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 (RIGHT Choice)

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

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

• Status: Completed
• 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

Detailed Description

Patients were randomly assigned to one of the below treatment arms in 1:1 ratio:

• Ribociclib arm: non-steroidal aromatase inhibitor (NSAI) + goserelin + Ribociclib
• Combination chemotherapy arm: Either of docetaxel + capecitabine, paclitaxel + gemcitabine, or capecitabine + vinorelbine based chemotherapy treatment Randomization was stratified by (1) the presence of liver metastases (present or absent) (2) disease-free interval (DFI) < 2 years (yes or no, de novo stage 4 was defined as DFI > 2 years).

The study consisted of a 28-day Screening phase, treatment phase (including end of treatment (EOT) visit and safety follow-up), and survival follow-up. Patients received study treatment until disease progression, unacceptable toxicity, death, or discontinuation from the study treatment for any other reason.

Patients were followed for survival regardless of treatment discontinuation for any reason (except if consent was withdrawn, patient was lost to follow-up, or until death) and regardless of achieving the primary endpoint, until death, withdrawal of consent, or loss to follow-up.

• Study Type: Interventional
• Enrollment (Actual): 222
• Phase: Phase 2

Contacts and Locations

Study Locations

• Egypt
  • Cairo, Egypt, 11566
    • Novartis Investigative Site
  • Cairo, Egypt, 12655
    • Novartis Investigative Site
  • Cairo, Egypt, 3247511
    • Novartis Investigative Site
  • Giza, Egypt, 11451
    • Novartis Investigative Site
• India
  • Mumbai, India, 400 012
    • Novartis Investigative Site
  • New Delhi, India, 110029
    • Novartis Investigative Site
  • Karnataka
    • Bangalore, Karnataka, India, 560 095
      • Novartis Investigative Site
  • Maharashtra
    • Pune, Maharashtra, India, 411004
      • Novartis Investigative Site
  • Telangana
    • Hyderabad, Telangana, India, 500082
      • Novartis Investigative Site
  • West Bengal
    • Kolkata, West Bengal, India, 700099
      • Novartis Investigative Site
• Jordan
  • Amman, Jordan, 11941
    • Novartis Investigative Site
• Lebanon
  • Beirut, Lebanon, 1107 2020
    • Novartis Investigative Site
  • Saida, Lebanon, 652
    • Novartis Investigative Site
  • Tripoli, Lebanon, 1434
    • Novartis Investigative Site
• Malaysia
  • Pulau Pinang, Malaysia, 10990
    • Novartis Investigative Site
  • Johor
    • Johor Bahru, Johor, Malaysia, 81100
      • Novartis Investigative Site
  • Sabah
    • Kota Kinabalu, Sabah, Malaysia, 88586
      • Novartis Investigative Site
  • Sarawak
    • Kuching, Sarawak, Malaysia, 93586
      • Novartis Investigative Site
  • Wilayah Persekutuan
    • Kuala Lumpur, Wilayah Persekutuan, Malaysia, 50586
      • Novartis Investigative Site
• Russian Federation
  • Moscow, Russian Federation, 115478
    • Novartis Investigative Site
  • Moscow, Russian Federation, 111123
    • Novartis Investigative Site
  • Pushkin Saint Petersburg, Russian Federation, 196603
    • Novartis Investigative Site
  • St Petersburg, Russian Federation, 197758
    • Novartis Investigative Site
• Saudi Arabia
  • Riyadh, Saudi Arabia, 11211
    • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 188770
    • Novartis Investigative Site
  • Singapore, Singapore, 258499
    • Novartis Investigative Site
  • Singapore, Singapore, 168583
    • Novartis Investigative Site
• South Africa
  • Pretoria, South Africa, 0081
    • Novartis Investigative Site
  • Pretoria, South Africa, 0002
    • Novartis Investigative Site
  • Kwazulu Natal
    • Durban, Kwazulu Natal, South Africa, 4091
      • Novartis Investigative Site
• Taiwan
  • Kaohsiung, Taiwan, 83301
    • Novartis Investigative Site
  • Taichung, Taiwan, 40447
    • Novartis Investigative Site
  • Tainan, Taiwan, 70403
    • Novartis Investigative Site
  • Taipei, Taiwan, 10002
    • Novartis Investigative Site
  • Taipei, Taiwan, 11217
    • Novartis Investigative Site
  • Taipei, Taiwan, 114
    • Novartis Investigative Site
  • Taipei, Taiwan, 10449
    • Novartis Investigative Site
  • Taoyuan, Taiwan, 33305
    • Novartis Investigative Site
• Thailand
  • Bangkok, Thailand, 10400
    • Novartis Investigative Site
  • Bangkok, Thailand, 10310
    • Novartis Investigative Site
  • Chiang Mai, Thailand, 50200
    • Novartis Investigative Site
  • Hat Yai
    • Songkhla, Hat Yai, Thailand, 90110
      • Novartis Investigative Site
• Turkey
  • Ankara, Turkey, 06520
    • Novartis Investigative Site
  • Antalya, Turkey, 07059
    • Novartis Investigative Site
  • Cankaya Ankara, Turkey, 06560
    • Novartis Investigative Site
  • Istanbul, Turkey, 34381
    • Novartis Investigative Site
  • Izmir, Turkey, 35040
    • Novartis Investigative Site
  • Kecioren Ankara, Turkey, 06010
    • Novartis Investigative Site
  • Malatya, Turkey, 44280
    • Novartis Investigative Site
• Vietnam
  • Hanoi, Vietnam, 100000
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 59 years (Adult)
• Accepts Healthy Volunteers: No

Description

INCLUSION CRITERIA

1. Patient was an adult female ≥ 18 years old and < 60 years old at the time of informed consent.
2. Patient had 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 have been more than 10% ER positive or Allred ≥5 by local laboratory testing.
3. Patient had 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 was required by local laboratory testing and based on the most recently analyzed tissue sample.

4. Women with inoperable locally advanced or metastatic breast cancer not amenable to curative therapy. Patients had to fulfill at least one of the following criteria to be considered that combination chemotherapy was needed according to PI's judgment. However, for patients who were eligible under inoperable locally advanced breast cancer or criteria 4c, the recruitment was 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 opted to give chemotherapy for rapid palliation of patient's symptoms.

5. Patient was premenopausal or perimenopausal at the time of study entry.

   1. Premenopausal status was 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 were in the premenopausal range, according to local laboratory definition.
      • In case of therapy induced amenorrhea, plasma estradiol and/or FSH were in the premenopausal range according to local laboratory definition.
      • Patients who had undergone bilateral oophorectomy were not eligible.
   2. Perimenopausal status was defined as neither premenopausal nor postmenopausal.
6. Patients had 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 were eligible. Patient had measurable disease.

EXCLUSION CRITERIA;

1. Patient 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 were eligible. If the prior neo (adjuvant) therapy included aromatase inhibitors, the treatment-free interval must have been greater than 12 months from the completion of aromatase inhibitor treatment until randomization.
   • If patients had 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 have been greater than 12 months.
   • Patients who were receiving ≤ 14 days of tamoxifen or NSAI or LHRH agonists ≤ 28 days for advanced breast cancer prior to randomization were eligible.
2. Patient had received extended-field radiotherapy ≤ 2 weeks prior to randomization or limited field radiotherapy ≤ 2 weeks prior to randomization, and had 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 had been previously irradiated were also excluded.
3. Patient had 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.
4. Patients who had lung metastases with oxygen demand in resting status.
5. Patients who had liver metastases with bilirubin > 1.5 ULN.

6. Patients with CNS involvement unless they met 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 was not allowed, even with stable clinical condition.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ribociclib 600 mg; Combination of non-steroidal aromatase inhibitor: NSAI (letrozole or anastrozole) + goserelin + ribociclib.; Ribociclib (600 mg) was dosed orally for the first 21 days out of a 28-day cycle.; Letrozole (2.5 mg) or anastrozole (1 mg) were dosed orally daily (28 days out of the 28-day cycle).; Goserelin (3.6 mg) was 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; Dose: 600 mg (200 mg * 3) Days 1 to 21 of each 28 day cycle Tablets for oral use; Other Names: Endocrine treatment arm:; NSAI + goserelin+ ribociclib; Drug: Letrozole OR Anastrozole; 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.; Other Names: Endocrine treatment arm:; NSAI + goserelin+ ribociclib; Drug: Goserelin; 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; Other Names: Endocrine treatment arm:; NSAI + goserelin+ ribociclib
Active Comparator: Combination Chemotherapy; Combination chemotherapies of docetaxel/capecitabine, paclitaxel/gemcitabine or capecitabine/vinorelbine were administered to patients enrolled in the control group. The chemotherapy regimen was decided by the treating physician.	Combination product: Docetaxel / Capecitabine; 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); Other Names: Combination chemotherapy group.; The chemotherapy regimen was decided by the treating physician.; Combination product: Capecitabine / Vinorelbine; 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]; Other Names: Combination chemotherapy group.; The chemotherapy regimen was decided by the treating physician.; Combination product: Paclitaxel / Gemcitabine; 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); Other Names: Combination chemotherapy group.; The chemotherapy regimen was decided by the treating physician.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival	Progression-free survival was 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. PFS was censored at the date of the last adequate tumor assessment if no PFS event was observed at the time of last patient, last visit (LPLV).	Up to approximately 34 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Treatment Failure	Time to treatment failure was 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'. Patients who did not achieve a confirmed PR or CR were censored at: the maximum follow-up time (i.e., LPLV - first patient first visit [FPFV] used for the analysis) for patients who had a PFS event (i.e., either progressed or died due to any cause); the last adequate tumor assessment date for all other patients.	Up to approximately 34 months
3-month Treatment Failure Rate	Treatment failure rate was defined as the percentage 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 3 months
Overall Response Rate (ORR)	Overall response rate (ORR) was defined as the percentage of patients with a best overall response (BOR) of complete response (CR) or partial response (PR, response without image confirmation), as per local review and according to RECIST 1.1.	Up to approximately 34 months
Clinical Benefit Rate	Clinical benefit rate was defined as the percentage of patients with a BOR of CR, PR, or stable disease (SD, response without image confirmation) lasting 24 weeks or longer, as defined by RECIST 1.1.	Up to approximately 34 months
Time to Response	Time to response was 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. Patients who did not achieve a confirmed PR or CR were censored at: the maximum follow-up time (i.e., LPLV - FPFV used for the analysis) for patients who had a PFS event (i.e., either progressed or died due to any cause); the last adequate tumor assessment date for all other patients.	Up to approximately 34 months
Overall Survival (OS)	Overall survival was defined as the time from the date of randomization to the date of death due to any cause. If a patient was not known to have died at the time of LPLV, then OS was censored at the last contact date.	Up to approximately 46 months
Change From Baseline in the Global Health Status/Quality of Life (QOL) Scale Score by Using the Functional Assessment of Cancer Therapy - Breast (FACT-B) Questionnaire	FACT-B is a self-reported instrument that measures multidimensional quality of life (QOL) in patients with breast cancer. The FACT-B consists of 37 questions that address physical, social, emotional, and functional well-being, with specific questions relevant to women with breast cancer. Each item has a score range of 0 (Not at all) to 4 (Very much), with a total score ranging from 0-148. The higher the score, the better the QOL reported by the participant. A positive change from baseline indicates improvement in QoL.	Up to approximately 46 months
Number of Patients With Adverse Events, Categorized by Severity	Adverse events were assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 or higher. If CTCAE grading did not exist for an adverse event, the severity of mild, moderate, severe, and life-threatening, corresponding to Grades 1 - 4, were used. A patient with multiple severity grades for an AE was only counted under the maximum grade. Data for Grades 3 and 4 are reported.	Up to approximately 46 months
Number of Patients With Laboratory Abnormalities	Grading of laboratory values was assigned programmatically as per NCI Common Terminology Criteria for Adverse Events (CTCAE) version available at the time of analysis. The calculation of CTCAE grades was based on the observed laboratory values only, clinical assessments were not be taken into account. CTCAE Grade 0 was assigned for all non-missing values not graded as 1 or higher. Grade 5 was not used. For laboratory tests where grades were not defined by CTCAE available at the time of analysis, results were categorized as low/normal/high based on laboratory normal ranges.	Up to approximately 46 months
Post-Hoc: All Collected Deaths	On-treatment deaths due to any cause were collected from first dose of study medication to 30 days after the last dose of study treatment. Post-treatment survival follow-up deaths were collected from day 31 after last dose of study medication to end of study.	On-treatment deaths: Up to approximately 46 months. Post-treatment survival follow-up deaths: Up to approximately 2 additional months.

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• A Plain Language Trial Summary is available on novctrd.com

Study record dates

Study Major Dates

• Study Start (Actual): February 25, 2019
• Primary Completion (Actual): April 12, 2022
• Study Completion (Actual): May 10, 2023

Study Registration Dates

• First Submitted: January 24, 2019
• First Submitted That Met QC Criteria: February 11, 2019
• First Posted (Actual): February 15, 2019

Study Record Updates

• Last Update Posted (Actual): October 9, 2024
• Last Update Submitted That Met QC Criteria: October 7, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: Ribociclib; Phase II; Premenopausal; advanced breast cancer; HER2-negative; Goserelin; ER-positive; PR-positive; HR-positive; Perimenopausal; NSAI; Docetaxel / capecitabine; Paclitaxel/gemcitabine; Capecitabine/vinorelbine; CDK4/6 inhibitors
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Docetaxel; Paclitaxel; Capecitabine; Letrozole; Goserelin; Vinorelbine; Anastrozole; Gemcitabine
• Other Study ID Numbers: CLEE011A3201C

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No