptor-positive/ HER2-negative Inoperable Locally Advanced or Metastatic Breast Cancer

Conditions
-----------------
Breast Cancer

Intervention / Treatment
-----------------
* Combination Product: Docetaxel / Capecitabine
* Combination Product: Capecitabine / Vinorelbine
* Combination Product: Paclitaxel / Gemcitabine
* Drug: Ribociclib
* Drug: Letrozole OR Anastrozole
* Drug: Goserelin


Participation Criteria
=================
Eligibility Criteria
-----------------
INCLUSION CRITERIA Patient is an adult female ≥ 18 years old and < 60 years old at the time of informed consent. Patient has a histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer based on the most recently analyzed tissue sample and all tested by local laboratory. ER should be more than 10% ER positive or Allred ≥5 by local laboratory testing. 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 and based on the most recently analyzed tissue sample. Women with inoperable locally advanced or metastatic breast cancer not amenable to curative therapy. Patients must fulfill at least one of the following criteria to be considered that combination chemotherapy is needed according to PI's judgment. However, for patients who are eligible under inoperable locally advanced breast cancer or criteria 4c, the recruitment is stopped to enrich patient population with visceral metastases. Symptomatic visceral metastases Rapid progression of disease or impending visceral compromise. Markedly symptomatic non visceral disease if the treating physician opt to give chemotherapy for rapid palliation of patients symptoms. Patient is premenopausal or perimenopausal at the time of study entry. Premenopausal status is defined as either: Patient had last menstrual period within the last 12 months. OR If on tamoxifen within the past 14 days, plasma estradiol and FSH are in the premenopausal range, according to local laboratory definition. In case of therapy induced amenorrhea, plasma estradiol and/or FSH are in the premenopausal range according to local laboratory definition. Patients who have undergone bilateral oophorectomy are not eligible. Perimenopausal status is defined as neither premenopausal nor postmenopausal Patients must have not received neither prior hormonal therapy nor chemotherapy for advanced breast cancer, except LHRH agonist. Patients who received ≤ 14 days of tamoxifen or a NSAI (letrozole or anastrozole) with or without LHRH agonist for advanced breast cancer prior to randomization are eligible. Patient must have measurable disease. EXCLUSION CRITERIA; Patient has received prior systemic anti-cancer therapy (including hormonal therapy and chemotherapy, or any CDK4/6 inhibitor for advanced breast cancer. Patients who received (neo) adjuvant therapy for breast cancer are eligible. If the prior neo (adjuvant) therapy included aromatase inhibitors, the treatment free interval must be greater than 12 months from the completion of aromatase inhibitor treatment until randomization. If patients have disease recurrence during adjuvant tamoxifen treatment, disease free interval (defined as duration between the date of patient received complete tumor resection for primary breast cancer lesion to the date of disease recurrence documented) must be greater than 12 months. Patients who are receiving ≤ 14 days of tamoxifen or NSAI or LHRH agonists ≤ 28 days for advanced breast cancer prior to randomization are eligible. Patient has received extended-field radiotherapy ≤ 2 weeks prior to randomization or limited field radiotherapy ≤ 2 weeks prior to randomization, and has not recovered to grade 1 or better from related side effects of such therapy (with the exception of alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion). Patient from whom ≥ 25% of the bone marrow has been previously irradiated are also excluded. Patient has a concurrent malignancy or malignancy within 3 years of randomization, with the exception of adequately treated, basal or squamous cell skin carcinoma or curatively resected cervical cancer in situ. Patients who have lung metastases with oxygen demand in resting status. Patients who have liver metastases with bilirubin > 1.5 ULN. Patients with CNS involvement unless they meet ALL of the following criteria: At least 4 weeks from prior therapy completion (including radiation and/or surgery) to starting the study treatment. Clinically stable CNS tumor at the time of screening and not receiving steroids and/or enzyme inducing anti-epileptic medications for brain metastases Leptomeningeal metastases is not allowed, even with stable clinical condition

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 59 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a randomized, phase II, open label, multi-center trial comparing the combination of NSAI (letrozole or anastrozole) + goserelin + ribociclib versus combination chemotherapy (either of docetaxel/capecitabine or paclitaxel/gemcitabine or capecitabine/vinorelbine). Premenopausal or perimenopausal women with HR+, HER2- negative, advanced breast cancer with ECOG performance status of 0 to 2 and having symptomatic visceral metastases, or rapid progression of disease or impending visceral compromise, or markedly symptomatic non visceral disease will be considered for this study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Comparator arm<br>Combination chemotherapies of docetaxel/capecitabine, paclitaxel/gemcitabine or capecitabine/vinorelbine will be administer to patients enrolled in the control group. The chemotherapy regimen will be decided by the treating physician. | Combination Product: Docetaxel / Capecitabine<br>* Docetaxel (IV Infusion) / Capecitabine (Tablets for oral use): Docetaxel once, on day 1 of the 3-weeks cycle. Capecitabine twice daily, on Days 1 to 14, followed by a 1-week rest period, in 3 weeks cycle. Docetaxel (60 - 75 mg/m²)/capecitabine (1600 - 2500 mg/m²/day)<br>* Other names: The chemotherapy regimen will be decided by the treating physician.;Combination Product: Capecitabine / Vinorelbine<br>* Capecitabine (Tablets for oral use) / Vinorelbine (Capsule for Oral use/IV infusion ). Capecitabine twice daily on day 1 to 14, followed by a 1-week rest period, in 3 weeks cycle. Vinorelbine, once, on Day 1 and Day 8 in 3 weeks cycles. Capecitabine (1600 - 2500 mg/m2/day)/vinorelbine (60 to 80 mg/m2/day [oral] or (25 to 30 mg/m2 [IV infusion]<br>* Other names: The chemotherapy regimen will be decided by the treating physician.;Combination Product: Paclitaxel / Gemcitabine<br>* Paclitaxel (IV Infusion) / Gemcitabine (IV Infusion): Paclitaxel via 3-hour intravenous (IV) infusion on Day 1 in 3-weeks cycles, OR Paclitaxel via 1 hour intravenous (IV) infusion on Day 1 and day 8- in 3-weeks cycles. Gemcitabine at via 30 minute IV infusion on Day 1 and Day 8 in 3 weeks cycles. Paclitaxel (175 mg/m2) (on Day 1 in 3-weeks cycles)/ gemcitabine (1000 - 1250 mg/m2) OR Paclitaxel (80 - 90 mg/m2) (on Day 1 and Day 8 in 3-weeks cycles) / gemcitabine (800 - 1250 mg/m2)<br>* Other names: The chemotherapy regimen will be decided by the treating physician.;|
| Experimental: Ribociclib arm<br>Combination of non-steroidal aromatase inhibitor: NSAI (letrozole or anastrozole) + goserelin + ribociclib. Ribociclib (600 mg) is dosed orally for the first 21 days out of a 28 day cycle. Letrozole (2.5 mg) or anastrozole (1 mg) are dosed orally daily (28 days out of the 28 day cycle). Goserelin (3.6 mg) is continuously released via a subcutaneous implant injected on Day 1 of each 28 day cycle (regardless of ribociclib treatment cycle) with an administration window of + 3 days. | Drug: Ribociclib<br>* Dose: 600 mg (200 mg * 3) Days 1 to 21 of each 28 day cycle Tablets for oral use<br>* Other names: NSAI + goserelin+ ribociclib;Drug: Letrozole OR Anastrozole<br>* Letrozole: Dose: 2.5 mg All days of every cycle without interruption). Tablets for oral use Anastrozole: dose: 1 mg All days of every cycle without interruption. Tablets for oral use The NSAI (letrozole or anastrozole) will be decided by the treating physician.<br>* Other names: NSAI + goserelin+ ribociclib;Drug: Goserelin<br>* Dose: 3.6 mg Day 1 of each 28 day cycle (regardless of ribociclib treatment cycle) with an administration window of + 3 days. Subcutaneous implant<br>* Other names: NSAI + goserelin+ ribociclib;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | Progression-free survival is defined as the time from the date of randomization to the date of the first documented progression as per local review and according to RECIST 1.1 or death due to any cause. | Up to approximately 34 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to treatment failure | Time to treatment failure is defined as the time from the date of randomization/start of treatment to the earliest of date of progression, date of death due to any cause, change to other anti-cancer therapy, or date of discontinuation due to reasons other than 'Protocol violation' or 'Administrative problems'. | Up to approximately 34 months | 
| Overall response rate (ORR) | Overall response rate (ORR) is defined as the proportion of patients whose best overall response is either complete response (CR) or partial response (PR), as per local review and according to RECIST 1.1. | Up to approximately 34 months | 
| Clinical benefit rate | Clinical benefit rate is defined as the proportion of patients with a best overall response of CR, or PR or stable disease, lasting for a duration of at least 24 weeks, as defined by RECIST 1.1. | Up to approximately 34 months | 
| Time to response | Time to response is defined as the time from the date of randomization to the first documented response of either CR or PR, which must be subsequently confirmed, as defined by RECIST 1.1. | Up to approximately 34 months | 
| Overall survival | Overall survival is defined as the time from the date of randomization to the date of death due to any cause. | Up to approximately 46 months | 
| Frequency/severity of adverse events, lab abnormalities. | Safety of ribociclib in combination with NSAI and goserelin, and combination chemotherapies | Up to approximately 46 months | 
| Change from baseline in the global health status/QOL scale score by using FACT-B questionnaire | Functional Assessment of Cancer Therapy - Breast (FACT-B) will be collected to assess health-related QoL, health status, functioning, disease symptoms, side effects, and cancer-related pain. Descriptive statistics will be used to summarize the overall score at each scheduled assessment time point. Additionally, change from baseline at the time of each assessment will be summarized. The distribution of time to definitive 10% deterioration in the global health status from FACT-B questionnaire will be assessed in the two treatment arms. Scores range from 0 to 4. no subscale. 0 score is the worst for social/family and functional wellbeing and 4 is the worst for physical, emotional wellbeing and additional concerns. | Up to approximately 46 months | 
| 3-month treatment failure rate | Treatment failure rate is defined as the proportion of patients who discontinued the study treatment due to progressive disease, death due to any cause, change to other anti-cancer therapy, or discontinuation due to reasons other than protocol violation or administrative problems. | Up to approximately 34 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Phase II, HR-positive, HER2-negative, advanced breast cancer, Ribociclib, NSAI, Goserelin, Docetaxel / capecitabine, Paclitaxel/gemcitabine, Capecitabine/vinorelbine, CDK4/6 inhibitors, ER-positive, PR-positive, Premenopausal, Perimenopausal