Clinical trial NCT02278120: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Advanced Metastatic Breast Cancer
Keywords: LEE011
ribociclib
HR-positive
HER2-negative
Advanced breast cancer
Letrozole
Anastrozole
Tamoxifen
Goserelin
CDK
CDK4
CDK6
CDK4/6
Phase III
ER-positive
PR-positive
Premenopausal
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2014-10-29
Enrollment: 672
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 59
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Progression Free Survival (PFS) by Investigator Assessment
timeFrame: From randomization to first documented progression or death, assessed up to approximately 29 months
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: From randomization to death, assessed up to approximately 45 months
measure: Overall Response Rate (ORR) by Investigator Assessment
timeFrame: Up to approximately 29 months
measure: Clinical Benefit Rate (CBR) by Investigator Assessment
timeFrame: Up to approximately 29 months
measure: Time to Response (TTR) by Investigator Assessment
timeFrame: Up to approximately 29 months
measure: Duration of Response (DOR) by Investigator Assessment
timeFrame: Up to approximately 29 months
measure: Time to Definitive Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) by at Least One Category of the Score
timeFrame: Baseline, up to approximately 29 months
measure: 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)
timeFrame: Up to approximately 29 months
measure: Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30
timeFrame: 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
Other outcomes:
Locations:
city: Bakersfield
country: United States
facility: Comprehensive Blood and Cancer SC-2
state: California
city: Los Angeles
country: United States
facility: University Of California Los Angeles Dept of Onc
state: California
city: Denver
country: United States
facility: Comprehensive Cancer Center at Saint Joseph Hospital SC
state: Colorado
city: Danbury
country: United States
facility: Danbury Hospital SC
state: Connecticut
city: Fort Myers
country: United States
facility: Florida Cancer Specialists Onc Dept
state: Florida
city: Fort Myers
country: United States
facility: Florida Cancer Specialists SC-2
state: Florida
city: Hollywood
country: United States
facility: Memorial Cancer Institute SC
state: Florida
city: Miami
country: United States
facility: University Of Miami Univ Miami 2
state: Florida
city: Marietta
country: United States
facility: NorthWest Georgia Oncology Centers IRB
state: Georgia
city: Honolulu
country: United States
facility: Moanalua Medical Center. Attn: Oncology Dept SC
state: Hawaii
city: Chicago
country: United States
facility: University of Chicago SC-3
state: Illinois
city: Louisville
country: United States
facility: Norton Cancer Institute SC
state: Kentucky
city: Baltimore
country: United States
facility: Sidney Kimmel CCC At JH Dept of Onc.
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital Onc Dept
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center Onc Dept
state: Michigan
city: Saint Louis
country: United States
facility: Washington Uni School of Med SC
state: Missouri
city: Neptune
country: United States
facility: Meridian Health Systems SC
state: New Jersey
city: Albuquerque
country: United States
facility: University of New Mexico Hospital SC-2
state: New Mexico
city: Lake Success
country: United States
facility: Clinical Research Alliance .
state: New York
city: Durham
country: United States
facility: Duke Univ Medical Center Duke (SC)
state: North Carolina
city: Hershey
country: United States
facility: Penn State University Milton S Hershey Medical Center
state: Pennsylvania
city: Greenville
country: United States
facility: Bon Secours Cancer Center SC
state: South Carolina
city: Chattanooga
country: United States
facility: Erlanger Medical Center SC
state: Tennessee
city: Nashville
country: United States
facility: SCRI Oncology Partners Tennessee Oncology (3)
state: Tennessee
city: Fort Worth
country: United States
facility: The Center for Cancer and Blood Disorders SC
state: Texas
city: Houston
country: United States
facility: Methodist Hospita Methodist Can Cen Dept of Oncology
state: Texas
city: Houston
country: United States
facility: Uni of TX MD Anderson Cancer Cntr SC-5
state: Texas
city: San Antonio
country: United States
facility: Mays Cancer Ctr Uthsa Mdacc SC-4
state: Texas
city: San Antonio
country: United States
facility: Brooke Army Medical Center SC
state: Texas
city: Ogden
country: United States
facility: Northern Utah Cancer Associates
state: Utah
city: Midlothian
country: United States
facility: Bon Secours Virginia Health System
state: Virginia
city: Everett
country: United States
facility: Providence Regional Cancer Partnership
state: Washington
city: Kennewick
country: United States
facility: Kadlec Clinic Hematology and Onco Kadlec Clinic Hematology & Onc
state: Washington
city: Tacoma
country: United States
facility: Northwest Medical Specialties Dept of Onc
state: Washington
city: Madison
country: United States
facility: University of Wisconsin / Paul P. Carbone Comp Cancer Center Univ Wisc 3
state: Wisconsin
city: Cordoba
country: Argentina
facility: Novartis Investigative Site
city: Jujuy
country: Argentina
facility: Novartis Investigative Site
city: La Rioja
country: Argentina
facility: Novartis Investigative Site
city: Waratah
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Box Hill
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Heidelberg
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Murdoch
country: Australia
facility: Novartis Investigative Site
state: Western Australia
city: Nedlands
country: Australia
facility: Novartis Investigative Site
state: Western Australia
city: Bruxelles
country: Belgium
facility: Novartis Investigative Site
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Namur
country: Belgium
facility: Novartis Investigative Site
city: Wilrijk
country: Belgium
facility: Novartis Investigative Site
city: Londrina
country: Brazil
facility: Novartis Investigative Site
state: PR
city: Ijuí
country: Brazil
facility: Novartis Investigative Site
state: RS
city: Passo Fundo
country: Brazil
facility: Novartis Investigative Site
state: RS
city: Barretos
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: São Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Sofia
country: Bulgaria
facility: Novartis Investigative Site
city: Varna
country: Bulgaria
facility: Novartis Investigative Site
city: Edmonton
country: Canada
facility: Novartis Investigative Site
state: Alberta
city: Vancouver
country: Canada
facility: Novartis Investigative Site
state: British Columbia
city: Ottawa
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Montréal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Quebec
country: Canada
facility: Novartis Investigative Site
city: Bogota
country: Colombia
facility: Novartis Investigative Site
city: Monteria
country: Colombia
facility: Novartis Investigative Site
city: Caen
country: France
facility: Novartis Investigative Site
city: Lille Cedex
country: France
facility: Novartis Investigative Site
city: Lyon
country: France
facility: Novartis Investigative Site
city: Montpellier
country: France
facility: Novartis Investigative Site
city: Paris
country: France
facility: Novartis Investigative Site
city: Rouen
country: France
facility: Novartis Investigative Site
city: Strasbourg
country: France
facility: Novartis Investigative Site
city: Toulouse
country: France
facility: Novartis Investigative Site
city: Bonn
country: Germany
facility: Novartis Investigative Site
city: Dresden
country: Germany
facility: Novartis Investigative Site
city: Erlangen
country: Germany
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Esslingen
country: Germany
facility: Novartis Investigative Site
city: Kiel
country: Germany
facility: Novartis Investigative Site
city: Leipzig
country: Germany
facility: Novartis Investigative Site
city: Muehlhausen
country: Germany
facility: Novartis Investigative Site
city: Muenchen
country: Germany
facility: Novartis Investigative Site
city: Offenbach
country: Germany
facility: Novartis Investigative Site
city: Ravensburg
country: Germany
facility: Novartis Investigative Site
city: Ulm
country: Germany
facility: Novartis Investigative Site
city: Thessaloniki
country: Greece
facility: Novartis Investigative Site
state: GR
city: Heraklion Crete
country: Greece
facility: Novartis Investigative Site
city: Hong Kong
country: Hong Kong
facility: Novartis Investigative Site
city: Kowloon
country: Hong Kong
facility: Novartis Investigative Site
city: Wan Chai
country: Hong Kong
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Debrecen
country: Hungary
facility: Novartis Investigative Site
city: Szeged
country: Hungary
facility: Novartis Investigative Site
city: Szolnok
country: Hungary
facility: Novartis Investigative Site
city: Bangalore
country: India
facility: Novartis Investigative Site
state: Karnataka
city: Nashik
country: India
facility: Novartis Investigative Site
state: Maharashtra
city: Kolkatta
country: India
facility: Novartis Investigative Site
state: West Bengal
city: Mumbai
country: India
facility: Novartis Investigative Site
city: L Aquila
country: Italy
facility: Novartis Investigative Site
state: AQ
city: Benevento
country: Italy
facility: Novartis Investigative Site
state: BN
city: Bologna
country: Italy
facility: Novartis Investigative Site
state: BO
city: Cremona
country: Italy
facility: Novartis Investigative Site
state: CR
city: Catania
country: Italy
facility: Novartis Investigative Site
state: CT
city: Meldola
country: Italy
facility: Novartis Investigative Site
state: FC
city: Cona
country: Italy
facility: Novartis Investigative Site
state: FE
city: Genova
country: Italy
facility: Novartis Investigative Site
state: GE
city: Lecce
country: Italy
facility: Novartis Investigative Site
state: LE
city: Lucca
country: Italy
facility: Novartis Investigative Site
state: LU
city: Macerata
country: Italy
facility: Novartis Investigative Site
state: MC
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Perugia
country: Italy
facility: Novartis Investigative Site
state: PG
city: Prato
country: Italy
facility: Novartis Investigative Site
state: PO
city: Pavia
country: Italy
facility: Novartis Investigative Site
state: PV
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Candiolo
country: Italy
facility: Novartis Investigative Site
state: TO
city: Terni
country: Italy
facility: Novartis Investigative Site
state: TR
city: Udine
country: Italy
facility: Novartis Investigative Site
state: UD
city: Napoli
country: Italy
facility: Novartis Investigative Site
city: Bundang Gu
country: Korea, Republic of
facility: Novartis Investigative Site
state: Gyeonggi Do
city: Gyeonggi do
country: Korea, Republic of
facility: Novartis Investigative Site
state: Korea
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: El Chouf
country: Lebanon
facility: Novartis Investigative Site
state: LBN
city: Ashrafieh
country: Lebanon
facility: Novartis Investigative Site
city: Beirut
country: Lebanon
facility: Novartis Investigative Site
city: Beirut
country: Lebanon
facility: Novartis Investigative Site
city: Beirut
country: Lebanon
facility: Novartis Investigative Site
city: Saida
country: Lebanon
facility: Novartis Investigative Site
city: Johor Bahru
country: Malaysia
facility: Novartis Investigative Site
state: Johor
city: Kuala Lumpur
country: Malaysia
facility: Novartis Investigative Site
city: Metepec
country: Mexico
facility: Novartis Investigative Site
state: Edo. De México
city: Leon
country: Mexico
facility: Novartis Investigative Site
state: Guanajuato
city: Monterrey Nuevo Leon
country: Mexico
facility: Novartis Investigative Site
state: Monterrey
city: Gdansk
country: Poland
facility: Novartis Investigative Site
city: Konin
country: Poland
facility: Novartis Investigative Site
city: Lisboa
country: Portugal
facility: Novartis Investigative Site
city: Lisboa
country: Portugal
facility: Novartis Investigative Site
city: Lisboa
country: Portugal
facility: Novartis Investigative Site
city: Porto
country: Portugal
facility: Novartis Investigative Site
city: Porto
country: Portugal
facility: Novartis Investigative Site
city: Arkhangelsk
country: Russian Federation
facility: Novartis Investigative Site
city: Saint Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Riyadh
country: Saudi Arabia
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Elche
country: Spain
facility: Novartis Investigative Site
state: Alicante
city: Almeria
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Malaga
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Sabadell
country: Spain
facility: Novartis Investigative Site
state: Barcelona
city: Sant Joan Despi
country: Spain
facility: Novartis Investigative Site
state: Barcelona
city: Badalona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Valencia
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: Santiago De Compostela
country: Spain
facility: Novartis Investigative Site
state: Galicia
city: Mallorca
country: Spain
facility: Novartis Investigative Site
state: Islas Baleares
city: Alcorcon
country: Spain
facility: Novartis Investigative Site
state: Madrid
city: San Sebastian
country: Spain
facility: Novartis Investigative Site
state: Pais Vasco
city: Baracaldo
country: Spain
facility: Novartis Investigative Site
state: Vizcaya
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Geneve
country: Switzerland
facility: Novartis Investigative Site
city: Changhua
country: Taiwan
facility: Novartis Investigative Site
city: Kaohsiung
country: Taiwan
facility: Novartis Investigative Site
city: New Taipei City
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Taoyuan
country: Taiwan
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Istanbul
country: Turkey
facility: Novartis Investigative Site
state: TUR
city: Adana
country: Turkey
facility: Novartis Investigative Site
city: Ankara
country: Turkey
facility: Novartis Investigative Site
city: Diyarbakir
country: Turkey
facility: Novartis Investigative Site
city: Edirne
country: Turkey
facility: Novartis Investigative Site
city: Izmir
country: Turkey
facility: Novartis Investigative Site
city: Al Ain Abu Dhabi
country: United Arab Emirates
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.