Clinical trial NCT02242942: Comparison of the Treatments of Obinutuzumab + Venetoclax Versus Obinutuzumab + Chlorambucil in Patients With Chronic Lymphocytic Leukemia
Official title: A Prospective, Open-Label, Multicenter Randomized Phase III Trial to Compare The Efficacy and Safety of A Combined Regimen of Obinutuzumab and Venetoclax Versus Obinutuzumab and Chlorambucil in Previously Untreated Patients With CLL and Coexisting Medical Conditions
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Lymphocytic Leukemia, Chronic
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
Collaborators: name: AbbVie
name: German CLL Study Group
First posted: 2014-09-17
Enrollment: 445
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: This open-label, multicenter, randomized Phase III study is designed to compare the efficacy and safety of a combined regimen of obinutuzumab and venetoclax versus obinutuzumab + chlorambucil in participants with chronic lymphocytic leukemia (CLL) and coexisting medical conditions. The time on study treatment was approximately one year and the follow-up period will be up to 9 years


Eligibility criteria: Inclusion Criteria:

* Documented previously untreated CLL according to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria
* CLL requiring treatment according to IWCLL criteria
* Total Cumulative Illness Rating Scale (CIRS score) greater than (\>) 6
* Adequate marrow function independent of growth factor or transfusion support within 2 weeks of screening as per protocol, unless cytopenia is due to marrow involvement of CLL
* Adequate liver function
* Life expectancy \> 6 months
* Agreement to use highly effective contraceptive methods per protocol

Exclusion Criteria:

* Transformation of CLL to aggressive Non-Hodgkin's lymphoma (Richter's transformation or pro-lymphocytic leukemia)
* Known central nervous system involvement
* Participants with a history of confirmed progressive multifocal leukoencephalopathy (PML)
* An individual organ/ system impairment score of 4 as assessed by the CIRS definition limiting the ability to receive the treatment regimen of this trial with the exception of eyes, ears, nose, throat organ system
* Participants with uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia
* Inadequate renal function
* History of prior malignancy, except for conditions as listed in the protocol if participants have recovered from the acute side effects incurred as a result of previous therapy
* Use of investigational agents or concurrent anti-cancer treatment within the last 4 weeks of registration
* Participants with active bacterial, viral, or fungal infection requiring systemic treatment within the last two months prior to registration
* History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products
* Hypersensitivity to chlorambucil, obinutuzumab, or venetoclax or to any of the excipients
* Pregnant women and nursing mothers
* Positive test results for chronic hepatitis B virus (HBV) infection (defined as positive hepatitis B surface antigen \[HBsAg\] serology) or positive test result for hepatitis C (hepatitis C virus \[HCV\] antibody serology testing)
* Participants with known infection with human immunodeficiency virus (HIV) or human T-cell leukemia virus-1 (HTLV-1)
* Requires the use of warfarin, marcumar, or phenprocoumon
* Received agents known to be strong and moderate Cytochrome P450 3A inhibitors or inducers within 7 days prior to the first dose of study drug

Primary outcomes:
measure: Progression Free Survival (PFS) Based on Investigator Assessment According to IWCLL Criteria
timeFrame: Baseline until disease progression or death up to approximately 3.75 years
Secondary outcomes:
measure: Progression Free Survival (PFS) Based on Institutional Review Committee (IRC)-Assessments According to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Criteria
timeFrame: Baseline until disease progression or death up to approximately 3.75 years
measure: Percentage of Participants With an Overall Response (OR) at Completion of Treatment, as Determined by the Investigator According to IWCLL Criteria
timeFrame: At the completion of treatment assessment 3 months after treatment completion (at approximately 15 months)
measure: Percentage of Participants With a Complete Response Rate (CRR) at the Completion of Treatment Assessment as Determined by the Investigator According to IWCLL Criteria
timeFrame: At the completion of treatment assessment 3 months after treatment completion (at approximately 15 months)
measure: Percentage of Participants With Minimal Residual Disease (MRD) Negativity in Peripheral Blood as Measured by Allele-Specific Oligonucleotide Polymerase Chain Reaction (ASO-PCR) at Completion of Treatment
timeFrame: At the completion of treatment assessment 3 months after treatment completion (at approximately 15 months)
measure: Percentage of Participants With MRD Negativity in Bone Marrow as Measured by ASO-PCR at Completion of Treatment
timeFrame: At the completion of treatment assessment 3 months after treatment completion (at approximately 15 months)
measure: Overall Survival (OS)
timeFrame: Baseline until death, up to approximately 10.75 years
measure: Percentage of Participants With MRD Negativity in Peripheral Blood as Measured by ASO-PCR at Completion of Combination Treatment Assessment
timeFrame: Day 1 Cycle 9 or 3 months after last IV infusion, approximately 9 months
measure: Percentage of Participants With MRD Negativity in Bone Marrow as Measured by ASO-PCR at Completion of Combination Treatment Assessment
timeFrame: Day 1 Cycle 9 or 3 months after last IV infusion at approximately 9 months
measure: Percentage of Participants With OR at Completion of Combination Treatment Response Assessment
timeFrame: Day 1 Cycle 7 or 28 days after last IV infusion, approximately 6 months
measure: Duration of Objective Response (DOR)
timeFrame: Time from the first occurrence of a documented objective response to the time of PD as determined by the investigator or death from any cause, up to approximately 10.75 years
measure: Percentage of Participants By Best Response Achieved (CR, CRi, PR, Stable Disease (SD), or PD)
timeFrame: Baseline up to the completion of treatment assessment 3 months after treatment completion (up to approximately 15 months)
measure: Event-Free Survival
timeFrame: Time between date of randomization and the date of disease progression/relapse on the basis of investigator-assessment, death, or start of a new anti-leukemic therapy, up to 10.75 years
measure: Time to Next Anti-Leukemic Treatment
timeFrame: Time between the date of randomization and the date of first intake of new anti-leukemic therapy, up to 10.75 years
measure: Number of Participants With Adverse Events (AEs)
timeFrame: Up to approximately 10.75 years
measure: Percentage of Participants With CD19 + /CD5+ B Cells or CD14+ Monocytes
timeFrame: Baseline up to approximately 10.75 years
measure: Percentage of Participants With Human-Anti-Human Antibodies
timeFrame: Baseline up to approximately 10.75 years
measure: Percentage of Participants Recorded as Premature Study Withdrawals
timeFrame: Up to approximately 10.75 years
measure: Plasma Concentrations of Venetoclax
timeFrame: Pre-venetoclax dose (0 hour) and 4 hours post- venetoclax dose on Day 1 Cycle 4
measure: Serum Concentrations of Obinutuzumab
timeFrame: Pre-obinutuzumab infusion (0 hour) and end of obinutuzumab infusion on Day 1 Cycle 4
measure: Change From Baseline in M.D. Anderson Symptom Inventory-CLL (MDASI-CLL) Score
timeFrame: Baseline up to approximately 10.75 years
measure: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQC30)
timeFrame: Baseline up to approximately 10.75 years
measure: Change From Baseline in EuroQol 5 Dimension Questionnaire (EQ-5D-3L)
timeFrame: Baseline up to approximately 10.75 years
Other outcomes:
Locations:
city: Gilbert
country: United States
facility: Banner MD Anderson Cancer Center
state: Arizona
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Winship Cancer Institute
state: Georgia
city: Harvey
country: United States
facility: Ingalls Memorial Hospital
state: Illinois
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Buenos Aires
country: Argentina
facility: Hospital Italiano
city: Liverpool BC
country: Australia
facility: Liverpool Hospital
state: New South Wales
city: Tweed Heads
country: Australia
facility: Tweed Hospital
state: New South Wales
city: Douglas
country: Australia
facility: The Townsville Hospital
state: Queensland
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital Woolloongabba
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Ashford
country: Australia
facility: Ashford Cancer Centre Research
state: South Australia
city: Box Hill
country: Australia
facility: Box Hill Hospital
state: Victoria
city: Epping
country: Australia
facility: The Northern Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Monash Medical Centre
state: Victoria
city: Innsbruck
country: Austria
facility: Tiroler Landeskrankenanstalten Ges.M.B.H.
city: Wien
country: Austria
facility: Medizinische Universität Wien
city: Wien
country: Austria
facility: Hanusch-Krankenhaus
city: Porto Alegre
country: Brazil
facility: Hospital das Clinicas - UFRGS
state: Rio Grande Do Sul
city: Sao Paulo
country: Brazil
facility: Instituto de Ensino e Pesquisa Sao Lucas - IEP
state: São Paulo
city: Sao Paulo
country: Brazil
facility: Hospital das Clinicas - FMUSP
state: São Paulo
city: Pleven
country: Bulgaria
facility: UMHAT Dr Georgi Stranski
city: Plovdiv
country: Bulgaria
facility: UMHAT " Sveti Georgi" Plovdiv - Clinic of Oncology and Hematology
city: Plovdiv
country: Bulgaria
facility: University Hospital Sv.Georgi Clnic of Hematology
city: Sofia
country: Bulgaria
facility: University Multiprofile Hospital For Active Treatment "Sveti Ivan Rilski" EAD
city: Vratsa
country: Bulgaria
facility: MHAT Hristo Botev
city: Calgary
country: Canada
facility: Arthur J.E. Child Comprehensive Cancer Center
state: Alberta
city: Halifax
country: Canada
facility: Queen Elizabeth II Health Sciences Centre
state: Nova Scotia
city: Montreal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Zagreb
country: Croatia
facility: University Hospital Center Zagreb
city: Zagreb
country: Croatia
facility: University Hospital Merkur Clinic for Internal Medicine/ Hematology
city: Herlev
country: Denmark
facility: Herlev Hospital
city: København Ø
country: Denmark
facility: Rigshospitalet
city: Roskilde
country: Denmark
facility: Sjaellands Universitetshospital, Roskilde
city: Vejle
country: Denmark
facility: Sygehus Lillebælt, Vejle
city: Tallinn
country: Estonia
facility: North Estonia medical Centre
city: Tartu
country: Estonia
facility: Tartu Uni Hospital
city: Caen
country: France
facility: Institut d'Hématologie de Basse Normandie
city: Creteil
country: France
facility: Hopital Henri Mondor
city: Grenoble
country: France
facility: CHU de Grenoble
city: Le Mans
country: France
facility: Centre Jean Bernard
city: Lyon
country: France
facility: Centre Leon Berard
city: Montpellier
country: France
facility: Hôpital Saint Eloi
city: Nantes
country: France
facility: Hopital Hotel Dieu Et Hme
city: Paris
country: France
facility: Hopital Saint Louis
city: Rouen
country: France
facility: Centre Henri Becquerel
city: Toulon
country: France
facility: CH de Toulon Hôpital Sainte Musse
city: Villejuif
country: France
facility: Institut Gustave Roussy - Hematologie
city: Aachen
country: Germany
facility: Uniklinik RWTH Aachen
city: Berlin
country: Germany
facility: Charite - Campus Virchow-Klinikum
city: Berlin
country: Germany
facility: Charite - Universitätsmedizin Berlin
city: Dresden
country: Germany
facility: BAG Freiberg-Richter, Jacobasch, Illmer, Wolf
city: Dresden
country: Germany
facility: Uniklinikum "Carl Gustav Carus";Med. Klinik 1
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Esslingen
country: Germany
facility: Klinik Esslingen
city: Frankfurt/Oder
country: Germany
facility: Klinikum Frankfurt/Oder
city: Freiburg
country: Germany
facility: Uniklinikum Freiburg
city: Heidelberg
country: Germany
facility: Universitaetsklinikum Heidelberg
city: Herne
country: Germany
facility: Stiftung Kathol. Krankenhaus Marienhospital Herne Klinik Mitte
city: Koblenz
country: Germany
facility: Praxisklinik für Hämatologie und Onkologie Koblenz
city: Köln
country: Germany
facility: Universitätsklinikum Köln
city: Mutlangen
country: Germany
facility: Klinikum Schwäbisch Gmünd
city: Mönchengladbach
country: Germany
facility: Kliniken Maria Hilf GmbH Innere Medizin I
city: München
country: Germany
facility: München Klinik Schwabing
city: München
country: Germany
facility: Klinikum der Universität München, Campus Großhadern
city: Paderborn
country: Germany
facility: Brüderkrankenhaus St. Josef Paderborn
city: Regensburg
country: Germany
facility: Krankenhaus Barmherzige Bruder Regensburg
city: Stuttgart
country: Germany
facility: Marienhospital
city: Stuttgart
country: Germany
facility: Robert-Bosch-Krankenhaus
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen
city: Ulm
country: Germany
facility: Universtitätsklinikum Ulm
city: Ferrara
country: Italy
facility: Arcispedale S. Anna
state: Emilia-Romagna
city: Roma
country: Italy
facility: Uni Cattolica
state: Lazio
city: Torino
country: Italy
facility: AOU Città della Salute e della Scienza di Torino - Presidio Le Molinette
state: Lazio
city: Milano
country: Italy
facility: Ospedale San Raffaele
state: Lombardia
city: Terni
country: Italy
facility: Az. Osp. S. Maria
state: Umbria
city: Venezia Mestre
country: Italy
facility: Ospedale dell' Angelo
state: Veneto
city: Culiacan
country: Mexico
facility: Hospital General de Culiacan
state: Sinaloa
city: Christchurch
country: New Zealand
facility: Canterbury Health Laboratories
city: Dunedin
country: New Zealand
facility: Dunedin Hospital
city: Palmerston North
country: New Zealand
facility: Midcentral District Health Board
city: Wellington
country: New Zealand
facility: Wellington Hospital
city: Chorzów
country: Poland
facility: Samodzielny Public Zaklad
city: Lodz
country: Poland
facility: Wojewódzki Szpital Specjalistyczny im. Miko?aja Kopernika
city: Slupsk
country: Poland
facility: Wojewodzki Szpital Specjalistyczny im. J. Korczaka
city: Wroclaw
country: Poland
facility: Samodzielny Publiczny Szpital Kliniczny Nr 1 we Wroc?awiu
city: Bucharest
country: Romania
facility: Fundeni Clinical Inst.
city: Iasi
country: Romania
facility: Institutul Regional de Oncologie Iasi
city: Targu-mures
country: Romania
facility: Spitalul Clinic Judetean de Urgenta Targu-Mures
city: Nizhny Novgorod
country: Russian Federation
facility: Regional Clinical Hospital N.A. Semashko
state: Niznij Novgorod
city: Kazan
country: Russian Federation
facility: Republican Clinical Oncologic Dispensary of Republic Of Tatarstan
state: Tatarstan
city: Penza
country: Russian Federation
facility: Penza Regional Oncology Dispensary
city: Pamplona
country: Spain
facility: Complejo Hospitalario de Navarra
state: Navarra
city: La Laguna
country: Spain
facility: Hospital Universitario de Canarias
state: Tenerife
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Clínic i Provincial
city: Madrid
country: Spain
facility: Hospital Universitario de la Princesa
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal
city: Madrid
country: Spain
facility: Hospital Univ. 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Toledo
country: Spain
facility: Complejo Hospitalario de Toledo- H. Virgen de la Salud
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
city: Bern
country: Switzerland
facility: Inselspital Bern
city: Luzern
country: Switzerland
facility: Luzerner Kantonsspital, Hämatologie
city: Zürich
country: Switzerland
facility: Universitätsspital Zürich Medizin Hämatologie
city: Birmingham
country: United Kingdom
facility: Birmingham Heartlands Hospital
city: Boston,Lincolnshire
country: United Kingdom
facility: Boston Pilgrim Hospital
city: Edinburgh
country: United Kingdom
facility: Western General Hospital
city: Lincoln
country: United Kingdom
facility: Lincoln County Hospital
city: Southhampton
country: United Kingdom
facility: University Hospital Southampton NHS Foundation Trust
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Badawi M, Chen X, Marroum P, Suleiman AA, Mensing S, Koenigsdorfer A, Schiele JT, Palenski T, Samineni D, Hoffman D, Menon R, Salem AH. Bioavailability Evaluation of Venetoclax Lower-Strength Tablets and Oral Powder Formulations to Establish Interchangeability with the 100 mg Tablet. Clin Drug Investig. 2022 Aug;42(8):657-668. doi: 10.1007/s40261-022-01172-4. Epub 2022 Jul 13.
citation: Samineni D, Gibiansky L, Wang B, Vadhavkar S, Rajwanshi R, Tandon M, Sinha A, Al-Sawaf O, Fischer K, Hallek M, Salem AH, Li C, Miles D. Pharmacokinetics and Exposure-Response Analysis of Venetoclax + Obinutuzumab in Chronic Lymphocytic Leukemia: Phase 1b Study and Phase 3 CLL14 Trial. Adv Ther. 2022 Aug;39(8):3635-3653. doi: 10.1007/s12325-022-02170-w. Epub 2022 Jun 16.
citation: Al-Sawaf O, Zhang C, Lu T, Liao MZ, Panchal A, Robrecht S, Ching T, Tandon M, Fink AM, Tausch E, Schneider C, Ritgen M, Bottcher S, Kreuzer KA, Chyla B, Miles D, Wendtner CM, Eichhorst B, Stilgenbauer S, Jiang Y, Hallek M, Fischer K. Minimal Residual Disease Dynamics after Venetoclax-Obinutuzumab Treatment: Extended Off-Treatment Follow-up From the Randomized CLL14 Study. J Clin Oncol. 2021 Dec 20;39(36):4049-4060. doi: 10.1200/JCO.21.01181. Epub 2021 Oct 28.
citation: Al-Sawaf O, Zhang C, Tandon M, Sinha A, Fink AM, Robrecht S, Samoylova O, Liberati AM, Pinilla-Ibarz J, Opat S, Sivcheva L, Le Du K, Fogliatto LM, Niemann CU, Weinkove R, Robinson S, Kipps TJ, Tausch E, Schary W, Ritgen M, Wendtner CM, Kreuzer KA, Eichhorst B, Stilgenbauer S, Hallek M, Fischer K. Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2020 Sep;21(9):1188-1200. doi: 10.1016/S1470-2045(20)30443-5.
citation: Fischer K, Al-Sawaf O, Bahlo J, Fink AM, Tandon M, Dixon M, Robrecht S, Warburton S, Humphrey K, Samoylova O, Liberati AM, Pinilla-Ibarz J, Opat S, Sivcheva L, Le Du K, Fogliatto LM, Niemann CU, Weinkove R, Robinson S, Kipps TJ, Boettcher S, Tausch E, Humerickhouse R, Eichhorst B, Wendtner CM, Langerak AW, Kreuzer KA, Ritgen M, Goede V, Stilgenbauer S, Mobasher M, Hallek M. Venetoclax and Obinutuzumab in Patients with CLL and Coexisting Conditions. N Engl J Med. 2019 Jun 6;380(23):2225-2236. doi: 10.1056/NEJMoa1815281. Epub 2019 Jun 4.