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

NCT ID: NCT03839823

Last Updated: 2024-10-09

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 222 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-02-25
• Study Completion Date: 2023-05-10

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

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Patients were followed for survival regardless of treatment discontinuation for any reason (except if consent was withdrawn, patient was lost to follow-up, or until death) and regardless of achieving the primary endpoint, until death, withdrawal of consent, or loss to follow-up.

Conditions

Breast Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Ribociclib 600 mg

Combination of non-steroidal aromatase inhibitor: NSAI (letrozole or anastrozole) + goserelin + ribociclib.

1. Ribociclib (600 mg) was dosed orally for the first 21 days out of a 28-day cycle.

2. Letrozole (2.5 mg) or anastrozole (1 mg) were dosed orally daily (28 days out of the 28-day cycle).

3. 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.

Group Type: EXPERIMENTAL

Ribociclib

Intervention Type: DRUG

Dose: 600 mg (200 mg \* 3) Days 1 to 21 of each 28 day cycle Tablets for oral use

Letrozole OR Anastrozole

Intervention Type: DRUG

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.

Goserelin

Intervention Type: DRUG

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

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.

Group Type: ACTIVE_COMPARATOR

Docetaxel / Capecitabine

Intervention Type: COMBINATION_PRODUCT

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)

Capecitabine / Vinorelbine

Intervention Type: COMBINATION_PRODUCT

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]

Paclitaxel / Gemcitabine

Intervention Type: COMBINATION_PRODUCT

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)

Interventions

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)

Intervention Type: 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]

Intervention Type: 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)

Intervention Type: COMBINATION_PRODUCT

Ribociclib

Dose: 600 mg (200 mg \* 3) Days 1 to 21 of each 28 day cycle Tablets for oral use

Intervention Type: 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.

Intervention Type: 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

Intervention Type: DRUG

Other Intervention Names

Combination chemotherapy group.; The chemotherapy regimen was decided by the treating physician.; Combination chemotherapy group.; The chemotherapy regimen was decided by the treating physician.; Combination chemotherapy group.; The chemotherapy regimen was decided by the treating physician.; Endocrine treatment arm: NSAI + goserelin+ ribociclib; Endocrine treatment arm: NSAI + goserelin+ ribociclib; Endocrine treatment arm: NSAI + goserelin+ ribociclib

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 59 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Novartis Pharmaceuticals

Role: STUDY_DIRECTOR

Novartis Pharmaceuticals

Locations

Novartis Investigative Site

Cairo, , Egypt

Novartis Investigative Site

Cairo, , Egypt

Novartis Investigative Site

Cairo, , Egypt

Novartis Investigative Site

Giza, , Egypt

Novartis Investigative Site

Bangalore, Karnataka, India

Novartis Investigative Site

Pune, Maharashtra, India

Novartis Investigative Site

Hyderabad, Telangana, India

Novartis Investigative Site

Kolkata, West Bengal, India

Novartis Investigative Site

Mumbai, , India

Novartis Investigative Site

New Delhi, , India

Novartis Investigative Site

Amman, , Jordan

Novartis Investigative Site

Beirut, , Lebanon

Novartis Investigative Site

Saida, , Lebanon

Novartis Investigative Site

Tripoli, , Lebanon

Novartis Investigative Site

Johor Bahru, Johor, Malaysia

Novartis Investigative Site

Kuala Lumpur, Kuala Lumpur, Malaysia

Novartis Investigative Site

Kota Kinabalu, Sabah, Malaysia

Novartis Investigative Site

Kuching, Sarawak, Malaysia

Novartis Investigative Site

Pulau Pinang, , Malaysia

Novartis Investigative Site

Moscow, , Russia

Novartis Investigative Site

Moscow, , Russia

Novartis Investigative Site

Pushkin Saint Petersburg, , Russia

Novartis Investigative Site

Saint Petersburg, , Russia

Novartis Investigative Site

Riyadh, , Saudi Arabia

Novartis Investigative Site

Singapore, , Singapore

Novartis Investigative Site

Singapore, , Singapore

Novartis Investigative Site

Singapore, , Singapore

Novartis Investigative Site

Durban, KwaZulu-Natal, South Africa

Novartis Investigative Site

Pretoria, , South Africa

Novartis Investigative Site

Pretoria, , South Africa

Novartis Investigative Site

Kaohsiung City, , Taiwan

Novartis Investigative Site

Taichung, , Taiwan

Novartis Investigative Site

Tainan City, , Taiwan

Novartis Investigative Site

Taipei, , Taiwan

Novartis Investigative Site

Taipei, , Taiwan

Novartis Investigative Site

Taipei, , Taiwan

Novartis Investigative Site

Taipei, , Taiwan

Novartis Investigative Site

Taoyuan District, , Taiwan

Novartis Investigative Site

Songkhla, Hat Yai, Thailand

Novartis Investigative Site

Bangkok, , Thailand

Novartis Investigative Site

Bangkok, , Thailand

Novartis Investigative Site

Chiang Mai, , Thailand

Novartis Investigative Site

Cankaya Ankara, Turkey, Turkey (Türkiye)

Novartis Investigative Site

Kecioren Ankara, Turkey, Turkey (Türkiye)

Novartis Investigative Site

Ankara, , Turkey (Türkiye)

Novartis Investigative Site

Antalya, , Turkey (Türkiye)

Novartis Investigative Site

Istanbul, , Turkey (Türkiye)

Novartis Investigative Site

Izmir, , Turkey (Türkiye)

Novartis Investigative Site

Malatya, , Turkey (Türkiye)

Novartis Investigative Site

Hanoi, , Vietnam

Countries

Egypt; India; Jordan; Lebanon; Malaysia; Russia; Saudi Arabia; Singapore; South Africa; Taiwan; Thailand; Turkey (Türkiye); Vietnam

References

Lu YS, Mahidin EIBM, Azim H, Eralp Y, Yap YS, Im SA, Rihani J, Gokmen E, El Bastawisy A, Karadurmus N, Lim YN, Lim CS, Duc LT, Chung WP, Babu KG, Penkov K, Bowles J, Alfaro TD, Wu J, Gao M, Slimane K, El Saghir NS. Final Results of RIGHT Choice: Ribociclib Plus Endocrine Therapy Versus Combination Chemotherapy in Premenopausal Women With Clinically Aggressive Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer. J Clin Oncol. 2024 Aug 10;42(23):2812-2821. doi: 10.1200/JCO.24.00144. Epub 2024 May 21.

Reference Type: DERIVED

PMID: 38771995 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

https://www.novctrd.com/ctrdweb/patientsummary/patientsummaries?patientSummaryId=2079

A Plain Language Trial Summary is available on novctrd.com

Other Identifiers

CLEE011A3201C

Identifier Type: -

Identifier Source: org_study_id