Clinical trial NCT05254743: A Study of Pirtobrutinib (LOXO-305) Versus Ibrutinib in Participants With Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)
Official title: A Phase 3 Open-Label, Randomized Study of Pirtobrutinib (LOXO-305) Versus Ibrutinib in Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (BRUIN-CLL-314)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Chronic Lymphocytic Leukemia
Leukemia, Lymphocytic
Leukemia, B-cell
Small Lymphocytic Lymphoma
Keywords: BTKi
Hematologic Disease
Lymphoma, non-Hodgkin's
Lymphoma, B-cell
Lead sponsor: Eli Lilly and Company
Sponsor class: INDUSTRY
First posted: 2022-02-24
Enrollment: 725
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of Part 1 of this study is to compare the efficacy and safety of pirtobruitinib (LOXO-305) to ibrutinib in participants with CLL/SLL; participants may or may not have already had treatment for their cancer. The purpose of Part 2 of this study evaluates pirtobrutinib monotherapy in treatment-naïve participants with CLL/SLL with 17p deletions. Participation could last up to six years for Part 1. Participation could last up to 2 years for Part 2.


Eligibility criteria: Inclusion Criteria:

* Confirmed diagnosis of CLL/SLL requiring therapy per iwCLL 2018 criteria
* Part 1 - Known 17p deletion status (wildtype or deleted). Part 2 - Must have deletion of 17p as determined by FISH testing
* Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2
* Adequate organ function

  * Platelets greater than or equal to ≥ 50 x 10⁹/liter (L) or ≥30 x 10⁹/L in participants with documented bone marrow involvement considered to impair hematopoiesis,
  * Hemoglobin ≥8 grams/deciliter (g/dL) or ≥6 g/dL in participants with documented bone marrow involvement considered to impair hematopoiesis
  * Absolute neutrophil count ≥0.75 x 10⁹/L or ≥0.50 × 10⁹/L in participants with documented bone marrow involvement considered to impair hematopoiesis
  * Kidney function: Estimated creatinine clearance ≥30 milliliters per minute (mL/min)

Exclusion Criteria:

* Known or suspected Richter's transformation to diffuse large B-cell lymphoma (DLBCL), prolymphocytic leukemia, or Hodgkin's lymphoma at any time preceding enrollment
* Known or suspected central nervous system (CNS) involvement
* A significant history of renal, neurologic, psychiatric, endocrine, metabolic or immunologic disease
* Active uncontrolled auto-immune cytopenia (e.g., autoimmune hemolytic anemia \[AIHA\], idiopathic thrombocytopenic purpura \[ITP\])
* Significant cardiovascular disease including ejection fraction \< 40% and any grade ongoing atrial fibrillation or atrial flutter
* Hepatitis B or hepatitis C testing indicating active/ongoing infection, based on Screening laboratory tests
* Active cytomegalovirus (CMV) infection
* Active uncontrolled systemic bacterial, viral, or fungal infection
* Known human immunodeficiency virus (HIV) infection, regardless of cluster of differentiation 4 (CD4) count
* Clinically significant active malabsorption syndrome or other condition likely to affect GI absorption of the oral-administered study treatments
* Ongoing inflammatory bowel disease
* Previous treatment for CLL/SLL - Part 1: Treatment-naïve and previously treated, except prior exposure to BTK inhibitor (covalent or noncovalent).

Part 2: participants must be treatment naïve

* Concurrent use of investigational agent or anticancer therapy except hormonal therapy
* Participants requiring therapeutic anticoagulation with warfarin or another Vitamin K antagonist
* Use of \> 20 mg prednisone daily or equivalent dose of steroid at the time of first dose of study drug
* Vaccination with a live vaccine within 28 days prior to randomization
* Participants receiving chronic therapy with a strong cytochrome P450 (CYP)3A inhibitor (except posaconazole and voriconazole) which cannot be stopped within 3-5 half lives of the CYP3A inhibitor therapy prior to start of study drug treatment
* Participants with known hypersensitivity, including anaphylaxis, to any component or excipient of pirtobrutinib or ibrutinib

Primary outcomes:
measure: Percentage of Participants Achieving Complete Response (CR), Complete Remission with Incomplete Hematologic Recovery (Cri), Nodular Partial Remission (nPR) or Partial Response (PR): Overall Response Rate (ORR) Part 1
timeFrame: Baseline to best overall response the best response recorded from Cycle 1 Day 1 until data cutoff date, PD, or start of new anticancer treatment, whichever is the earliest] (approximately 3 years and 5 months)
measure: Percentage of Participants Achieving Complete Response (CR), Complete Remission with Incomplete Hematologic Recovery (CRi), Nodular Partial Remission (nPR) or Partial Response (PR): Overall Response Rate (ORR) Part 2
timeFrame: Baseline to best overall response the best response recorded from Cycle 1 Day 1 until data cutoff date, PD, or start of new anticancer treatment, whichever is the earliest (Approximately 2 years and 3 months)
Secondary outcomes:
measure: IRC-assessed Progression-Free Survival (PFS)
timeFrame: Randomization to PD (per iwCLL 2018 criteria) or death from any cause (approximately 5 years 8 months)
measure: Investigator assessed Progression-Free Survival (PFS)
timeFrame: Randomization to PD (per iwCLL 2018 criteria) or death from any cause (approximately 5 years 8 months)
measure: Event-Free Survival (EFS)
timeFrame: Randomization to first occurrence of treatment discontinuation due to adverse event/toxicity, treatment-emergent atrial fibrillation or atrial flutter of any grade, progressive disease (PD) or death (approximately 4 years)
measure: Duration of Response (DOR)
timeFrame: Time from the date of the first documented response of CR, CRi, nPR or PR to the earlier of documentation of definitive PD (per iwCLL 2018 criteria) or death from any cause (approximately 2 years)
measure: Overall Survival (OS)
timeFrame: Randomization to death from any cause (approximately 6 years)
measure: Time to Next Treatment (TTNT)
timeFrame: Randomization to initiation of the next systemic anticancer therapy for CLL/SLL or death from any cause, whichever occurs first (approximately 6 years)
measure: Time to Worsening (TTW) of CLL/SLL Related Symptoms
timeFrame: Randomization to time to worsening symptoms (approximately 4 years)
measure: Comparative Tolerability
timeFrame: From Baseline to Treatment Discontinuation for Any Reason (approximately 4 years)
measure: Percentage of Participants Achieving DOR Part 2
timeFrame: Time from the date of the first documented response of CR, CRi, nPR, or PR to the earlier of the documentation of definitive PD or death from any cause] (Approximately 2 years)
Other outcomes:
Locations:
city: Hot Springs
country: United States
facility: Genesis Cancer Center
state: Arkansas
city: Anaheim
country: United States
facility: Pacific Cancer Medical Center, Inc
state: California
city: Berkeley
country: United States
facility: Alta Bates Summit Medical Center
state: California
city: Cerritos
country: United States
facility: TOI Clinical Research
state: California
city: Palo Alto
country: United States
facility: Stanford School of Medicine-Cancer Clinical Trials Office
state: California
city: Rancho Mirage
country: United States
facility: Eisenhower Army Medical Center
state: California
city: San Diego
country: United States
facility: Sharp Memorial Hospital
state: California
city: San Marcos
country: United States
facility: California Cancer Associates for Research and Excellence
state: California
city: Norwich
country: United States
facility: Eastern Connecticut Hematology/Oncology Assoc.
state: Connecticut
city: Brooksville
country: United States
facility: Asclepes Research Centers Florida
state: Florida
city: Fort Myers
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Jacksonville
country: United States
facility: Cancer Specialists of North Florida -St Augustine
state: Florida
city: Lakeland
country: United States
facility: Lakeland Regional Health Systems Inc
state: Florida
city: Saint Petersburg
country: United States
facility: Florida Cancer Specialists
state: Florida
city: West Palm Beach
country: United States
facility: Florida Cancer Specialists East
state: Florida
city: Savannah
country: United States
facility: Summit Cancer Care, P.C.
state: Georgia
city: Louisville
country: United States
facility: Baptist Healthcare System, Inc.
state: Kentucky
city: Baton Rouge
country: United States
facility: Hematology Oncology Clinic
state: Louisiana
city: New Orleans
country: United States
facility: Tulane Cancer Center Office of Clinical Research
state: Louisiana
city: Bethesda
country: United States
facility: American Oncology Partners of Maryland, PA
state: Maryland
city: Salisbury
country: United States
facility: TidalHealth Peninsula Regional, Inc.
state: Maryland
city: Billings
country: United States
facility: St. Vincent Frontier Cancer Center
state: Montana
city: Hawthorne
country: United States
facility: Westchester Medical Center
state: New York
city: Charlotte
country: United States
facility: Novant Cancer Institute Charlotte
state: North Carolina
city: Columbus
country: United States
facility: The James Cancer Hospital
state: Ohio
city: York
country: United States
facility: Cancer Care Associates of York
state: Pennsylvania
city: Providence
country: United States
facility: Lifespan Cancer Institute
state: Rhode Island
city: Greenville
country: United States
facility: Prisma Health Cancer Institute
state: South Carolina
city: Chattanooga
country: United States
facility: Sarah Cannon Research Institute SCRI
state: Tennessee
city: Houston
country: United States
facility: Kelsey Research Foundation
state: Texas
city: Houston
country: United States
facility: Houston Methodist Hospital Cancer Center
state: Texas
city: Kingwood
country: United States
facility: Lumi Research
state: Texas
city: Round Rock
country: United States
facility: Baylor Scott & White Health
state: Texas
city: Richmond
country: United States
facility: Virginia Cancer Institute
state: Virginia
city: Spokane
country: United States
facility: Summit Cancer Treatment Center
state: Washington
city: Spokane
country: United States
facility: MultiCare Health System Institute for Research and Innovation
state: Washington
city: Mar Del Plata
country: Argentina
facility: Hospital Privado De Comunidad
state: Buenos Aires
city: ABB
country: Argentina
facility: Hospital Italiano de Buenos Aires
state: Ciudad Autónoma De Buenos Aire
city: Ciudad Autonoma Buenos Aires
country: Argentina
facility: Instituto Alexander Fleming
city: Santa Fe
country: Argentina
facility: Clínica de Nefrología, Urología y Enfermedades Cardiovasculares
city: St Albans
country: Australia
facility: Sunshine Hospital
state: Victoria
city: Nedlands
country: Australia
facility: One Clinical Research
state: Western Australia
city: West Perth
country: Australia
facility: The Perth Blood Institute
city: Linz
country: Austria
facility: Ordensklinikum Linz
state: Oberösterreich
city: Vienna
country: Austria
facility: Hanusch Krankenhaus
city: Sint-Niklaas
country: Belgium
facility: VITAZ
state: Oost-Vlaanderen
city: Roeselare
country: Belgium
facility: AZ Delta
state: West Flanders
city: Leuven
country: Belgium
facility: Universitaire Ziekenhuizen Leuven - Campus Gasthuisberg
city: Curitiba
country: Brazil
facility: Centro Integrado de Oncologia de Curitiba
state: Paraná
city: Curitiba
country: Brazil
facility: Hospital Erasto Gaertner - Liga Paranaense de Combate ao Câncer
state: Paraná
city: Passo Fundo
country: Brazil
facility: Instituto do Câncer - Hospital São Vicente de Paulo
state: Rio Grande Do Sul
city: Porto Alegre
country: Brazil
facility: Centro Gaucho Integrado de Oncologia, Hematologia, Ensino e Pesquisa - Hospital Mae de Deus
state: Rio Grande Do Sul
city: Botucatu
country: Brazil
facility: UNESP - Faculdade de Medicina da Universidade Estadual Paulista - Campus Botucatu
state: Sao Paulo
city: Campinas
country: Brazil
facility: Centro de Hematologia e Hemoterapia - Hemocentro de Campinas - UNICAMP
state: Sao Paulo
city: Sao Jose Rio Preto
country: Brazil
facility: Fundação Faculdade Regional de Medicina de São José do Rio Preto
state: Sao Paulo
city: Barretos
country: Brazil
facility: Fundação Pio XII - Hospital de Câncer de Barretos
state: São Paulo
city: Ribeirão Preto
country: Brazil
facility: Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (USP) - HCFMRP
state: São Paulo
city: Santo André
country: Brazil
facility: CEPHO - Centro de Estudos e Pesquisas de Hematologia e Oncologia
state: São Paulo
city: Cascavel
country: Brazil
facility: Hospital Uopeccan - Centro de Pesquisa Clinica
city: Sao Paulo
country: Brazil
facility: Hospital Beneficência Portuguesa de São Paulo
city: Sao Paulo
country: Brazil
facility: Hospital Santa Marcelina
city: São Paulo
country: Brazil
facility: Hospital das Clínicas da Faculdade de Medicina da USP
city: Winnipeg
country: Canada
facility: Cancer Care Manitoba
state: Manitoba
city: Barrie
country: Canada
facility: Royal Victoria Regional Health Centre
state: Ontario
city: Québec
country: Canada
facility: Hopital de L'Enfant Jesus
city: Temuco
country: Chile
facility: Sociedad de Investigaciones Médicas Limitada
state: IX Región
city: Santiago
country: Chile
facility: CeCim Biocinetic
state: Región Metropolitana
city: Providencia
country: Chile
facility: Centro de Estudios Clinicos SAGA
state: Santiago
city: Viña del Mar
country: Chile
facility: Centro de Investigaciones Clínicas Viña del Mar (CIC)
state: Valparaíso
city: Hefei
country: China
facility: Anhui Provincial Hospital
state: Anhui
city: Hefei
country: China
facility: The Second Hospital of Anhui Medical University
state: Anhui
city: Guangzhou
country: China
facility: Sun Yat-sen University Cancer Center
state: Guangdong
city: Guangzhou
country: China
facility: Southern Medical University Nanfang Hospital
state: Guangdong
city: Nanning
country: China
facility: Guangxi Medical University Affiliated Tumor Hospital
state: Guangxi
city: Wuhan City
country: China
facility: Wu Han Tongji Hospital
state: Hubei
city: Changsha
country: China
facility: The 2nd Xiangya Hospital of Central South University
state: Hunan
city: Changsha
country: China
facility: Hunan Cancer Hospital
state: Hunan
city: Nanchang
country: China
facility: The First Affiliated Hospital of Nanchang University
state: Jiangxi
city: Nanchang
country: China
facility: Jiangxi Provincial Cancer Hospital
state: Jiangxi
city: Shanghai
country: China
facility: Fudan University Shanghai Cancer Center
state: Shanghai
city: Tianjin
country: China
facility: Blood Institute of the Chinese Academy of Medical science
state: Tianjin
city: Tianjin
country: China
facility: Tianjin Medical University General Hospital
state: Tianjin
city: Urumqi
country: China
facility: The Affiliated Cancer Hospital of Xinjiang Medical university
state: Xinjiang
city: Hangzhou
country: China
facility: The Second Affiliated Hospital of Zhejiang University School of Medicine
state: Zhejiang
city: Yiwu
country: China
facility: The Fourth Affiliated Hospital Zhejiang University School of Medicine
state: Zhejiang
city: Haikou
country: China
facility: Hainan General Hospital
city: Hangzhou
country: China
facility: First Affiliated Hosp of College of Med, Zhejiang University
city: Wuhan
country: China
facility: Union Hospital Tongji Medical College Huazhong University of Science and Technology
city: Brno
country: Czechia
facility: Fakultni nemocnice Brno
city: Hradec Kralove
country: Czechia
facility: Fakultni nemocnice Hradec Kralove
city: Ostrava-Poruba
country: Czechia
facility: Fakultni Nemocnice Ostrava
city: Plzen - Lochotin
country: Czechia
facility: Fakultni Nemocnice Plzen
city: Praha 10
country: Czechia
facility: Fakultni nemocnice Kralovske Vinohrady
city: Praha 2
country: Czechia
facility: Vseobecna fakultni nemocnice v Praze
city: Paris
country: France
facility: Hopital de la Pitie Salpetriere
state: Cedex 13
city: Nantes
country: France
facility: CHU de Nantes - Hotel Dieu
state: Cedex 1
city: Rennes
country: France
facility: Hôpital de Pontchaillou
state: Cedex 9
city: Pierre Benite
country: France
facility: Centre Hospitalier Lyon Sud
state: Cedex
city: Nice
country: France
facility: Centre Antoine Lacassagne
state: Nice Cedex 2
city: Tours
country: France
facility: CHRU De Tours
state: Tours Cedex 9
city: La Roche sur Yon
country: France
facility: CHD Vendee
city: Le Mans
country: France
facility: Centre Hospitalier du Mans
city: Limoges
country: France
facility: Centre Hospitalier Universitaire (Limoges) (CHU DUPUYTREN 1)
city: Rouen Cedex
country: France
facility: Centre Henri Becquerel
city: Ulm
country: Germany
facility: Universitaetsklinikum Ulm
state: Baden
city: Kerpener
country: Germany
facility: Uniklinik Köln
state: Köln
city: Dortmund
country: Germany
facility: GEFOS (Gesellschaft für onkologische Studien) Dortmund mbH
state: Nordrhein Westfalen
city: Dresden
country: Germany
facility: Gemeinschaftspraxis Haematologie und Onkologie
state: Sachsen Anhalt
city: Dresden
country: Germany
facility: Universitaetsklinikum Carl Gustav Carus TU Dresden
state: Sachsen
city: Debrecen
country: Hungary
facility: Debreceni Egyetem
city: Szombathely
country: Hungary
facility: Markusovszky Egyetemi Oktatokorhaz
city: Jerusalem
country: Israel
facility: Hadassah Medical Center
city: Petach-Tikva
country: Israel
facility: Rabin Medical Center-Beilinson Campus
city: Ramat Gan
country: Israel
facility: Chaim Sheba Medical Center
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center
city: Meldola
country: Italy
facility: IRCCS Istituto Scientifico Romagnolo Per Lo Studio e La Cura Dei Tumori "Dino Amadori" - IRST
state: Forlì-Cesena
city: Torino
country: Italy
facility: A.O.U. Citta' della Salute e della Scienza di Torino
state: Otago
city: Candiolo
country: Italy
facility: Fondazione del Piemonte per l'Oncologia IRCCS Candiolo
state: Torino
city: Alessandria
country: Italy
facility: Azienda Ospedaliera Nazionale Santi Antonio e Biagio e Cesare Arrigo
city: Bologna
country: Italy
facility: Azienda Ospedaliera Universitaria Policlinico Sant'Orsola Malpighi IRCCS
city: Milano
country: Italy
facility: Fondazione IRCCS CA' Granda Ospedale Maggiore Policlinico
city: Milano
country: Italy
facility: IRCCS Ospedale San Raffaele
city: Milano
country: Italy
facility: IEO Istituto Europeo di Oncologia
city: Reggio Emilia
country: Italy
facility: Azienda Unita Sanitaria Locale di Reggio Emilia
city: Verona
country: Italy
facility: Centro Ricerche Cliniche di Verona s.r.l.
city: Isehara
country: Japan
facility: Tokai University Hospital- Isehara Campus
state: Kanagawa
city: Kumamoto
country: Japan
facility: Kumamoto University Hospital
city: Yamagata
country: Japan
facility: Yamagata University Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
state: Seoul, Korea
city: Seocho-Gu
country: Korea, Republic of
facility: The Catholic University of Korea-Seoul St. Mary's Hospital
state: Seoul
city: Busan
country: Korea, Republic of
facility: Inje Univ Busan Paik Hospital
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Newtown
country: New Zealand
facility: P3 Research
state: Wellington
city: Dunedin
country: New Zealand
facility: Dunedin Hospital
city: Hamilton
country: New Zealand
facility: Waikato Hospital
city: Otahuhu
country: New Zealand
facility: Middlemore Hospital
city: Gdansk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne
state: Pomorskie
city: Skorzewo
country: Poland
facility: Centrum Medyczne Pratia Poznan
state: Poznan
city: Biała Podlaska
country: Poland
facility: KO-MED Centra Kliniczne
city: Bydgoszcz
country: Poland
facility: Szpital Uniwersytecki nr 2 im. dr Jana Biziela w BydgoszczyKlinika Hematologii
city: Katowice
country: Poland
facility: Pratia Onkologia Katowice
city: Krakow
country: Poland
facility: Pratia MCM Krakow
city: Lublin
country: Poland
facility: Klinika Hematoonkologii i Transplantacji Szpiku
city: Opole
country: Poland
facility: Szpital Wojewodzki w Opolu
city: Wrocław
country: Poland
facility: Uniwersytecki Szpital Kliniczny im. Jana Mikulicza-Radeckiego we Wrocławiu Klinika Hematologii
city: Girona
country: Spain
facility: Institut Català d'Oncologia de Girona (ICO Girona)
state: Cataluna
city: Badalona
country: Spain
facility: Hospital Germans Trias i Pujol
state: Catalunya [Cataluña]
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
state: Cataluña
city: Majadahonda
country: Spain
facility: Hospital Universitario Puerta de Hierro Majadahonda
state: Madrid, Comunidad De
city: Marbella
country: Spain
facility: Hospital Costa Del Sol
state: Malaga
city: Pamplona
country: Spain
facility: Hospital De Navarra
state: Navarra
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: L'Hospitalet de Llobregat
country: Spain
facility: Hospital Duran i Reynals
city: Las Palmas de Gran Canaria
country: Spain
facility: Hospital De Gran Canaria Dr. Negrin
city: Madrid
country: Spain
facility: Clinica Universitaria De Navarra
city: Madrid
country: Spain
facility: Hospital Universitario Infanta Leonor
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal
city: Santander
country: Spain
facility: Hospital Universitario Marqués de Valdecilla
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Macarena
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Del Rocio
city: Putz
country: Taiwan
facility: Chang Gung Memorial Hospital - Chiayi
state: Chiayi Hsien
city: Changhua
country: Taiwan
facility: Chang Bing Show Chwan Memorial Hospital
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital
city: Taipei
country: Taiwan
facility: Koo Foundation Sun Yan-Sen Cancer Center
city: Mamak
country: Turkey
facility: Ankara University Medicine Hospital
state: Ankara
city: Balçova
country: Turkey
facility: 9 Eylul University Hospital
state: İzmir
city: Bornova
country: Turkey
facility: Ege University Medical Faculty
state: Izmir
city: Ankara
country: Turkey
facility: Gazi University Faculty of Medicine
state: Yenimahalle
city: Istanbul
country: Turkey
facility: Koc University American Hospital
city: Istanbul
country: Turkey
facility: Acıbadem Maslak Hastanesi
city: Istanbul
country: Turkey
facility: Istanbul University Istanbul Medical Faculty
city: Bristol
country: United Kingdom
facility: Bristol Haematology and Oncology Centre
state: Bristol, City Of
city: Hull
country: United Kingdom
facility: Castle Hill Hospital
state: East Riding Of Yorkshire
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary
state: Leicestershire
city: London
country: United Kingdom
facility: St Bartholomew's Hospital
state: London, City Of
city: Swansea
country: United Kingdom
facility: Singleton Hospital
Study officials:
affiliation: Eli Lilly and Company
name: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)
role: STUDY_DIRECTOR
References: