Study of Efficacy and Safety in Premenopausal Women With Hormone Receptor Positive, HER2-negative Advanced Breast Cancer (MONALEESA-7)

• ClinicalTrials.gov Identifier: NCT02278120
• Recruitment Status: Completed
• First Posted: October 29, 2014
• Results First Posted: February 26, 2019
• Last Update Posted: March 12, 2024
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: October 22, 2014
• First Posted Date: October 29, 2014
• Results First Submitted Date: August 17, 2018
• Results First Posted Date: February 26, 2019
• Last Update Posted Date: March 12, 2024
• Actual Study Start Date: November 20, 2014
• Actual Primary Completion Date: August 21, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 13, 2024)

Progression Free Survival (PFS) by Investigator Assessment [ Time Frame: From randomization to first documented progression or death, assessed up to approximately 29 months ]

PFS was defined as the period starting from the date of randomization to the date of the first documented progression or death caused by any reason. In cases where patients did not experience an event, the PFS was censored at the date of the last adequate tumor assessment. Clinical deterioration without objective radiological evidence was not considered as documented disease progression. PFS was assessed via local radiology assessment according to RECIST 1.1. As per protocol, the final PFS analysis was conducted after approximately 392 PFS events were documented. The Kaplan-Meier method was used to estimate PFS, and the median PFS, along with 95% confidence intervals, was reported for each treatment group. A stratified Cox regression model was used to estimate the hazard ratio of PFS, along with 95% confidence interval

Original Primary Outcome Measures (submitted: October 28, 2014)

Progression Free Survival (PFS) [ Time Frame: Up to approximatley 25 months ]

PFS, defined as the time from the date of randomization to the date of the first documented progression or death due to any cause and assessed according to RECIST 1.1

Current Secondary Outcome Measures (submitted: February 13, 2024)

• Overall Survival (OS) [ Time Frame: From randomization to death, assessed up to approximately 45 months ]
  OS was defined as the time from the date of randomization to the date of death from any cause. In cases where the patient's death was not recorded, the OS value was censored at the date of the last known patient's survival status. OS was estimated using the Kaplan-Meier method. As per protocol, the final OS analysis was conducted after approximately 189 deaths were documented. The median OS, along with 95% confidence intervals, was reported for each treatment group.The distribution of OS between the two treatment arms was compared using a log-rank test at one-sided cumulative 2.5% level of significance. A stratified Cox regression was used to estimate the OS hazard ratio and the associated 95% CI.
• Overall Response Rate (ORR) by Investigator Assessment [ Time Frame: Up to approximately 29 months ]
  ORR is the percentage of participants with the best overall response of complete response (CR) or partial response (PR) according to RECIST 1.1 as per local assessment. CR = Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm; PR = At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
• Clinical Benefit Rate (CBR) by Investigator Assessment [ Time Frame: Up to approximately 29 months ]
  Percentage of participants with complete response (CR) or partial response (PR) or stable disease (SD) lasting 24 weeks or longer as defined in RECIST 1.1 and local assessment. CR = Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm; PR = At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters; SD = Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease: PD = At least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20% the sum must also demonstrate an absolute increase of at least 5 mm.
• Time to Response (TTR) by Investigator Assessment [ Time Frame: Up to approximately 29 months ]
  Time to response is the time from the date of randomization to the first documented response (CR or PR, which must be confirmed subsequently) according to RECIST 1.1 as per local assessment. The Kaplan-Meier method was used to estimate TTR, and the median TTR, along with 95% confidence intervals, was reported for each treatment group. Participants who did not achieve a confirmed response were censored at the maximum follow-up time for patients who had a PFS event (i.e. either progressed or died due to any cause) or at the date of last adequate tumor assessment otherwise. CR = Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm; PR = At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
• Duration of Response (DOR) by Investigator Assessment [ Time Frame: Up to approximately 29 months ]
  DOR was defined as the time from the first documented response (CR or PR) to the first documented progression or death due to underlying cancer as defined in RECIST 1.1 per investigator assessment. The Kaplan-Meier method was used to estimate DOR, and the median DOR, along with 95% confidence intervals, was reported for each treatment group. If a participant had not had an event, duration was censored at the date of last adequate tumor assessment. CR = Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm; PR = At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
• Time to Definitive Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) by at Least One Category of the Score [ Time Frame: Baseline, up to approximately 29 months ]
  ECOG PS categorized patients based on their ability to perform daily activities and self-care, with scores ranging from 0 to 5. A score of 0 indicated no restrictions in activity, while higher scores indicated increasing limitations. Time to definitive deterioration was defined as the time from the date of randomization to the date of the event, defined as experiencing an increase in ECOG PS by at least one category from the baseline or death. A deterioration was considered definitive if no improvements in the ECOG PS were observed at a subsequent time. The Kaplan-Meier method was used to estimate the distribution, and the median time to definitive deterioration, along with 95% confidence intervals, was reported for each treatment group. Patients receiving any further therapy prior to definitive worsening were censored at their date of last assessment prior to start of therapy. Patients that had not worsened at the data cutoff point were censored at the date of last assessment.
• Time to Definitive 10% Deterioration in the Global Health Status/Quality of Life (GHS/QoL) Scale Score of the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC QLQ-C30) [ Time Frame: Up to approximately 29 months ]
  The EORTC QLQ-C30 is a questionnaire that includes 5 functional scales, 3 symptom scales, 1 GHS/QoL scale, and 6 single items. GHS/QoL scale score ranges between 0 and 100. A high score for GHS/QoL represents better functioning or QoL.The time to definitive 10% deterioration is defined as the time from the date of randomization to the date of event, which is defined as at least 10% relative to baseline worsening of the QoL score (without further improvement above the threshold) or death due to any cause. The Kaplan-Meier method was used to estimate the distribution, and the median time to definitive 10% deterioration, along with 95% confidence intervals, was reported for each treatment group. If a patient had not had an event, time to deterioration was censored at the date of the last adequate QoL evaluation.
• Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 [ Time Frame: Baseline, every 2 cycles after randomization during 18 months, then every 3 cycles up to end of treatment (EOT); EOT; and every 8 or 12 weeks post-treatment until progression, assessed up to approximately 29 months. Cycle=28 days ]
  The EORTC QLQ-C30 is a questionnaire that includes 5 functional scales, 3 symptom scales, 1 GHS/QoL scale, and 6 single items. GHS/QoL scale score ranges between 0 and 100. A high score for GHS/QoL represents better functioning or QoL.The change from baseline in the GHS/QoL score was assessed. A positive change from baseline indicated improvement. For subjects who discontinued treatment without disease progression, post-treatment efficacy visits occurred every 8 weeks during the initial 18 months since start of treatment, followed by visits every 12 weeks until disease progression.

Original Secondary Outcome Measures (submitted: October 28, 2014)

• Overall survival (OS) [ Time Frame: Up to approximately 69 months ]
  Time from date of randomization to the date of death from any cause
• Clinical Benefit Rate (CBR) [ Time Frame: Up to approximately 25 months ]
  Proportion of patients with complete response (CR) or partial response (PR) or stable disease (SD) lasting 24 weeks or longer as defined in RECIST 1.1
• Safety and Tolerability of LEE011 determined by type, frequency and severity of adverse events and laboratory abnormalities per Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 [ Time Frame: Up to approximately 26 months ]
  Safety and tolerability will be determined by type, frequency and severity of adverse events and laboratory abnormalities per Common Terminology Criteria for Adverse Events (CTCAE) version 4.03
• Time to Response (TTR) [ Time Frame: Up to approximately 25 months ]
  Time from randomization to the first documented and confirmed response (complete response or partial response)
• Duration of Response (DOR) [ Time Frame: Up to approximately 25 months ]
  Time from the first documented response (CR or PR) to the first documented progression or death due to underlying cancer
• Time to definitive deterioration of the ECOG PS from baseline [ Time Frame: Baseline, up to approximately 25 months ]
  Time to deterioration of Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)
• Time to 10% deterioration in the global health status/QOL scale score of the EORTC QLQ-C30 [ Time Frame: Up to approximately 25 months ]
  Patient reported outcomes for health related quality of life
• Change from baseline in the global health status/QOL scale score of the EORTC QLQ-C30 [ Time Frame: Up to approximately 25 months ]
  Patient reported outcomes for health related quality of life
• Overall Response Rate (ORR) [ Time Frame: Up to approximately 25 months ]
  Proportion of patients with the best overall response of complete response (CR) or partial response (PR) according to RECIST 1.1.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of Efficacy and Safety in Premenopausal Women With Hormone Receptor Positive, HER2-negative Advanced Breast Cancer
• Official Title: A Phase III Randomized, Double-blind, Placebo-controlled Study of LEE011 or Placebo in Combination With Tamoxifen and Goserelin or a Non-steroidal Aromatase Inhibitor (NSAI) and Goserelin for the Treatment of Premenopausal Women With Hormone Receptor Positive, HER2-negative, Advanced Breast Cancer
• Brief Summary: The purpose of this study was to determine whether treatment with tamoxifen or a non-steroidal aromatase inhibitors (NSAI) + goserelin + LEE011 prolonged progression-free survival (PFS) compared to treatment with tamoxifen or a NSAI + goserelin + placebo in premenopausal women with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer.

Detailed Description

This was a randomized, Phase III, double-blind, global study comparing the treatment efficacy and safety of ribociclib + goserelin + tamoxifen or a NSAI (letrozole or anastrozole) versus placebo + goserelin + tamoxifen or a NSAI in premenopausal women with HR+, HER2- advanced breast cancer.

Eligible participants were randomized in a 1:1 ratio to either the ribociclib arm or the placebo arm. Study treatment continued until disease progression, unacceptable toxicity, death, or discontinuation for any other reason.

Participants who discontinued treatment due to reasons other than disease progression or withdrawal of consent for efficacy follow-up continued to be monitored until disease progression, death, withdrawal of consent, loss to follow-up, or subject/guardian decision (post-treatment efficacy follow-up).

All participants who discontinued treatment were followed for survival until the predetermined number of overall survival (OS) events was reached.

Following the final OS analysis (performed when approximately 189 deaths were recorded) and with protocol amendment 6 (dated 18-Jul-2019), participants and investigators were unblinded and those participants in the placebo arm had the opportunity to cross-over to the ribociclib arm to receive ribociclib + goserelin + NSAI. Cross-over was optional and was conducted at the investigator's discretion and upon participant consent.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Advanced Metastatic Breast Cancer

Intervention

• Drug: Ribociclib
  Ribociclib (600 mg, in three 200 mg hard gelatin capsules) was administered orally once daily on Days 1-21 of each 28-day cycle.
  Other Name: LEE011
• Drug: Tamoxifen
  Tamoxifen (20 mg, tablets) was administered orally on a continuous daily schedule (days 1-28 of each 28-day cycle)
• Drug: Letrozole
  Letrozole (2.5 mg, tablets) was administered orally once daily on a continuous daily schedule (days 1-28 of each 28-day cycle)
• Drug: Anastrozole
  Anastrozole (1 mg, tablets) was administered orally once daily on a continuous daily schedule (days 1-28 of each 28-day cycle)
• Drug: Goserelin
  Goserelin (3.6 mg, subcutaneous implant) was administered on day 1 of every 28-day cycle
• Drug: Placebo
  Placebo (hard gelatin capsules) was administered orally once daily on Days 1-21 of each 28-day cycle.

Study Arms

• Experimental: Ribociclib + NSAI/tamoxifen + goserelin
  Ribociclib 600 mg daily oral (3 weeks on/ 1 week off) in combination with NSAI or tamoxifen (tamoxifen 20 mg daily oral or letrozole 2.5 mg daily oral or anastrozole 1 mg daily oral) and goserelin 3.6 mg subcutaneous injection (once every 28 days)
  Interventions:

  • Drug: Ribociclib
  • Drug: Tamoxifen
  • Drug: Letrozole
  • Drug: Anastrozole
  • Drug: Goserelin
• Placebo Comparator: Placebo + NSAI/tamoxifen + goserelin

  Placebo daily oral (3 weeks on/ 1 week off) in combination with NSAI or tamoxifen (tamoxifen 20 mg daily oral or letrozole 2.5 mg daily oral or anastrozole 1 mg daily oral) and goserelin 3.6 mg subcutaneous injection (once every 28 days).

  Participants were unblinded once the final OS analysis was conducted and after the implementation of protocol amendment 6 (16-Jul-2019) and were given the option to crossover to treatment with ribociclib +NSAI/tamoxifen + goserelin.

  Interventions:

  • Drug: Tamoxifen
  • Drug: Letrozole
  • Drug: Anastrozole
  • Drug: Goserelin
  • Drug: Placebo

Publications *

• Lu YS, Im SA, Colleoni M, Franke F, Bardia A, Cardoso F, Harbeck N, Hurvitz S, Chow L, Sohn J, Lee KS, Campos-Gomez S, Villanueva Vazquez R, Jung KH, Babu KG, Wheatley-Price P, De Laurentiis M, Im YH, Kuemmel S, El-Saghir N, O'Regan R, Gasch C, Solovieff N, Wang C, Wang Y, Chakravartty A, Ji Y, Tripathy D. Updated Overall Survival of Ribociclib plus Endocrine Therapy versus Endocrine Therapy Alone in Pre- and Perimenopausal Patients with HR+/HER2- Advanced Breast Cancer in MONALEESA-7: A Phase III Randomized Clinical Trial. Clin Cancer Res. 2022 Mar 1;28(5):851-859. doi: 10.1158/1078-0432.CCR-21-3032.
• Bardia A, Su F, Solovieff N, Im SA, Sohn J, Lee KS, Campos-Gomez S, Jung KH, Colleoni M, Vazquez RV, Franke F, Hurvitz S, Harbeck N, Chow L, Taran T, Rodriguez Lorenc K, Babbar N, Tripathy D, Lu YS. Genomic Profiling of Premenopausal HR+ and HER2- Metastatic Breast Cancer by Circulating Tumor DNA and Association of Genetic Alterations With Therapeutic Response to Endocrine Therapy and Ribociclib. JCO Precis Oncol. 2021 Sep 1;5:PO.20.00445. doi: 10.1200/PO.20.00445. eCollection 2021. Erratum In: JCO Precis Oncol. 2023 Mar;7:e2300102.
• Burris HA, Chan A, Bardia A, Thaddeus Beck J, Sohn J, Neven P, Tripathy D, Im SA, Chia S, Esteva FJ, Hart L, Zarate JP, Ridolfi A, Lorenc KR, Yardley DA. Safety and impact of dose reductions on efficacy in the randomised MONALEESA-2, -3 and -7 trials in hormone receptor-positive, HER2-negative advanced breast cancer. Br J Cancer. 2021 Aug;125(5):679-686. doi: 10.1038/s41416-021-01415-9. Epub 2021 Jun 22.
• Prat A, Chaudhury A, Solovieff N, Pare L, Martinez D, Chic N, Martinez-Saez O, Braso-Maristany F, Lteif A, Taran T, Babbar N, Su F. Correlative Biomarker Analysis of Intrinsic Subtypes and Efficacy Across the MONALEESA Phase III Studies. J Clin Oncol. 2021 May 1;39(13):1458-1467. doi: 10.1200/JCO.20.02977. Epub 2021 Mar 26. Erratum In: J Clin Oncol. 2021 Nov 1;39(31):3525. J Clin Oncol. 2023 Apr 20;41(12):2299-2301.
• Yardley DA. MONALEESA clinical program: a review of ribociclib use in different clinical settings. Future Oncol. 2019 Aug;15(23):2673-2686. doi: 10.2217/fon-2019-0130. Epub 2019 Jul 15.
• Im SA, Lu YS, Bardia A, Harbeck N, Colleoni M, Franke F, Chow L, Sohn J, Lee KS, Campos-Gomez S, Villanueva-Vazquez R, Jung KH, Chakravartty A, Hughes G, Gounaris I, Rodriguez-Lorenc K, Taran T, Hurvitz S, Tripathy D. Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer. N Engl J Med. 2019 Jul 25;381(4):307-316. doi: 10.1056/NEJMoa1903765. Epub 2019 Jun 4.
• Tripathy D, Im SA, Colleoni M, Franke F, Bardia A, Harbeck N, Hurvitz SA, Chow L, Sohn J, Lee KS, Campos-Gomez S, Villanueva Vazquez R, Jung KH, Babu KG, Wheatley-Price P, De Laurentiis M, Im YH, Kuemmel S, El-Saghir N, Liu MC, Carlson G, Hughes G, Diaz-Padilla I, Germa C, Hirawat S, Lu YS. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol. 2018 Jul;19(7):904-915. doi: 10.1016/S1470-2045(18)30292-4. Epub 2018 May 24.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 7, 2018): 672
• Original Estimated Enrollment (submitted: October 28, 2014): 660
• Actual Study Completion Date: April 20, 2023
• Actual Primary Completion Date: August 21, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

Key inclusion criteria:

• Patients had advanced (locoregionally recurrent or metastatic) breast cancer not amenable to curative therapy
• Patients were premenopausal or perimenopausal at the time of study entry
• Patients who had received (neo) adjuvant therapy for breast cancer were eligible
• Patients had a histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer
• Patients had HER2-negative breast cancer
• Patients must have either had measurable disease or If no measurable disease was present, then at least one predominantly lytic bone lesion
• Patients had an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Patients had adequate bone marrow and organ function

Key exclusion criteria:

• Patients who had received a prior CDK4/6 inhibitor
• Patients were postmenopausal
• Patients who currently had inflammatory breast cancer at screening.
• Patients who had received any prior hormonal anti-cancer therapy for advanced breast cancer, except for ≤ 14 days of tamoxifen or NSAI ± goserelin for advanced breast cancer prior to randomization.
• Patients had a concurrent malignancy or malignancy within 3 years of randomization, with the exception of adequately treated basal cell skin carcinoma, squamous cell skin carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer.
• Patients with CNS metastases.
• Patients had active cardiac disease or a history of cardiac dysfunction
• Patients were currently using other antineoplastic agents
• Patients were pregnant or nursing or physiologically capable of becoming pregnant and not using highly effective contraception.

Sex/Gender

• Sexes Eligible for Study: Female
• Gender Based Eligibility: Yes

• Ages: 18 Years to 59 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, Colombia, France, Germany, Greece, Hong Kong, Hungary, India, Italy, Korea, Republic of, Lebanon, Malaysia, Mexico, Poland, Portugal, Russian Federation, Saudi Arabia, Singapore, Spain, Switzerland, Taiwan, Thailand, Turkey, United Arab Emirates, United States

Administrative Information

• NCT Number: NCT02278120
• Other Study ID Numbers: CLEE011E2301; 2014-001931-36 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes

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

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: February 2024