Comparison of the Treatments of Obinutuzumab + Venetoclax Versus Obinutuzumab + Chlorambucil in Patients With Chronic Lymphocytic Leukemia

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Lymphocytic Leukemia, Chronic
• Intervention / Treatment: Drug: Venetoclax; Drug: Obinutuzumab; Drug: Chlorambucil

• Study Type: Interventional
• Enrollment (Actual): 445
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1181ACH
    • Hospital Italiano
• Australia
  • New South Wales
    • Liverpool, New South Wales, Australia, 2170
      • Liverpool Hospital
    • Tweed Heads, New South Wales, Australia, 2485
      • Tweed Hospital
  • Queensland
    • Douglas, Queensland, Australia, 4814
      • The Townsville Hospital
    • Woolloongabba, Queensland, Australia, 4102
      • Princess Alexandra Hospital Woolloongabba; Clinical Hematology and Medical Oncology
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital; Haematology Clinical Trials
    • Ashford, South Australia, Australia, 5035
      • Ashford Cancer Centre Research; Internal Medicine/Medical Oncology
  • Victoria
    • Box Hill, Victoria, Australia, 3128
      • Box Hill Hospital
    • Epping, Victoria, Australia, VIC 3076
      • The Northern Hospital
    • Melbourne, Victoria, Australia, 3168
      • Monash Medical Centre; Haematology
• Austria
  • Innsbruck, Austria, 6020
    • Tiroler Landeskrankenanstalten Ges.M.B.H.; Innere Medizin Abt. Für Hämatologie & Onkologie
  • Wien, Austria, 1160
    • Wilhelminenspital; I. Medizinische Abt.
  • Wien, Austria, 1090
    • Medizinische Universität Wien; Univ.Klinik für Innere Medizin I - Hämatologie & Hämostaseologie
  • Wien, Austria, 1140
    • Hanusch-Krankenhaus; Iii. Medizinische Abt.
• Brazil
  • RS
    • Porto Alegre, RS, Brazil, 90035-903
      • Hospital das Clinicas - UFRGS
  • SP
    • Sao Paulo, SP, Brazil, 01308-050
      • Hospital Sirio-Libanes
    • Sao Paulo, SP, Brazil, 01236-030
      • Instituto de Ensino e Pesquisa Sao Lucas - IEP
    • Sao Paulo, SP, Brazil, 08270-070
      • Hospital Santa Marcelina
    • Sao Paulo, SP, Brazil, 05403-010
      • Hospital das Clinicas - FMUSP
• Bulgaria
  • Pleven, Bulgaria, 5800
    • UMHAT Dr Georgi Stranski; Hematology
  • Plovdiv, Bulgaria, 4002
    • UMHAT " Sveti Georgi" Plovdiv - Clinic of Oncology and Hematology
  • Plovdiv, Bulgaria, 4002
    • University Hospital Sv.Georgi Clnic of Hematology; Hematology
  • Sofia, Bulgaria, 1431
    • University Multiprofile Hospital For Active Treatment "Sveti Ivan Rilski" EAD; clinical hematology
  • Vratsa, Bulgaria, 3000
    • MHAT Hristo Botev; First Internal Department
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N2
      • Tom Baker Cancer Centre; Dept of Medicine
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 2Y9
      • Queen Elizabeth II Health Sciences Centre; Oncology
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • Jewish General Hospital
• Croatia
  • Zagreb, Croatia, 10000
    • University Hospital Center Zagreb; Haematology Department
  • Zagreb, Croatia, 10000
    • University Hospital Merkur Clinic for Internal Medicine/ Hematology
• Denmark
  • Herlev, Denmark, 2730
    • Herlev Hospital
  • København Ø, Denmark, 2100
    • Rigshospitalet
  • Roskilde, Denmark, 4000
    • Sjaellands Universitetshospital, Roskilde
  • Vejle, Denmark, 7100
    • Sygehus Lillebælt, Vejle
• Estonia
  • Tallinn, Estonia, 13419
    • North Estonia medical Centre; Hematology
  • Tartu, Estonia, 51014
    • Tartu Uni Hospital; Hematology - Oncology Clinic
• France
  • Besançon Cedex, France, 25030
    • CHU Besançon - Hôpital Jean Minjoz
  • Caen, France, 14000
    • Institut d'Hématologie de Basse Normandie
  • Clermont Ferrand, France, 63003
    • Chu Estaing; Hematologie Clinique Adultes
  • Creteil, France, 94000
    • Hôpital Henri Mondor
  • Dijon, France, 21000
    • CHU de Dijon - Hopital le Bocage
  • Grenoble, France, 38043
    • CHU de Grenoble
  • Le Mans, France, 72015
    • Centre Jean Bernard
  • Lyon, France, 69373
    • Centre Leon Berard; Departement Oncologie Medicale
  • Montpellier, France, 34295
    • Hôpital Saint Eloi; Service d?Hématologie et Oncologie Clinique - Recherche Clinique
  • Nantes, France, 44093
    • Hopital Hotel Dieu Et Hme;Hopital De Jour
  • Paris, France, 75475
    • Hopital Saint Louis ; Service d Oncologie Medicale Fougere 6 (Pr Misset)
  • Rennes, France, 35033
    • Hopital Pontchaillou; Hematologie Clinique
  • Rouen, France, 76038
    • Centre Henri Becquerel; Hematologie
  • Toulon, France, 83056
    • CH de Toulon Hôpital Sainte Musse
  • Villejuif, France, 94805
    • Institut Gustave Roussy - Hematologie
• Germany
  • Aachen, Germany, 52074
    • Uniklinik RWTH Aachen; Klinik IV; Klinik Hämatologie, Onkologie, Hämostaseologie und Stamm.
  • Amberg, Germany, 92224
    • Gesundheitszentrum St. Marien GmbH; Med. II, Hämatologie/Onkologie
  • Berlin, Germany, 13353
    • Charite - Campus Virchow-Klinikum
  • Berlin, Germany, 12203
    • Charité - Universitätsmedizin Berlin
  • Dresden, Germany, 01307
    • BAG Freiberg-Richter, Jacobasch, Illmer, Wolf; Gemeinschaftspraxis Hämatologie-Onkologie
  • Dresden, Germany, 01307
    • Uniklinikum "Carl Gustav Carus"; Med. Klinik 1; Hämatologie, Zelltherapie und Medizinische Onkologie
  • Essen, Germany, 45122
    • Universitätsklinikum Essen; Klinik für Hämatologie
  • Esslingen, Germany, 73730
    • Klinik Esslingen; Klinik für Allgemeine Innere Medizin, Onkologie/Haematologie
  • Frankfurt/Oder, Germany, 15236
    • Klinikum Frankfurt/Oder
  • Freiburg, Germany, 79106
    • Uniklinikum Freiburg
  • Göttingen, Germany, 37075
    • Uni Göttingen, Georg-August-Universität; Klinik für Hämatologie und Medizinische Onkologie
  • Heidelberg, Germany, 69120
    • Universitaetsklinikum Heidelberg
  • Herne, Germany, 44625
    • Stiftung Kathol. Krankenhaus Marienhospital Herne Klinik Mitte
  • Koblenz, Germany, 56068
    • Praxisklinik für Hämatologie und Onkologie Koblenz
  • Köln, Germany, 50931
    • Universitätsklinikum Köln; Innere Medizin I; Onkologie, Hämatologie
  • Landshut, Germany, 84028
    • Tagesklinik Landshut; Hämatologie/Onkologie
  • Munchen, Germany, 81675
    • Klinikum rechts der Isar der Technischen Universität München
  • Mutlangen, Germany, 73557
    • Klinikum Schwäbisch Gmünd
  • Mönchengladbach, Germany, 41063
    • Kliniken Maria Hilf GmbH Innere Medizin I
  • München, Germany, 80804
    • München Klinik Schwabing; Klinik für Hämatologie, Onkologie, Immunologie
  • München, Germany, 81377
    • Klinikum der Universität München, Campus Großhadern; Medizinische Klinik und Poliklinik III
  • Neunkirchen/Saar, Germany, 66538
    • Gemeinschaftspraxis Dr. med. Holger Klaproth
  • Paderborn, Germany, 33098
    • Brüderkrankenhaus St. Josef Paderborn
  • Regensburg, Germany, 93049
    • Krankenhaus Barmherzige Brüder Regensburg
  • Stuttgart, Germany, 70376
    • Robert-Bosch-Krankenhaus
  • Stuttgart, Germany, 70199
    • Marienhospital
  • Tübingen, Germany, 72076
    • Universitätsklinikum Tübingen
  • Ulm, Germany, 89081
    • Universtitätsklinikum Ulm; Klinik für Innere Medizin III
  • Weiden, Germany, 92367
    • Medizinisches Versorgungszentrum Nuklearmedizin-Strahlentherapie-Onkologie
• Italy
  • Emilia-Romagna
    • Ferrara, Emilia-Romagna, Italy, 44100
      • Arcispedale S. Anna; Sezione Di Ematologia
  • Lazio
    • Messina, Lazio, Italy, 98158
      • Ospedali Riuniti Papardo-Piemonte; Struttura Complessa Di Ematologia
    • Roma, Lazio, Italy, 00168
      • Uni Cattolica; Divisione Di Ematologia
    • Torino, Lazio, Italy, 10126
      • AOU Città della Salute e della Scienza di Torino - Presidio Le Molinette
  • Lombardia
    • Milano, Lombardia, Italy, 20132
      • Ospedale San Raffaele
  • Umbria
    • Terni, Umbria, Italy, 05100
      • Az. Osp. S. Maria; Dept. Di Oncologia Medica
  • Veneto
    • Venezia Mestre, Veneto, Italy, 30174
      • Ospedale dell' Angelo; U.O. Ematologia
• Mexico
  • Sinaloa
    • Culiacan, Sinaloa, Mexico, 80230
      • Hospital General de Culiacan
• New Zealand
  • Christchurch, New Zealand, 8011
    • Canterbury Health Laboratories; Haematology
  • Dunedin, New Zealand
    • Dunedin Hospital
  • Palmerston North, New Zealand, 4442
    • Midcentral District Health Board
  • Wellington, New Zealand, 6012
    • Wellington Hospital
• Poland
  • Bialystok, Poland, 15-2
    • Uniwersytecki Szpital Kliniczny w Bia?ymstoku, Klinika Hematologii z Pododdzia?em Chorob Naczyn
  • Chorzów, Poland, 41-500
    • Samodzielny Public Zaklad
  • Lodz, Poland, 9351
    • Wojewódzki Szpital Specjalistyczny im.Miko?ajaKopernika;KlinikaHematologiiUniwersytetuMedycznego
  • Slupsk, Poland, 76-200
    • Wojewodzki Szpital Specjalistyczny im. J. Korczaka; Oddzia? Chorób Wewnetrznych/Hematologiczny
  • Wroclaw, Poland, 5036
    • Samodzielny Publiczny Szpital Kliniczny Nr 1 we Wroc?awiu; Klinika Hematologii
• Romania
  • Bucharest, Romania, 022328
    • Fundeni Clinical Inst. ; Hematology Dept
  • Iasi, Romania, 700483
    • Institutul Regional de Oncologie Iasi; Clinica de Hematologie
  • Targu-mures, Romania, 540136
    • Spitalul Clinic Judetean de Urgenta Targu-Mures; compartiment Hematologie
• Russian Federation
  • Penza, Russian Federation, 440071
    • Penza Regional Oncology Dispensary
  • Perm, Russian Federation, 614077
    • Clinical MSCh No1
  • Baskortostan
    • UFA, Baskortostan, Russian Federation, 450000
      • SBEI of HPE ?Bashkir State Medical University? of MoH RF
  • Moskovskaja Oblast
    • Moscow, Moskovskaja Oblast, Russian Federation, 123182
      • Moscow State Budgetary Healthcare Institution
  • Niznij Novgorod
    • Nizhny Novgorod, Niznij Novgorod, Russian Federation, 603126
      • Regional Clinical Hospital N.A. Semashko; Hematology
  • Rostov
    • Rostov-na-donu, Rostov, Russian Federation, 344022
      • Rostov State Medical Uni ; Hematology
  • Tatarstan
    • Kazan, Tatarstan, Russian Federation, 420029
      • Republican Clinical Oncologic Dispensary of Republic Of Tatarstan
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron; Servicio de Hematologia
  • Barcelona, Spain, 08036
    • Hospital Clínic i Provincial; Servicio de Hematología y Oncología
  • Barcelona, Spain, 08003
    • Hospital del Mar; Servicio de Hematologia
  • Madrid, Spain, 28034
    • Hospital Universitario Ramon y Cajal
  • Madrid, Spain, 28034
    • Hospital Universitario La Paz
  • Madrid, Spain, 28006
    • Hospital Universitario de la Princesa; Servicio de Hematologia
  • Madrid, Spain, 28041
    • Hospital Univ. 12 de Octubre; Servicio de Hematologia
  • Salamanca, Spain, 37007
    • Hospital Clinico Universitario de Salamanca;Servicio de Hematologia
  • Sevilla, Spain, 41013
    • Hospital Universitario Virgen del Rocio
  • Toledo, Spain, 45004
    • Complejo Hospitalario de Toledo- H. Virgen de la Salud; Servicio de Hematología
  • Valencia, Spain, 46010
    • Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia
  • Valencia, Spain, 46015
    • Hospital Arnau de Vilanova (Valencia) Servicio de Hematologia
  • Navarra
    • Pamplona, Navarra, Spain, 31008
      • Complejo Hospitalario de Navarra
  • Tenerife
    • La Laguna, Tenerife, Spain, 38320
      • Hospital Universitario de Canarias;servicio de Hematologia
• Switzerland
  • Bern, Switzerland, 3010
    • Inselspital Bern; Hämatologie und Hämatologisches Zentrallabor
  • Luzern, Switzerland, 6000
    • Luzerner Kantonsspital, Hämatologie
  • Zürich, Switzerland, 8091
    • Universitätsspital Zürich Medizin Hämatologie; Klinik für Hämatologie
• United Kingdom
  • Birmingham, United Kingdom, B9 5SS
    • Birmingham Heartlands Hospital
  • Boston,Lincolnshire, United Kingdom, PE21 9QS
    • Boston Pilgrim Hospital
  • Edinburgh, United Kingdom, EH4 2XU
    • Western General Hospital; Department of Haematology
  • Lincoln, United Kingdom, LN2 5QY
    • Lincoln County Hospital
  • Southhampton, United Kingdom, SO16 6YD
    • University Hospital Southampton NHS Foundation Trust
• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope
    • Encinitas, California, United States, 92024-1375
      • San Diego Pacific Hematology Assocates
    • La Jolla, California, United States, 92093
      • UC San Diego Health System
  • Colorado
    • Greeley, Colorado, United States, 85234
      • Banner MD Anderson Cancer Center
  • Florida
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Winship Cancer Institute
  • Illinois
    • Harvey, Illinois, United States, 60426
      • Ingalls Memorial Hospital
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
  • Texas
    • Lubbock, Texas, United States, 79410
      • Joe Arrington Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Safety Run-in Obinutuzumab + Venetoclax; Subjects received obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles comprised of 28 days.	Drug: Venetoclax; Venetoclax, oral tablet: 20 mg daily during Cycle 1, Day 22-28; 50 mg daily during Cycle 2, Day 1-7; 100 mg daily during Cycle 2, Day 8-14; 200 mg daily during Cycle 2, Day 15-21; 400 mg daily during Cycle 2, Day 22-28 and on Day 1-28 for all subsequent cycles until the end of Cycle 12.; Other Names: ABT-0199, GDC-0199; Drug: Obinutuzumab; Obinutuzumab, IV infusion: 100 mg or 1000 mg, depending on splitting rules, at Cycle 1, Day 1 (if 100 mg was received on Day 1, 900 mg will be administered on Cycle 1, Day 2); 1000 mg at Cycle 1, Day 8 and Day 15; 1000 mg at Day 1 for all subsequent cycles until the end of Cycle 6; Other Names: GA-101; Gazyva
Experimental: Obinutuzumab + Chlorambucil; Participants will receive obinutuzumab for 6 cycles and chlorambucil for 12 cycles. Cycles will comprise 28 days.	Drug: Obinutuzumab; Obinutuzumab, IV infusion: 100 mg or 1000 mg, depending on splitting rules, at Cycle 1, Day 1 (if 100 mg was received on Day 1, 900 mg will be administered on Cycle 1, Day 2); 1000 mg at Cycle 1, Day 8 and Day 15; 1000 mg at Day 1 for all subsequent cycles until the end of Cycle 6; Other Names: GA-101; Gazyva; Drug: Chlorambucil; Chlorambucil 0.5 milligrams per kilogram (mg/kg) orally at Day 1 and Day 15 at of each 28 day cycle for 12 cycles.
Experimental: Obinutuzumab + Venetoclax; Participants will receive obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles will comprise 28 days.	Drug: Venetoclax; Venetoclax, oral tablet: 20 mg daily during Cycle 1, Day 22-28; 50 mg daily during Cycle 2, Day 1-7; 100 mg daily during Cycle 2, Day 8-14; 200 mg daily during Cycle 2, Day 15-21; 400 mg daily during Cycle 2, Day 22-28 and on Day 1-28 for all subsequent cycles until the end of Cycle 12.; Other Names: ABT-0199, GDC-0199; Drug: Obinutuzumab; Obinutuzumab, IV infusion: 100 mg or 1000 mg, depending on splitting rules, at Cycle 1, Day 1 (if 100 mg was received on Day 1, 900 mg will be administered on Cycle 1, Day 2); 1000 mg at Cycle 1, Day 8 and Day 15; 1000 mg at Day 1 for all subsequent cycles until the end of Cycle 6; Other Names: GA-101; Gazyva

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS) Based on Investigator Assessment According to IWCLL Criteria	PFS was determined according to IWCLL 2008 criteria and defined as the time from randomization to the first occurrence of PD or death from any cause. Disease progression was characterized by at least one of the following: 1) >/= 50% increase in the absolute number of circulating lymphocytes to at least 5*10^9/L, 2) Appearance of new palpable lymph nodes (> 15 mm in longest diameter) or any new extra-nodal lesion; 3) >/= 50% increase in the longest diameter of any previous site of lymphadenopathy; 4) >/= 50% increase in the enlargement of the liver and/or spleen; 5) Transformation to a more aggressive histology.	Baseline until disease progression or death up to approximately 3.75 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS) Based on Institutional Review Committee (IRC)-Assessments According to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Criteria	PFS was determined according to IWCLL 2008 criteria and defined as the time from randomization to the first occurrence of progressive disease (PD) or death from any cause. Disease progression was characterized by at least one of the following: 1) >/= 50% increase in the absolute number of circulating lymphocytes to at least 5*10^9/L, 2) Appearance of new palpable lymph nodes (> 15 mm in longest diameter) or any new extra-nodal lesion; 3) >/= 50% increase in the longest diameter of any previous site of lymphadenopathy; 4) >/= 50% increase in the enlargement of the liver and/or spleen; 5) Transformation to a more aggressive histology.	Baseline until disease progression or death up to approximately 3.75 years
Percentage of Participants With an Overall Response (OR) at Completion of Treatment, as Determined by the Investigator According to IWCLL Criteria	OR was defined as complete response (CR), CR with incomplete bone marrow recovery (CRi), or partial response (PR) according to IWCLL 2008 criteria. CR requires all of the following: peripheral blood lymphocytes below 4x10^9/L, absence of lymphadenopathy by physical examination and computed tomography (CT) scan, no hepatomegaly or splenomegaly, absence of disease or constitutional symptoms, blood counts of neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L, bone marrow at least normocellular for age without clonal infiltrate (except for Cri). PR: two of the following features for at least 2 months: >/= 50% decrease in peripheral blood lymphocyte count from the pretreatment value, >/=50% reduction in lymphadenopathy, >/=50% reduction of liver and/or spleen enlargement, and at least one of the following blood counts: neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L.	At the completion of treatment assessment 3 months after treatment completion (at approximately 15 months)
Percentage of Participants With a Complete Response Rate (CRR) at the Completion of Treatment Assessment as Determined by the Investigator According to IWCLL Criteria	CRR was defined as the rate of a clinical response of CR or CRi according to IWCLL 2008 criteria. CR requires all of the following: peripheral blood lymphocytes below 4x10^9/L, absence of lymphadenopathy by physical examination and CT scan, no hepatomegaly or splenomegaly, absence of disease or constitutional symptoms, blood counts of neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L, bone marrow at least normocellular for age without clonal infiltrate (except for Cri).	At the completion of treatment assessment 3 months after treatment completion (at approximately 15 months)
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	MRD negativity was defined as having < 1 CLL cell per 10,000 leucocytes in peripheral blood.	At the completion of treatment assessment 3 months after treatment completion (at approximately 15 months)
Percentage of Participants With MRD Negativity in Bone Marrow as Measured by ASO-PCR at Completion of Treatment	MRD negativity was defined as having < 1 CLL cell per 10,000 leucocytes in bone marrow.	At the completion of treatment assessment 3 months after treatment completion (at approximately 15 months)
Overall Survival (OS)	OS was defined as the time between the date of randomization and the date of death due to any cause.	Baseline until death, up to approximately 10.75 years
Percentage of Participants With MRD Negativity in Peripheral Blood as Measured by ASO-PCR at Completion of Combination Treatment Assessment	MRD negativity was defined as having < 1 CLL cell per 10,000 leucocytes in peripheral blood.	Day 1 Cycle 9 or 3 months after last IV infusion, approximately 9 months
Percentage of Participants With MRD Negativity in Bone Marrow as Measured by ASO-PCR at Completion of Combination Treatment Assessment	MRD negativity was defined as having < 1 CLL cell per 10,000 leucocytes in bone marrow.	Day 1 Cycle 9 or 3 months after last IV infusion at approximately 9 months
Percentage of Participants With OR at Completion of Combination Treatment Response Assessment	OR was defined as CR, CRi or PR according to IWCLL 2008 criteria. CR required all of the following: peripheral blood lymphocytes below 4x10^9/L, absence of lymphadenopathy by physical examination, no hepatomegaly or splenomegaly, absence of disease or constitutional symptoms, blood counts of neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L. PR: two of the following features for at least 2 months: >/= 50% decrease in peripheral blood lymphocyte count from the pretreatment value, >/=50% reduction in lymphadenopathy, >/=50% reduction of liver and/or spleen enlargement, and at least one of the following blood counts: neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L.	Day 1 Cycle 7 or 28 days after last IV infusion, approximately 6 months
Duration of Objective Response (DOR)	PD was defined as lymphadenopathy, >=50% increase in liver or spleen size, >=50% increase in lymphocyte count, transformation to a more aggressive histology or occurrence of cytopenia.	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
Percentage of Participants By Best Response Achieved (CR, CRi, PR, Stable Disease (SD), or PD)	CR: peripheral blood lymphocytes below 4x10^9/L, absence of lymphadenopathy by physical examination and CT scan, no hepatomegaly or splenomegaly, absence of disease or constitutional symptoms, blood counts of neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L, bone marrow at least normocellular for age without clonal infiltrate (except for Cri). PR: any two for at least 2 months: >/= 50% decrease in peripheral blood lymphocyte count from the pretreatment value, >/=50% reduction in lymphadenopathy, >/=50% reduction of liver and/or spleen enlargement, and at least one of the following blood counts: neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L. PD: lymphadenopathy, >=50% increase in liver or spleen size, >=50% increase in lymphocyte count, transformation to a more aggressive histology or occurrence of cytopenia. SD: a non-response and used to characterize participants who did not achieve a CR or a PR, and who have not exhibited PD.	Baseline up to the completion of treatment assessment 3 months after treatment completion (up to approximately 15 months)
Event-Free Survival		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
Time to Next Anti-Leukemic Treatment		Time between the date of randomization and the date of first intake of new anti-leukemic therapy, up to 10.75 years
Number of Participants With Adverse Events (AEs)	An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as AEs.	Up to approximately 10.75 years
Percentage of Participants With CD19 + /CD5+ B Cells or CD14+ Monocytes		Baseline up to approximately 10.75 years
Percentage of Participants With Human-Anti-Human Antibodies		Baseline up to approximately 10.75 years
Percentage of Participants Recorded as Premature Study Withdrawals		Up to approximately 10.75 years
Plasma Concentrations of Venetoclax		Pre-venetoclax dose (0 hour) and 4 hours post- venetoclax dose on Day 1 Cycle 4
Serum Concentrations of Obinutuzumab		Pre-obinutuzumab infusion (0 hour) and end of obinutuzumab infusion on Day 1 Cycle 4
Change From Baseline in M.D. Anderson Symptom Inventory-CLL (MDASI-CLL) Score	The MDASI-CLL is a questionnaire of 25 items related to CLL specific symptoms that a participant may have experienced in the past 24 hours. Participants were asked to rate the severity of 13 symptoms called mean core symptom severity (i.e., pain, fatigue, nausea, disturbed sleep, distressed, shortness of breath, remembering things, lack of appetite, drowsy, dry mouth, sadness, vomiting, and numbness or tingling), 6 disease-specific symptoms called mean module symptom severity (night sweats, fevers and chills, lymph node swelling, diarrhea, easy bruising or bleeding, and constipation) and 6 mean interference on life questions (i.e., general activity, walking, work, mood, relations with other people, and enjoyment of life) on a scale from 0 to 10 with 0 indicating that the symptom is "not present" or "did not interfere" with the participant's activities and 10 indicating "as bad as you can imagine" or "interfered completely". Scores were averaged (range 0 to 10) for each of three parts.	Baseline up to approximately 10.75 years
Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQC30)	The EORTC QLQ-C30 is a validated and reliable self-report measure consisting of 30 questions incorporated into five functional scales (physical, role, cognitive, emotional, and social scales), three symptom scales (fatigue, pain, nausea, and vomiting scales), and a global health status/global quality-of-life scale. The remaining single items (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea) assess the additional symptoms experienced by patients with cancer and the perceived financial burden of treatment. The 28 function and symptom items were scored on a 4-point scale that ranged from "not at all" to "very much," and the 2 global health status/global quality-of-life items were scored on a 7-point scale that ranged from "very poor" to "excellent." Raw average scale scores were linearly transformed to range 0-100 with higher scores indicating higher response levels (i.e., higher functioning, higher symptom severity).	Baseline up to approximately 10.75 years
Change From Baseline in EuroQol 5 Dimension Questionnaire (EQ-5D-3L)	The EQ-5D-3L questionnaire is a generic, preference based health utility measure that assesses 5 health states (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and is used to build a composite of the patient's health status. The EQ-5D-3L was employed in this study to calculate health utilities for economic modeling, which ranged 0-1. The EQ-5D-3L also contained a visual analog scale (VAS) to assess the participant's overall health, which ranged from 0-100 with a higher score indicating a worse health status.	Baseline up to approximately 10.75 years

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche
• Collaborators: AbbVie; German CLL Study Group
• Investigators: Study Director: Clinical Trials, Hoffmann-La Roche

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): December 31, 2014
• Primary Completion (Actual): August 17, 2018
• Study Completion (Estimated): August 31, 2025

Study Registration Dates

• First Submitted: September 16, 2014
• First Submitted That Met QC Criteria: September 16, 2014
• First Posted (Estimated): September 17, 2014

Study Record Updates

• Last Update Posted (Actual): March 12, 2024
• Last Update Submitted That Met QC Criteria: March 8, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Hematologic Diseases; Leukemia, B-Cell; Chronic Disease; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Antineoplastic Agents, Immunological; Venetoclax; Obinutuzumab; Chlorambucil
• Other Study ID Numbers: BO25323; 2014-001810-24 (EudraCT Number); CLL14

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No