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

Advanced Metastatic Breast Cancer Clinical Trial

— MONALEESA-7  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02278120
• Other study ID #: CLEE011E2301
• Secondary ID: 2014-001931-36
• Status: Completed
• Phase: Phase 3
• Start date: November 20, 2014
• Est. completion date: April 20, 2023

Study information

• Verified date: February 2024
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 672
• Est. completion date: April 20, 2023
• Est. primary completion date: August 21, 2017
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 59 Years

Eligibility

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.

Related Conditions & MeSH terms

• Advanced Metastatic Breast Cancer
• Breast Neoplasms

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

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Cordoba
Argentina	Novartis Investigative Site	Jujuy
Argentina	Novartis Investigative Site	La Rioja
Australia	Novartis Investigative Site	Box Hill	Victoria
Australia	Novartis Investigative Site	Heidelberg	Victoria
Australia	Novartis Investigative Site	Murdoch	Western Australia
Australia	Novartis Investigative Site	Nedlands	Western Australia
Australia	Novartis Investigative Site	Waratah	New South Wales
Belgium	Novartis Investigative Site	Bruxelles
Belgium	Novartis Investigative Site	Leuven
Belgium	Novartis Investigative Site	Namur
Belgium	Novartis Investigative Site	Wilrijk
Brazil	Novartis Investigative Site	Barretos	SP
Brazil	Novartis Investigative Site	Ijuí	RS
Brazil	Novartis Investigative Site	Londrina	PR
Brazil	Novartis Investigative Site	Passo Fundo	RS
Brazil	Novartis Investigative Site	Sao Paulo	SP
Brazil	Novartis Investigative Site	Sao Paulo	SP
Brazil	Novartis Investigative Site	São Paulo	SP
Bulgaria	Novartis Investigative Site	Sofia
Bulgaria	Novartis Investigative Site	Varna
Canada	Novartis Investigative Site	Edmonton	Alberta
Canada	Novartis Investigative Site	Montréal	Quebec
Canada	Novartis Investigative Site	Ottawa	Ontario
Canada	Novartis Investigative Site	Quebec
Canada	Novartis Investigative Site	Toronto	Ontario
Canada	Novartis Investigative Site	Vancouver	British Columbia
Colombia	Novartis Investigative Site	Bogota
Colombia	Novartis Investigative Site	Monteria
France	Novartis Investigative Site	Caen
France	Novartis Investigative Site	Lille Cedex
France	Novartis Investigative Site	Lyon
France	Novartis Investigative Site	Montpellier
France	Novartis Investigative Site	Paris
France	Novartis Investigative Site	Rouen
France	Novartis Investigative Site	Strasbourg
France	Novartis Investigative Site	Toulouse
Germany	Novartis Investigative Site	Bonn
Germany	Novartis Investigative Site	Dresden
Germany	Novartis Investigative Site	Erlangen
Germany	Novartis Investigative Site	Essen
Germany	Novartis Investigative Site	Esslingen
Germany	Novartis Investigative Site	Kiel
Germany	Novartis Investigative Site	Leipzig
Germany	Novartis Investigative Site	Muehlhausen
Germany	Novartis Investigative Site	Muenchen
Germany	Novartis Investigative Site	Offenbach
Germany	Novartis Investigative Site	Ravensburg
Germany	Novartis Investigative Site	Ulm
Greece	Novartis Investigative Site	Heraklion Crete
Greece	Novartis Investigative Site	Thessaloniki	GR
Hong Kong	Novartis Investigative Site	Hong Kong
Hong Kong	Novartis Investigative Site	Kowloon
Hong Kong	Novartis Investigative Site	Wan Chai
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Debrecen
Hungary	Novartis Investigative Site	Szeged
Hungary	Novartis Investigative Site	Szolnok
India	Novartis Investigative Site	Bangalore	Karnataka
India	Novartis Investigative Site	Kolkatta	West Bengal
India	Novartis Investigative Site	Mumbai
India	Novartis Investigative Site	Nashik	Maharashtra
Italy	Novartis Investigative Site	Benevento	BN
Italy	Novartis Investigative Site	Bologna	BO
Italy	Novartis Investigative Site	Candiolo	TO
Italy	Novartis Investigative Site	Catania	CT
Italy	Novartis Investigative Site	Cona	FE
Italy	Novartis Investigative Site	Cremona	CR
Italy	Novartis Investigative Site	Genova	GE
Italy	Novartis Investigative Site	L Aquila	AQ
Italy	Novartis Investigative Site	Lecce	LE
Italy	Novartis Investigative Site	Lucca	LU
Italy	Novartis Investigative Site	Macerata	MC
Italy	Novartis Investigative Site	Meldola	FC
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Napoli
Italy	Novartis Investigative Site	Pavia	PV
Italy	Novartis Investigative Site	Perugia	PG
Italy	Novartis Investigative Site	Prato	PO
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Terni	TR
Italy	Novartis Investigative Site	Udine	UD
Korea, Republic of	Novartis Investigative Site	Bundang Gu	Gyeonggi Do
Korea, Republic of	Novartis Investigative Site	Gyeonggi do	Korea
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Lebanon	Novartis Investigative Site	Ashrafieh
Lebanon	Novartis Investigative Site	Beirut
Lebanon	Novartis Investigative Site	Beirut
Lebanon	Novartis Investigative Site	Beirut
Lebanon	Novartis Investigative Site	El Chouf	LBN
Lebanon	Novartis Investigative Site	Saida
Malaysia	Novartis Investigative Site	Johor Bahru	Johor
Malaysia	Novartis Investigative Site	Kuala Lumpur
Mexico	Novartis Investigative Site	Leon	Guanajuato
Mexico	Novartis Investigative Site	Metepec	Edo. De México
Mexico	Novartis Investigative Site	Monterrey Nuevo Leon	Monterrey
Poland	Novartis Investigative Site	Gdansk
Poland	Novartis Investigative Site	Konin
Portugal	Novartis Investigative Site	Lisboa
Portugal	Novartis Investigative Site	Lisboa
Portugal	Novartis Investigative Site	Lisboa
Portugal	Novartis Investigative Site	Porto
Portugal	Novartis Investigative Site	Porto
Russian Federation	Novartis Investigative Site	Arkhangelsk
Russian Federation	Novartis Investigative Site	Saint Petersburg
Saudi Arabia	Novartis Investigative Site	Riyadh
Singapore	Novartis Investigative Site	Singapore
Singapore	Novartis Investigative Site	Singapore
Spain	Novartis Investigative Site	Alcorcon	Madrid
Spain	Novartis Investigative Site	Almeria	Andalucia
Spain	Novartis Investigative Site	Badalona	Catalunya
Spain	Novartis Investigative Site	Baracaldo	Vizcaya
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Elche	Alicante
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Malaga	Andalucia
Spain	Novartis Investigative Site	Mallorca	Islas Baleares
Spain	Novartis Investigative Site	Sabadell	Barcelona
Spain	Novartis Investigative Site	San Sebastian	Pais Vasco
Spain	Novartis Investigative Site	Sant Joan Despi	Barcelona
Spain	Novartis Investigative Site	Santiago De Compostela	Galicia
Spain	Novartis Investigative Site	Valencia	Comunidad Valenciana
Switzerland	Novartis Investigative Site	Geneve
Taiwan	Novartis Investigative Site	Changhua
Taiwan	Novartis Investigative Site	Kaohsiung
Taiwan	Novartis Investigative Site	New Taipei 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
Thailand	Novartis Investigative Site	Bangkok
Thailand	Novartis Investigative Site	Bangkok
Turkey	Novartis Investigative Site	Adana
Turkey	Novartis Investigative Site	Ankara
Turkey	Novartis Investigative Site	Diyarbakir
Turkey	Novartis Investigative Site	Edirne
Turkey	Novartis Investigative Site	Istanbul	TUR
Turkey	Novartis Investigative Site	Izmir
United Arab Emirates	Novartis Investigative Site	Al Ain Abu Dhabi
United States	University of New Mexico Hospital SC-2	Albuquerque	New Mexico
United States	University of Michigan Comprehensive Cancer Center Onc Dept	Ann Arbor	Michigan
United States	Comprehensive Blood and Cancer SC-2	Bakersfield	California
United States	Sidney Kimmel CCC At JH Dept of Onc.	Baltimore	Maryland
United States	Massachusetts General Hospital Onc Dept	Boston	Massachusetts
United States	Erlanger Medical Center SC	Chattanooga	Tennessee
United States	University of Chicago SC-3	Chicago	Illinois
United States	Danbury Hospital SC	Danbury	Connecticut
United States	Comprehensive Cancer Center at Saint Joseph Hospital SC	Denver	Colorado
United States	Duke Univ Medical Center Duke (SC)	Durham	North Carolina
United States	Providence Regional Cancer Partnership	Everett	Washington
United States	Florida Cancer Specialists Onc Dept	Fort Myers	Florida
United States	Florida Cancer Specialists SC-2	Fort Myers	Florida
United States	The Center for Cancer and Blood Disorders SC	Fort Worth	Texas
United States	Bon Secours Cancer Center SC	Greenville	South Carolina
United States	Penn State University Milton S Hershey Medical Center	Hershey	Pennsylvania
United States	Memorial Cancer Institute SC	Hollywood	Florida
United States	Moanalua Medical Center. Attn: Oncology Dept SC	Honolulu	Hawaii
United States	Methodist Hospita Methodist Can Cen Dept of Oncology	Houston	Texas
United States	Uni of TX MD Anderson Cancer Cntr SC-5	Houston	Texas
United States	Kadlec Clinic Hematology and Onco Kadlec Clinic Hematology & Onc	Kennewick	Washington
United States	Clinical Research Alliance .	Lake Success	New York
United States	University Of California Los Angeles Dept of Onc	Los Angeles	California
United States	Norton Cancer Institute SC	Louisville	Kentucky
United States	University of Wisconsin / Paul P. Carbone Comp Cancer Center Univ Wisc 3	Madison	Wisconsin
United States	NorthWest Georgia Oncology Centers IRB	Marietta	Georgia
United States	University Of Miami Univ Miami 2	Miami	Florida
United States	Bon Secours Virginia Health System	Midlothian	Virginia
United States	SCRI Oncology Partners Tennessee Oncology (3)	Nashville	Tennessee
United States	Meridian Health Systems SC	Neptune	New Jersey
United States	Northern Utah Cancer Associates	Ogden	Utah
United States	Washington Uni School of Med SC	Saint Louis	Missouri
United States	Brooke Army Medical Center SC	San Antonio	Texas
United States	Mays Cancer Ctr Uthsa Mdacc SC-4	San Antonio	Texas
United States	Northwest Medical Specialties Dept of Onc	Tacoma	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  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, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression Free Survival (PFS) by Investigator Assessment	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	From randomization to first documented progression or death, assessed up to approximately 29 months
Secondary	Overall Survival (OS)	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.	From randomization to death, assessed up to approximately 45 months
Secondary	Overall Response Rate (ORR) by Investigator Assessment	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.	Up to approximately 29 months
Secondary	Clinical Benefit Rate (CBR) by Investigator Assessment	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.	Up to approximately 29 months
Secondary	Time to Response (TTR) by Investigator Assessment	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.	Up to approximately 29 months
Secondary	Duration of Response (DOR) by Investigator Assessment	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.	Up to approximately 29 months
Secondary	Time to Definitive Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) by at Least One Category of the Score	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.	Baseline, up to approximately 29 months
Secondary	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)	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.	Up to approximately 29 months
Secondary	Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30	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.	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