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Effekt og sikkerhed af Ribociclib hos præ- og postmenopausale kinesiske kvinder med HR-positiv, HER2-negativ, avanceret brystkræft.

11. juni 2026 opdateret af: Novartis Pharmaceuticals

Fase II randomiseret, dobbeltblind, placebokontrolleret undersøgelse af LEE011(Ribociclib) eller placebo i kombination med endokrin terapi til behandling af præ- og postmenopausale kinesiske kvinder med HR-positiv, HER2-negativ, avanceret brystkræft, inklusive en undergruppe med Farmakokinetisk analyse.

Dette er et fase II randomiseret, dobbeltblindt, placebokontrolleret studie, der involverer præmenopausale og postmenopausale kinesiske kvinder plus en åben enkelt arm af farmakokinetisk kohorte af LEE011 i kombination med Letrozol i kinesiske postmenopausale kvinder med HR+, HER2-negativ fremskreden brystkræft. .

Tre kohorter af patienter vil blive indskrevet: PK kohorte, præmenopausal kohorte og postmenopausal kohorte.

Studieoversigt

Status

Afsluttet

Betingelser

Intervention / Behandling

Detaljeret beskrivelse

The study included three cohorts of subjects: a premenopausal cohort and a postmenopausal cohort, both randomized and double-blind, and an open-label, single-arm pharmacokinetic (PK) cohort of postmenopausal women.

The premenopausal cohort assessed the efficacy and safety of treatment with a non-steroidal aromatase inhibitor (NSAI; letrozole or anastrozole) combined with goserelin and ribociclib, compared with NSAI plus goserelin and placebo. The postmenopausal cohort assessed the efficacy and safety of ribociclib plus letrozole versus placebo plus letrozole.

The study consisted of three periods: screening, treatment, and follow-up.

  1. Screening phase: The study began with a 28-day screening period during which potential participants were evaluated against inclusion and exclusion criteria before initiating treatment on Day 1.
  2. Treatment phase: Eligible participants in the premenopausal and postmenopausal cohorts were randomized in a 1:1 ratio to one of two treatment arms, while participants in the PK cohort were not randomized. Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent, loss to follow-up, or study termination. Following a statistically significant progression-free survival (PFS) benefit observed at the primary analysis and implementation of Protocol Amendment 5 (dated 18-Oct-2022), participants and investigators were unblinded. Participants still receiving placebo were offered the option to cross over to ribociclib, at the investigator's discretion and with participant consent.

  3. Follow-up phase:

    • Safety follow-up: All participants were followed for safety for up to 30 days after the last dose of study treatment, except in cases of death, loss to follow-up, or withdrawal of consent.
    • Efficacy follow-up: Tumor assessments were performed at baseline and every 8 weeks (±1 week) from randomization for the first 18 months, then every 12 weeks (±1 week) until 36 months, and thereafter as clinically indicated until progression. Participants who discontinued treatment for reasons other than disease progression continued tumor assessments according to the same schedule until progression, death, withdrawal of consent, or loss to follow-up.
    • Survival follow-up: Survival status was assessed every 12 weeks (±1 week) for all participants, regardless of treatment discontinuation reason, unless consent was withdrawn.

The end of the study was defined as the earliest occurrence of one of the following: all participants had discontinued or died; a new clinical study offering ribociclib became available and all ongoing participants were eligible for transfer; or participants still benefiting from treatment could continue receiving it through an alternative setting.

Undersøgelsestype

Interventionel

Tilmelding (Faktiske)

327

Fase

  • Fase 2

Kontakter og lokationer

Dette afsnit indeholder kontaktoplysninger for dem, der udfører undersøgelsen, og oplysninger om, hvor denne undersøgelse udføres.

Studiesteder

  • Kina
      • Beijing, Kina, 100036
        • Novartis Investigative Site
      • Fuzhou, Kina, 350001
        • Novartis Investigative Site
      • Qingdao, Kina, 266000
        • Novartis Investigative Site
      • Shanghai, Kina, 200032
        • Novartis Investigative Site
      • Shanghai, Kina, 200025
        • Novartis Investigative Site
      • Tianjin, Kina, 300480
        • Novartis Investigative Site
    • Anhui
      • Hefei, Anhui, Kina, 230001
        • Novartis Investigative Site
    • Beijing Municipality
      • Beijing, Beijing Municipality, Kina, 100044
        • Novartis Investigative Site
    • Chongqing Municipality
      • Chongqing, Chongqing Municipality, Kina, 404100
        • Novartis Investigative Site
    • Guangdong
      • Guangzhou, Guangdong, Kina, 510000
        • Novartis Investigative Site
    • Hebei
      • Shijiazhuang, Hebei, Kina, 050011
        • Novartis Investigative Site
    • Heilongjiang
      • Harbin, Heilongjiang, Kina, 150081
        • Novartis Investigative Site
    • Hunan
      • Changsha, Hunan, Kina, 410013
        • Novartis Investigative Site
    • Jiangsu
      • Nanjing, Jiangsu, Kina, 210029
        • Novartis Investigative Site
      • Suzhou, Jiangsu, Kina, 215004
        • Novartis Investigative Site
    • Jiangxi
      • Nanchang, Jiangxi, Kina, 330009
        • Novartis Investigative Site
    • Jilin
      • Changchun, Jilin, Kina, 130021
        • Novartis Investigative Site
    • Liaoning
      • Shengyang, Liaoning, Kina, 110016
        • Novartis Investigative Site
      • Shengyang, Liaoning, Kina, 110042
        • Novartis Investigative Site
    • Shanxi
      • Xian, Shanxi, Kina, 710061
        • Novartis Investigative Site
    • Sichuan
      • Chengdu, Sichuan, Kina, 610041
        • Novartis Investigative Site
    • Yunnan
      • Kunming, Yunnan, Kina, 650106
        • Novartis Investigative Site
    • Zhejiang
      • Hangzhou, Zhejiang, Kina, 310016
        • Novartis Investigative Site
      • Hangzhou, Zhejiang, Kina, 310006
        • Novartis Investigative Site

Deltagelseskriterier

Forskere leder efter personer, der passer til en bestemt beskrivelse, kaldet berettigelseskriterier. Nogle eksempler på disse kriterier er en persons generelle helbredstilstand eller tidligere behandlinger.

Berettigelseskriterier

Aldre berettiget til at studere

18 år til 60 år (Voksen)

Tager imod sunde frivillige

Ingen

Beskrivelse

Inklusionskriterier:

  • Patienten har en histologisk og/eller cytologisk bekræftet diagnose af østrogenreceptor (ER) positiv og/eller progesteronreceptor positiv brystkræft af lokalt laboratorium (baseret på senest analyseret biopsi).
  • Patienten har HER2-negativ brystkræft (baseret på senest analyseret biopsi) defineret som en negativ in situ hybridiseringstest eller en immunhistokemi (IHC) status på 0, 1+ eller 2+. Hvis IHC er 2+, kræves en negativ in situ hybridiseringstest (FISH, CISH eller SISH) ved lokal laboratorietest.

  • Patienten skal have enten:

    • Målbar sygdom, dvs. mindst 1 målbar læsion i henhold til Respons Evaluation Criteria in Solid Tumors (RECIST) 1.1 kriterier (en læsion på et tidligere bestrålet sted kan kun tælles som en mållæsion, hvis der er et tydeligt tegn på progression siden bestrålingen ). ELLER
    • Hvis der ikke er nogen målbar sygdom til stede, skal mindst 1 overvejende lytisk knoglelæsion være til stede (patienter uden målbar sygdom og kun 1 overvejende lytisk knoglelæsion, der tidligere er blevet bestrålet, er berettiget, hvis der er dokumenteret tegn på sygdomsprogression af knoglelæsionen efter bestråling).
  • Patienten har ECOG-ydelsesstatus 0 eller 1.

For præmenopausal kohorte:

  • Patienten er en voksen, kvinde ≥ 18 år og < 60 år på tidspunktet for informeret samtykke og har underskrevet informeret samtykke, før der udføres forsøgsrelaterede aktiviteter og i overensstemmelse med lokale retningslinjer.
  • Bekræftet negativ serumgraviditetstest før start af undersøgelsesbehandling eller patienten har fået foretaget en hysterektomi.
  • Patienten har fremskreden (loko regionalt tilbagevendende ikke modtagelig for helbredende terapi eller metastatisk) brystkræft, der ikke er modtagelig for helbredende terapi (f.eks.

kirurgi og/eller strålebehandling).

  • Patienter, der modtog ≤ 14 dage af en NSAI (letrozol eller anastrozol) med eller uden goserelin eller goserelin ≤ 28 dage for fremskreden brystkræft før randomisering, er kvalificerede. Patienter skal fortsætte behandlingen med det samme hormonelle middel + goserelin under undersøgelsen. Ingen behandlingsafbrydelse er nødvendig for disse patienter før randomisering.
  • Patienter, der har modtaget op til 1 linje kemoterapi for fremskreden brystkræft og er blevet seponeret 28 dage før randomisering, er kvalificerede.

For postmenopausal kohorte:

  • Patienten er en voksen, kvinde ≥ 18 år gammel på tidspunktet for informeret samtykke og har underskrevet informeret samtykke før alle forsøgsrelaterede aktiviteter og i henhold til lokale retningslinjer.
  • Kvinder med fremskreden (lokoregionalt tilbagevendende eller metastatisk) brystkræft, der ikke er modtagelige for helbredende behandling.

Ekskluderingskriterier:

  • Patient, som tidligere har modtaget en CDK4/6-hæmmer.
  • Patient med symptomatisk visceral sygdom eller enhver sygdomsbyrde, der gør patienten ude af stand til endokrin behandling efter investigatorens bedste vurdering
  • Patient med CNS-metastaser.
  • Patient, som ikke har haft opløsning af kliniske og laboratoriemæssige akutte toksiciteter relateret til tidligere anti-cancerterapi til National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 Grade ≤1.
  • Patienten har en kendt historie med infektion med humant immundefektvirus (HIV) (test er ikke obligatorisk).
  • Klinisk signifikant, ukontrolleret hjertesygdom og/eller hjerterepolariseringsabnormitet
  • Patienten modtager i øjeblikket et af stofferne som defineret i protokollen, som ikke kan seponeres 7 dage før starten af ​​behandlingen:

For præmenopausal kohorte:

  • Gravide eller ammende (ammende) kvinder.
  • Kvinder i den fødedygtige alder, defineret som alle kvinder, der er fysiologisk i stand til at blive gravide, medmindre de bruger højeffektive præventionsmetoder under dosering af undersøgelsesbehandlingen og i 21 dage efter ophør med undersøgelsesmedicinering.

Bemærk: Brug af orale (østrogen og progesteron), transdermale, injicerede eller implanterede hormonelle præventionsmetoder samt hormonal erstatningsterapi er ikke tilladt i denne undersøgelse.

For postmenopausal kohorte:

- Patient, som tidligere har modtaget systemisk anti-cancerbehandling (inklusive hormonbehandling og kemoterapi) for fremskreden brystkræft.

Bemærk: Patienter, der modtog neo (adjuverende) behandling for brystkræft, er kvalificerede. Hvis den tidligere neo- (adjuverende) behandling omfattede letrozol eller anastrozol, skal det sygdomsfrie interval være større end 12 måneder fra afsluttet behandling til randomisering.

- Patienter, der har modtaget ≤ 14 dage med letrozol eller anastrozol for fremskreden sygdom før randomisering er kvalificerede.

Anden protokoldefineret inklusion/udelukkelse kan være gældende.

Studieplan

Dette afsnit indeholder detaljer om studieplanen, herunder hvordan undersøgelsen er designet, og hvad undersøgelsen måler.

Hvordan er undersøgelsen tilrettelagt?

Design detaljer

  • Primært formål: Behandling
  • Tildeling: Randomiseret
  • Interventionel model: Parallel tildeling
  • Maskning: Firedobbelt

Våben og indgreb

Deltagergruppe / Arm
Intervention / Behandling
Eksperimentel: Ribociclib

Patients in premenopausal and postmenopausal cohorts were randomized in a 1:1 ratio to either the experimental arm or the control arm.

Premenopausal experimental arm:

Non-steroidal aromatase inhibitor (NSAI) + Goserelin + Ribociclib. For premenopausal patients only, the patient was an adult female who was ≥ 18 years old and < 60 years old at the time of providing informed consent. The choice of non-steroidal aromatase inhibitor was based on the investigator's assessment of the patient's past medical history.

Postmenopausal experimental arm:

Letrozole + Ribociclib.

Pharmacokinetic (PK) Cohort:

Open-label treatment with Ribociclib + Letrozole combination. For postmenopausal patients only, the patient was an adult female who was ≥ 18 years old at the time of providing informed consent.
Medicin: NSAI: Letrozol eller Anastrazol

Letrozol: Tabletter til oral brug, 2,5 mg dagligt (alle dage i hver cyklus uden afbrydelse).

Anastrazol: Tabletter til oral brug, 1 mg dagligt (alle dage i hver cyklus uden afbrydelse) For præmenopausal kohorte er det efterforskernes valg til NSAI baseret på patientens tidligere historie.

For postmenopausale og PK-kohorter vil alle patienter være på Letrozol.

Medicin: Goserelin
Subkutant implantat, 3,6 mg på dag 1 i hver 28-dages cyklus
Medicin: Ribociclib
Film-coated tablets for oral use (200 mg x 3) from days 1 to 21 of each 28 day cycle.
Andre navne:
  • LEE011
Placebo komparator: Ribociclib Placebo

Patients in premenopausal and postmenopausal cohorts were randomized in a 1:1 ratio to either the experimental arm or the control arm.

Premenopausal control arm:

Non-steroidal aromatase inhibitor (NSAI) + Goserelin + Placebo. For premenopausal patients only, the patient was an adult female who was ≥ 18 years old and < 60 years old at the time of providing informed consent. The choice of non-steroidal aromatase inhibitor was based on the investigator's assessment of the patient's past medical history.

Postmenopausal control arm:

Letrozole + Placebo. For postmenopausal patients only, the patient was an adult female who was ≥ 18 years old at the time of providing informed consent.
Medicin: NSAI: Letrozol eller Anastrazol

Letrozol: Tabletter til oral brug, 2,5 mg dagligt (alle dage i hver cyklus uden afbrydelse).

Anastrazol: Tabletter til oral brug, 1 mg dagligt (alle dage i hver cyklus uden afbrydelse) For præmenopausal kohorte er det efterforskernes valg til NSAI baseret på patientens tidligere historie.

For postmenopausale og PK-kohorter vil alle patienter være på Letrozol.

Medicin: Goserelin
Subkutant implantat, 3,6 mg på dag 1 i hver 28-dages cyklus
Medicin: Ribociclib Placebo
Film-coated tablets for oral use (200 mg x 3) from days 1 to 21 of each 28 day cycle.
Andre navne:
  • LEE011 Placebo

Hvad måler undersøgelsen?

Primære resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
Pre and Postmenopausal Cohorts: Progressive Free Survival (PFS) Based on Local Assessment by RECIST 1.1 Guideline
Tidsramme: After approximately 100 progression-free survival (PFS) events had been observed in each cohort, using data collected up to the analysis cut-off date of 25-Apr-2022, an average of 43 months.
Progression-free survival (PFS) was defined as the time from randomization to the first documented disease progression or death from any cause. PFS was assessed by local investigators based on tumor evaluations using RECIST version 1.1 criteria. Patients who had not experienced progression or death by the analysis cut-off date of 25 April 2022 were censored at the date of their last adequate tumor assessment prior to that cut-off.
After approximately 100 progression-free survival (PFS) events had been observed in each cohort, using data collected up to the analysis cut-off date of 25-Apr-2022, an average of 43 months.

Sekundære resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
PK Cohort: Maximum Observed Plasma Concentration (Cmax) of Ribociclib and Its Metabolite LEQ803
Tidsramme: Cycle 1 Days 1/15 (0/Pre-dose, 1, 2, 4, 8 and 24 hours post-dose). 1 cycle = 28 days.
Venous whole blood samples were collected for activity-based pharmacokinetic characterization. The maximum plasma concentration (Cmax) was listed and summarized using descriptive statistics. Actual sampling times were taken into consideration for the pharmacokinetic analysis.
Cycle 1 Days 1/15 (0/Pre-dose, 1, 2, 4, 8 and 24 hours post-dose). 1 cycle = 28 days.
PK Cohort: Time to Maximum Observed Plasma Concentration (Tmax) of Ribociclib and Its Metabolite LEQ803
Tidsramme: Cycle 1 Days 1/15 (0/Pre-dose, 1, 2, 4, 8 and 24 hours post-dose). 1 cycle = 28 days.
Venous whole blood samples were collected for activity-based pharmacokinetic characterization. The time to reach maximum plasma concentration (Tmax) was listed and summarized using descriptive statistics. Actual sampling times were taken into consideration for the pharmacokinetic analysis.
Cycle 1 Days 1/15 (0/Pre-dose, 1, 2, 4, 8 and 24 hours post-dose). 1 cycle = 28 days.
PK Cohort: Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours (AUC0-24h) of Ribociclib and Its Metabolite LEQ803
Tidsramme: Cycle 1 Days 1/15 (0/Pre-dose, 1, 2, 4, 8 and 24 hours post-dose). 1 cycle = 28 days.
Venous whole blood samples were collected for activity-based pharmacokinetic characterization. The area under the concentration-time curve from time zero to 24 hours post-dose (AUC₀-₂₄h) was listed and summarized using descriptive statistics. Actual sampling times were taken into consideration for the pharmacokinetic analysis.
Cycle 1 Days 1/15 (0/Pre-dose, 1, 2, 4, 8 and 24 hours post-dose). 1 cycle = 28 days.
Pre and Postmenopausal Cohorts: Overall Survival (OS)
Tidsramme: Up to approximately 80 months
Overall Survival (OS) was defined as the time from date of first dose to date of death due to any cause. If a participant was not known to have died, then OS was censored at the latest date the participant was known to be alive (on or before the cut-off date).
Up to approximately 80 months
Pre and Postmenopausal Cohorts: Overall Response Rate (ORR)
Tidsramme: Up to approximately 80 months

Overall Response Rate (ORR) was defined as the proportion of participants with best overall response (BOR) of complete response (CR) or partial response (PR) by Investigator assessment as per RECIST 1.1 criteria:

  • 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 80 months
Pre and Postmenopausal Cohorts: Clinical Benefit Rate (CBR)
Tidsramme: Up to approximately 80 months

Clinical Benefit Rate (CBR) was defined as the proportion of patients achieving a complete response (CR) or partial response (PR) per RECIST 1.1 criteria, or stable disease (SD) lasting at least 24 weeks, based on Investigator assessment using RECIST 1.1 criteria:

  • 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).
Up to approximately 80 months
Pre and Postmenopausal Cohorts: Time To Response (TTR)
Tidsramme: Up to approximately 80 months
Time to Response (TTR) was defined as the duration from randomization to the first documented evidence of either a complete response (CR) (the disappearance of all target and non-target lesions) or a partial response (PR) (at least a 30% reduction in the sum of the longest diameters of target lesions from baseline) as assessed by the investigator.
Up to approximately 80 months
Pre and Postmenopausal Cohorts: Duration of Response (DoR)
Tidsramme: Up to approximately 80 months
Duration of Response (DoR) only applies to participants whose Best Overall Response (BOR) was complete response (CR) or partial response (PR) according to RECIST 1.1 based on tumor response data per local review. The start date is the date of first documented response of CR or PR (i.e. the start date of response, not the date when response was confirmed), and the end date is defined as the date of the first documented progression or death due to any cause. Participants continuing without progression or death were censored at the date of their last adequate tumor assessment.
Up to approximately 80 months
Pre and Postmenopausal Cohorts: Time to Definitive Deterioration of ECOG Performance Status From Baseline
Tidsramme: Baseline up to approximately 43 months
Time to definitive deterioration in ECOG performance status was defined as the time from the date of randomization to the date when ECOG performance status had definitively deteriorated by at least 1 category compared with baseline. Deterioration was considered definitive if there was no subsequent improvement in ECOG performance status back to the baseline category or above. The ECOG performance status scale assesses a patient's functional level, ranging from 0 (fully active) to 5 (dead). Patients were censored if no definitive deterioration in ECOG performance status was observed before the first to occur between: (i) the analysis cut-off date, and (ii) the date when a new anti-neoplastic therapy was started. The censoring date was the date of the last performance status assessment prior to cut-off/start of new anti-neoplastic therapy. Time to definitive deterioration of ECOG performance status from baseline was estimated by using the Kaplan-Meier method.
Baseline up to approximately 43 months

Samarbejdspartnere og efterforskere

Det er her, du vil finde personer og organisationer, der er involveret i denne undersøgelse.

Sponsor

Novartis Pharmaceuticals

Efterforskere

  • Studieleder: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Datoer for undersøgelser

Disse datoer sporer fremskridtene for indsendelser af undersøgelsesrekord og resumeresultater til ClinicalTrials.gov. Studieregistreringer og rapporterede resultater gennemgås af National Library of Medicine (NLM) for at sikre, at de opfylder specifikke kvalitetskontrolstandarder, før de offentliggøres på den offentlige hjemmeside.

Studer store datoer

Studiestart (Faktiske)

29. august 2018

Primær færdiggørelse (Faktiske)

25. april 2022

Studieafslutning (Faktiske)

9. maj 2025

Datoer for studieregistrering

Først indsendt

12. september 2018

Først indsendt, der opfyldte QC-kriterier

12. september 2018

Først opslået (Faktiske)

14. september 2018

Opdateringer af undersøgelsesjournaler

Sidste opdatering sendt (Faktiske)

8. juli 2026

Sidste opdatering indsendt, der opfyldte kvalitetskontrolkriterier

11. juni 2026

Sidst verificeret

1. juni 2026

Mere information

Begreber relateret til denne undersøgelse

Nøgleord

Yderligere relevante MeSH-vilkår

Andre undersøgelses-id-numre

  • CLEE011A2206

Plan for individuelle deltagerdata (IPD)

Planlægger du at dele individuelle deltagerdata (IPD)?

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IPD-planbeskrivelse

Novartis er forpligtet til at dele med kvalificerede eksterne forskere, adgang til data på patientniveau og understøttende kliniske dokumenter fra kvalificerede undersøgelser. Disse anmodninger gennemgås og godkendes af et uafhængigt bedømmelsespanel på grundlag af videnskabelig fortjeneste. Alle opgivne data er anonymiseret for at respektere privatlivets fred for patienter, der har deltaget i forsøget i overensstemmelse med gældende love og regler.

Tilgængeligheden af ​​denne forsøgsdata er i overensstemmelse med kriterierne og processen beskrevet på www.clinicalstudydatarequest.com

Lægemiddel- og udstyrsoplysninger, undersøgelsesdokumenter

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