Clinical trial NCT02273973: A Study of Neoadjuvant Letrozole + Taselisib Versus Letrozole + Placebo in Post-Menopausal Women With Breast Cancer (LORELEI)
Official title: A Phase II Randomized, Double-Blind Study of Neoadjuvant Letrozole Plus GDC-0032 Versus Letrozole Plus Placebo in Postmenopausal Women With ER-positive/HER2-negative, Early Stage Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Breast Cancer
Lead sponsor: Genentech, Inc.
Sponsor class: INDUSTRY
Collaborators: name: SOLTI Breast Cancer Research Group
name: Breast International Group
name: Austrian Breast and Colorectal Cancer Group
First posted: 2014-10-24
Enrollment: 334
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a two-arm, randomized, double-blind, multicenter, pre-operative study to evaluate the effect of combining letrozole and GDC-0032 (also known as taselisib) versus letrozole and placebo in postmenopausal women with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2 (HER2) untreated, Stage I-III operable breast cancer. Participants will be randomized into one of the two treatment arms with a 1:1 randomization ratio. Letrozole at 2.5 milligrams (mg) will be dosed once daily plus either Taselisib at 4 mg (two 2-mg tablets) or placebo on a 5 days-on/ 2 days-off schedule for a total of 16 weeks.


Eligibility criteria: Inclusion Criteria:

* Female participants
* Postmenopausal status
* Histologically confirmed invasive breast carcinoma, with all of the following characteristics: (i) Primary tumor greater than or equal to (\>/=) 2 centimeters (cm) in largest diameter (cT1-3) by MRI; (ii) Stage I to operable Stage III breast cancer; (iii) Documented absence of distant metastases (M0)
* Estrogen receptor-positive (ER+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancer
* Breast cancer eligible for primary surgery
* Tumor tissue from formalin-fixed paraffin-embedded cores (FFPE) core biopsy of breast primary tumor that is confirmed as evaluable for phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutation status by central histopathology laboratory
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* Fasting glucose less than or equal to (\</=) 125 milligrams per deciliter (mg/dL)
* Adequate hematological, renal, and hepatic function
* Absence of any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
* Ability and willingness to comply with study visits, treatment, testing, and to comply with the protocol, in the investigator's judgment

Exclusion Criteria:

* Any prior treatment for primary invasive breast cancer
* Participants with cT4 or cN3 stage breast tumors
* Bilateral invasive, multicentric, or metastatic breast cancer
* Participants who have undergone excisional biopsy of primary tumor and/or axillary lymph nodes or sentinel lymph node biopsy
* Type 1 or 2 diabetes requiring antihyperglycemic medication
* Inability or unwillingness to swallow pills
* Malabsorption syndrome or other condition that would interfere with enteric absorption
* History of prior or currently active small or large intestine inflammation (such as Crohn's disease or ulcerative colitis). Any predisposition for gastrointestinal (GI) toxicity requires prior approval from the Medical Monitor.
* Congenital long QT syndrome or QT interval corrected using Fridericia's formula (QTcF) \>470 milliseconds (msec)
* Diffusing capacity of the lungs for carbon monoxide (DLCO) \<60% of the predicted values
* Clinically significant (i.e., active) cardiovascular disease, uncontrolled hypertension, unstable angina, history of myocardial infarction, cardiac failure class II-IV
* Any contraindication to MRI examination
* Active infection requiring intravenous antibiotics
* Participants requiring any daily supplemental oxygen
* Clinically significant history of liver disease, including viral or other known hepatitis, current alcohol abuse, or cirrhosis
* Any other diseases, active or uncontrolled pulmonary dysfunction, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, that may affect the interpretation of the results, or renders the participants at high risk from treatment complications
* Significant traumatic injury within 3 weeks prior to initiation of study treatment
* Major surgical procedure within 4 weeks prior to initiation of study treatment
* Inability to comply with study and follow-up procedures
* History of other malignancy within 5 years prior to screening, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I uterine cancer

Primary outcomes:
measure: Percentage of Participants With Objective Response (OR) by Centrally Assessed Breast Magnetic Resonance Imaging (MRI) Via Modified Response Evaluation Criteria in Solid Tumors (mRECIST) Version 1.1
timeFrame: From Baseline to 16 weeks
measure: Percentage of Participants With Total Pathologic Complete Response (Total pCR), Defined as Having pCR in Both Breast and Axilla, Using American Joint Committee on Cancer (AJCC) Staging System
timeFrame: From Baseline to 16 weeks
measure: Percentage of Participants With OR by Centrally Assessed Breast MRI Via mRECIST Version 1.1 in Phosphatidylinositol-4,5-Bisphosphate 3-Kinase, Catalytic Subunit Alpha (PIK3CA) Mutant (MT) Participants
timeFrame: From Baseline to 16 weeks
measure: Percentage of Participants With Total pCR , Defined as Having pCR in Both Breast and Axilla, Using AJCC Staging System in PIK3CA MT Participants
timeFrame: From Baseline to 16 weeks
Secondary outcomes:
measure: Percentage of Participants With OR by Centrally Assessed Breast MRI Via mRECIST Version 1.1 in PIK3CA Wildtype (WT) Participants
timeFrame: From Baseline to 16 weeks
measure: Percentage of Participants With Total pCR Defined as Having pCR in Both Breast and Axilla, Using AJCC Staging System in PIK3CA WT Participants
timeFrame: From Baseline to 16 weeks
measure: Percentage of Participants With OR by Breast Ultrasound Via mRECIST Version 1.1 in PIK3CA MT Participants
timeFrame: From Baseline to 16 weeks
measure: Percentage of Participants With OR by Breast Ultrasound Via mRECIST Version 1.1 in PIK3CA WT Participants
timeFrame: From Baseline to 16 weeks
measure: Percentage of Participants With OR by Mammography Via mRECIST Version 1.1 in PIK3CA MT Participants
timeFrame: From Baseline to 16 weeks
measure: Percentage of Participants With OR by Mammography Via mRECIST Version 1.1 in PIK3CA WT Participants
timeFrame: From Baseline to 16 weeks
measure: Percentage of Participants With OR by Clinical Breast Exam (Palpation) Via mRECIST Version 1.1 in PIK3CA MT Participants
timeFrame: From Baseline to 16 weeks
measure: Percentage of Participants With OR by Clinical Breast Exam (Palpation) Via mRECIST Version 1.1 in PIK3CA WT Participants
timeFrame: From Baseline to 16 weeks
measure: Central Assessments of Changes in Ki67 Levels
timeFrame: From Baseline to Week 3 and Surgery (Weeks 17-18); and Week 3 to Surgery (Weeks 17-18)
measure: Preoperative Endocrine Prognostic Index (PEPI ) Score
timeFrame: Week 16
measure: Percent Change From Baseline to Surgery in Enhancing Tumor Volume as Measured by Breast MRI
timeFrame: From Baseline to Surgery (Weeks 17-18)
measure: Mean Score for Health-Related Quality of Life Measured by the European Organization for Research C30 (EORTC QLQ-C30)
timeFrame: Weeks 1, 5, 9, 13, 16, 4-week Post-Surgery
measure: Mean Score for Treatment of Cancer Quality of Life Questionnaire BR23 (QLQ-BR23)
timeFrame: Weeks 1, 5, 9, 13, 16, 4-week Post-Surgery
measure: Percentage of Participants With Adverse Events
timeFrame: Baseline up to 22 weeks
Other outcomes:
Locations:
city: Santa Ana
country: United States
facility: Breastlink Med Group Inc
state: California
city: Boston
country: United States
facility: MGH Cancer Center
state: Massachusetts
city: Basking Ridge
country: United States
facility: MSKCC at Basking Ridge
state: New Jersey
city: Commack
country: United States
facility: MSKCC @ Commack
state: New York
city: Harrison
country: United States
facility: MSKCC @ West Harrison
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center; Hematology/Oncology
state: New York
city: Rockville Centre
country: United States
facility: MSKC @ Rockville
state: New York
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Darlinghurst
country: Australia
facility: Kinghorn Cancer Centre; St Vincents Hospital
state: New South Wales
city: Waratah
country: Australia
facility: Newcastle Mater Misericordiae Hospital; Oncology
state: New South Wales
city: East Melbourne
country: Australia
facility: Victorian Breast and Oncology Care
state: Victoria
city: Malvern
country: Australia
facility: Cabrini Medical Centre; Oncology
state: Victoria
city: Murdoch
country: Australia
facility: Fiona Stanley Hospital
state: Western Australia
city: Graz
country: Austria
facility: Lkh-Univ. Klinikum Graz; Klinik Für Gynäkologie
city: Graz
country: Austria
facility: LKH-UNIV. KLINIKUM GRAZ; Klinische Abteilung für Onkologie
city: Innsbruck
country: Austria
facility: Tiroler Landeskrankenanstalten Ges.M.B.H.; Abt. Für Gynäkologie
city: Linz
country: Austria
facility: Ordensklinikum Linz Barmherzige Schwestern ; Abt. f. Allgemein- und Viszeralchirurgie
city: Salzburg
country: Austria
facility: Lkh Salzburg - Univ. Klinikum Salzburg; Iii. Medizinische Abt.
city: St. Veit/Glan
country: Austria
facility: Brustzentrum - Ordination Dr. Wette
city: Wels
country: Austria
facility: Klinikum Kreuzschwestern Wels; Iii. Interne Abt.
city: Wien
country: Austria
facility: Medizinische Universität Wien; Univ.Klinik für Chirurgie - Abt. für Allgemeinchirurgie
city: Wien
country: Austria
facility: Medizinische Universität Wien; Univ.Klinik für Frauenheilkunde - Klinik für Gynäkologie
city: Wien
country: Austria
facility: Krankenhaus Der Stadt Wien-Hietzing; Abt. Für Gynäkologie U. Geburtshilfe
city: Brussels
country: Belgium
facility: Institut Jules Bordet
city: Bruxelles
country: Belgium
facility: CHU Brugmann (Victor Horta)
city: Bruxelles
country: Belgium
facility: Cliniques Universitaires St-Luc
city: Edegem
country: Belgium
facility: UZ Antwerpen
city: Namur
country: Belgium
facility: Clinique Ste-Elisabeth
city: Porto Alegre
country: Brazil
facility: Hospital Sao Lucas - PUCRS
state: RS
city: Itajai
country: Brazil
facility: Clinica de Neoplasias Litoral
state: SC
city: Barretos
country: Brazil
facility: Hospital de Cancer de Barretos
state: SP
city: Sao Paulo
country: Brazil
facility: Instituto do Cancer do Estado de Sao Paulo - ICESP
state: SP
city: São Paulo
country: Brazil
facility: Instituto Brasileiro De Controle Do Câncer - IBCC; Laboratório De Patologia
state: SP
city: Viña del Mar
country: Chile
facility: Hospital Clinico Vina del Mar
city: Hradec Kralove
country: Czechia
facility: Fakultni Nemocnice Hradec Kralove; Dept of Radiotherapy & Oncology
city: Olomouc
country: Czechia
facility: Fakultni nemocnice Olomouc; Onkologicka klinika
city: Pardubice
country: Czechia
facility: MULTISCAN, s.r.o., Radiologicke centrum Pardubice
city: Pribram
country: Czechia
facility: Oblastni nemocnice Pribram
city: Salvador
country: El Salvador
facility: Hospital Oncologia; Oncology
city: Clermont Ferrand
country: France
facility: Centre Jean Perrin; Division De Recherche Clinique
city: Le Mans
country: France
facility: Centre Jean Bernard
city: Paris
country: France
facility: Institut Curie; Oncologie Medicale
city: Paris
country: France
facility: Hopital Saint Louis; Service Onco Thoracique
city: Saint Cloud
country: France
facility: Centre Rene Huguenin; ONCOLOGIE GENETIQUE
city: Toulon
country: France
facility: CHI de Toulon - Hôpital Sainte Musse
city: Vandoeuvre-Les-Nancy
country: France
facility: Institut de Cancérologie de Lorraine
city: Berlin
country: Germany
facility: Praxisklinik Krebsheilkunde für Frauen / Brustzentrum (Dres. Kittel/Klare)
city: Berlin
country: Germany
facility: Studienzentrum Berlin City
city: Bielefeld
country: Germany
facility: Onkologische Schwerpunktpraxis Bielefeld
city: Dresden
country: Germany
facility: Universitätsklinikum "Carl Gustav Carus" der Technischen Universität Dresden
city: Essen
country: Germany
facility: Klinikum Essen-Mitte Ev. Huyssens-Stiftung / Knappschafts GmbH; Klinik für Senologie / Brustzentrum
city: Gelsenkirchen
country: Germany
facility: Evangelische Kliniken Gelsenkirchen GmbH; Brustzentrum
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf (UKE); Klinik und Poliklinik für Gynäkologie
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover, Klinik für Frauenheilkunde und Geburtshilfe
city: Lübeck
country: Germany
facility: Universitätsklinikum Schleswig-Holstein / Campus Lübeck; Klinik für Frauenheilkunde und Geburtshilfe
city: Muenchen
country: Germany
facility: Rotkreuzklinikum München; Frauenklinik
city: Münster
country: Germany
facility: Universitätsklinikum Münster; Klinik für Frauenheilkunde und Geburtshilfe
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm Am Michelsberg; Frauenklinik
city: Witten
country: Germany
facility: Marien-Hospital Witten; Frauenklinik Brustzentrum
city: Guatemala City
country: Guatemala
facility: Grupo Angeles
city: Guatemala
country: Guatemala
facility: Centro Oncológico Sixtino / Centro Oncológico SA
city: Budapest
country: Hungary
facility: Szent Margit Hospital; Dept. of Oncology
city: Debrecen
country: Hungary
facility: Debreceni Egyetem, Klinikai Kozpont, Onkologiai Klinika
city: Kecskemet
country: Hungary
facility: Bacs-Kiskun Megyei Korhaz, SZTE AOK Oktato Korhaza, Onkoradiologiai Kozpont
city: Miskolc
country: Hungary
facility: B-A-Z County Hospital
city: Szeged
country: Hungary
facility: Szegedi Tudomanyegyetem, AOK, Szent-Gyorgyi Albert Klinikai Kozpont, Onkoterapias Klinika
city: Bologna
country: Italy
facility: Azienda Ospedaliero-Universitaria S.Orsola-Malpighi; Unità Operativa Oncologia Medica
state: Emilia-Romagna
city: Rimini
country: Italy
facility: Ospedale degli Infermi
state: Emilia-Romagna
city: Genova
country: Italy
facility: Uni Degli Studi Di Genova ; Clinica Di Medicina Interna Ad Indirizzo Oncologico
state: Liguria
city: Cremona
country: Italy
facility: ASST DI CREMONA; Dip. Medicina - S.C. Oncologia
state: Lombardia
city: Legnago
country: Italy
facility: Ospedale Per Acuti Mater Salutis Di Legnago
state: Lombardia
city: Milano
country: Italy
facility: Irccs Istituto Nazionale Dei Tumori (Int);S.C. Medicina Oncologica 1
state: Lombardia
city: Milano
country: Italy
facility: Irccs Istituto Europeo Di Oncologia (IEO); Ricerca Di Senologia Medica
state: Lombardia
city: Gyeonggi-do
country: Korea, Republic of
facility: National Cancer Center; Medical Oncology
city: Seoul
country: Korea, Republic of
facility: Seoul National Uni Hospital; Dept. of Internal Medicine/Hematology/Oncology
city: Seoul
country: Korea, Republic of
facility: Yonsei University Severance Hospital; Medical Oncology
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Centre; Division of Hematology/Oncology
city: Chihuahua
country: Mexico
facility: Centro Estatal de Cancerología
city: Distrito Federal
country: Mexico
facility: Instituto Nacional De Cancerologia; Oncology; Tumores Mamarios
city: Mexico City
country: Mexico
facility: Consultorio de Medicina Especializada; Dentro de Condominio San Francisco
city: Panama
country: Panama
facility: Centro Oncologico America
city: Lima
country: Peru
facility: Hospital Nacional Cayetano Heredia; Hematology - Oncology
city: Lima
country: Peru
facility: Oncosalud Sac; Oncología
city: Lima
country: Peru
facility: Clinica Internacional, Sede San Borja; Unidad de Investigacion de Clínica Internacional
city: Bydgoszcz
country: Poland
facility: Centrum Onkologii;Im. Franciszka Lukaszczyka;Onkologii
city: Gdańsk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne, Klinika Onkologii i Radioterapii
city: Lodz
country: Poland
facility: Wojewódzki Szpital Specjalistyczny im. M. Kopernika; Oddział Chemioterapii
city: Otwock
country: Poland
facility: Europejskie Centrum Zdrowia Otwock Szpital im. Fryderyka Chopina, Klinika Onkologii
city: Poznan
country: Poland
facility: Wielkopolskie Centrum Onkologii; im. Marii Skłodowskiej-Curie
city: Warszawa
country: Poland
facility: Cent.Onkologii-Instytut im. M. S-Curie, Klinika Now. Piersi i Chirurgii Rekon
city: Lisboa
country: Portugal
facility: IPO de Lisboa; Servico de Oncologia Medica
city: Lisboa
country: Portugal
facility: Centro Clinico Champalimaud; Oncologia Medica
city: Porto
country: Portugal
facility: IPO do Porto; Servico de Oncologia Medica
city: Córdoba
country: Spain
facility: Hospital Universitario Reina Sofia; Servicio de Oncologia
state: Cordoba
city: Santiago de Compostela
country: Spain
facility: Complejo Hospitalario Universitario de Santiago (CHUS) ; Servicio de Oncologia
state: LA Coruña
city: Barcelona
country: Spain
facility: Instituto Universitario Dexeus; Servicio de Oncología
city: Barcelona
country: Spain
facility: Hospital Univ Vall d'Hebron; Servicio de Oncologia
city: Barcelona
country: Spain
facility: Institut Catala d Oncologia Hospital Duran i Reynals
city: Caceres
country: Spain
facility: Hospital San Pedro De Alcantara; Servicio de Oncologia
city: Castellon
country: Spain
facility: Hospital Provincial de Castellon; Servicio de Oncologia
city: Girona
country: Spain
facility: Hospital Universitari de Girona Dr. Josep Trueta; Servicio de Oncologia
city: Jaen
country: Spain
facility: Complejo Hospitalario de Jaen-Hospital Universitario Medico Quirurgico; Servicio de Oncologia
city: Lerida
country: Spain
facility: Hospital Universitari Arnau de Vilanova de Lleida; Servicio de Oncologia
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre; Servicio de Oncologia
city: Madrid
country: Spain
facility: Centro Integral Oncologico Clara Campal (CIOCC); Dirección Médica
city: Madrid
country: Spain
facility: Hospital Universitario de Fuenlabrada; Servicio de Oncologia
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio; Servicio de Oncologia
city: Valencia
country: Spain
facility: Hospital Clinico Universitario; Oncologia
city: Valencia
country: Spain
facility: Hospital Arnau de Vilanova (Valencia) Servicio de Oncologia
city: Valencia
country: Spain
facility: Fundación IVO
city: Baden
country: Switzerland
facility: Kantonsspital Baden; Frauenklinik
city: Chur
country: Switzerland
facility: Kantonsspital Graubünden;Onkologie und Hämatologie
city: Locarno
country: Switzerland
facility: Fondazione Oncologia Lago Maggiore
city: Bournemouth
country: United Kingdom
facility: Royal Bournemouth General Hospital; Oncology
city: Camberley
country: United Kingdom
facility: Frimley Park Hospital; Breast Resaerch Team
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre
city: Manchester
country: United Kingdom
facility: Christie Hospital
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
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citation: Saura C, Hlauschek D, Oliveira M, Zardavas D, Jallitsch-Halper A, de la Pena L, Nuciforo P, Ballestrero A, Dubsky P, Lombard JM, Vuylsteke P, Castaneda CA, Colleoni M, Santos Borges G, Ciruelos E, Fornier M, Boer K, Bardia A, Wilson TR, Stout TJ, Hsu JY, Shi Y, Piccart M, Gnant M, Baselga J, de Azambuja E. Neoadjuvant letrozole plus taselisib versus letrozole plus placebo in postmenopausal women with oestrogen receptor-positive, HER2-negative, early-stage breast cancer (LORELEI): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2019 Sep;20(9):1226-1238. doi: 10.1016/S1470-2045(19)30334-1. Epub 2019 Aug 8.