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A Study to Evaluate the Benefit of Venetoclax Plus Rituximab Compared With Bendamustine Plus Rituximab in Participants With Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) (MURANO)

Primary Purpose

Chronic Lymphocytic Leukemia

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Bendamustine

Venetoclax

Rituximab

About this trial

This is an interventional treatment trial for Chronic Lymphocytic Leukemia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Diagnosis of CLL per diagnostic criteria for relapsed or refractory CLL per the international workshop on chronic lymphocytic leukemia (iwCLL) guidelines
Previously treated with 1-3 lines of therapy (example: completed greater than or equal to [>/=] 2 treatment cycles per therapy), including at least one standard chemotherapy-containing regimen
Participants previously treated with bendamustine only if their duration of response was >/= 24 months
Eastern Cooperative Oncology Group (ECOG) performance score of less than or equal to (</=) 1
Adequate bone marrow function
Adequate renal and hepatic function
Participants must use effective birth control throughout study until at least 30 days after study treatment or 1 year after rituximab treatment, whichever is later; female participants must not be pregnant or breast-feeding
For participants with the 17p deletion, previously treated with 1-3 lines of therapy, including at least one prior standard chemotherapy-containing regimen or at least one prior alemtuzumab-containing therapy

Inclusion Criteria R/C Substudy:

Participants randomized to Arm A or Arm B with a confirmed disease progression of CLL per iwCLL criteria
Participants who have not received new anti-CLL therapy following disease progression in Arm A or Arm B
Adequate renal and hepatic function per laboratory reference range

Exclusion Criteria:

Transformation of CLL to aggressive non-Hodgkin lymphoma or central nervous system (CNS) involvement by CLL
Undergone an allogenic stem cell transplant
A history of significant renal, neurologic, psychiatric, endocrine, metabolic, immunologic, cardiovascular or hepatic disease
Hepatitis B or C or known human immunodeficiency virus (HIV) positive
Receiving warfarin treatment
Received an anti-CLL monoclonal antibody within 8 weeks prior to the first dose of study drug
Received any anti-cancer or investigational therapy within 28 days prior to the first dose of study drug or has not recovered to less than Grade 2 clinically significant adverse effect(s)/toxicity(ies) of any previous therapy
Received cytochrome P450 3A4 (CYP3A4) inhibitors (such as fluconazole, ketoconazole and clarithromycin) or inducers (such as rifampin, carbamazapine, phenytoin, St. John's Wort) within 7 days prior to the first dose of venetoclax
History of prior venetoclax treatment
Participants with another cancer, history of another cancer considered uncured on in complete remission for <5 years, or currently under treatment for another suspected cancer except non-melanoma skin cancer or carcinoma in situ of the cervix that has been treated or excised and is considered resolved
Malabsorption syndrome or other condition that precludes enteral route of administration
Other clinically significant uncontrolled condition(s) including, but not limited to, systemic infection (viral, bacterial or fungal)
Vaccination with a live vaccine within 28 days prior to randomization
Consumed grapefruit or grapefruit products, seville oranges (including marmalade containing seville oranges), or star fruit within 3 days prior to the first dose of study treatment
A cardiovascular disability status of New York Heart Association Class >/=3. Class 3 is defined as cardiac disease in which participants are comfortable at rest but have marked limitation of physical activity due to fatigue, palpitations, dyspnea, or anginal pain
Major surgery within 30 days prior to the first dose of study treatment
A participant who is pregnant or breastfeeding
Known allergy to both xanthine oxidase inhibitors and rasburicase

Exclusion Criteria R/C Substudy:

Transformation of CLL to aggressive NHL (e.g., Richter's transformation, prolymphocytic leukemia, or DLBCL) or CNS involvement by CLL
Evidence of other clinically significant uncontrolled condition(s) including, but not limited to, uncontrolled systemic infection (viral, bacterial, or fungal)
Development of other malignancy since enrollment into the study, with the exception of curatively treated basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma in situ of the cervix
Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia
History of severe (i.e., requiring permanent discontinuation of prior rituximab therapy) prior allergic or anaphylactic reactions to rituximab
Known HIV positivity
Positive test results for chronic hepatitis B infection (defined as positive hepatitis B surface antigen [HbsAg] serology)
Positive test results for hepatitis C virus (HCV; HCV antibody serology testing)
Requires the use of warfarin (due to potential drug interactions that may potentially increase the exposure of warfarin)
Has not recovered to less than Grade 2 clinically significant adverse effect(s)/toxicity(ies) of any previous therapy
Received potent CYP3A4 inhibitors (such as fluconazole, ketoconazole, and clarithromycin) within 7 days prior to the first dose of study treatment
Received potent CYP3A4 inducers (such as rifampin, carbamazepine, phenytoin, St. John's wort) within 7 days prior to the first dose of study treatment
Consumed grapefruit or grapefruit products, Seville oranges (including marmalade containing Seville oranges), or star fruit within 3 days prior to the first dose of study treatment
A cardiovascular disability status of New York Heart Association Class >/= 3
A significant history of renal, neurologic, psychiatric, endocrine, metabolic, immunologic, cardiovascular, or hepatic disease that, in the opinion of the investigator, would adversely affect the participants's participation in this study or interpretation of study outcomes
Major surgery within 30 days prior to the first dose of study treatment
A participant who is pregnant or breastfeeding
Malabsorption syndrome or other condition that precludes enteral route of administration
Known allergy to both xanthine oxidase inhibitors and rasburicase
Vaccination with a live vaccine within 28 days prior to randomization

Sites / Locations

University of California San Diego Medical Center
Henry Ford Health System
Memorial Sloan Kettering Cancer Center; Clinical Trials Office
Perlmutter Cancer Center NYU Langone Health
Huntsman Cancer Institute; University of Utah
The Canberra Hospital
Concord Repatriation General Hospital
St George Hospital
Princess Alexandra Hospital
Royal Adelaide Hospital
Flinders Medical Centre
Royal Hobart Hospital
Frankston Hospital
Monash Medical Centre; Haematology
Slade Health Pharmacy
Peter MacCallum Cancer Center
Royal Melbourne Hospital
The Perth Blood Institute
Medizinische Universität Innsbruck
LKH - Universitätsklinikum der PMU Salzburg
Medizinische Universität Wien
Klinik Ottakring
ZNA Antwerpen; Department Hematology
Cliniques Universitaires Saint-Luc; Hematology
AZ Groeninge
UZ Leuven; Department Hematology
CHU UCL Mont-Godinne
AZ Delta (Campus Rumbeke)
Foothills Medical Centre; Centre Dept of Medical Clinical Neuroscience
Juravinski Cancer Clinic
Jewish General Hospital
Saskatoon City Hospital;Saskatchewan Cancer Centre
Fakultni nemocnice Brno
Fakultni nemocnice Hradec Kralove
Fakultní nemocnice Olomouc
Fakultni nemocnice Ostrava
Vseobecna fakultni nemocnice v Praze
Fakultni nemocnice Kralovske Vinohrady
Herlev Hospital
Rigshospitalet
Odense Universitetshospital
Sjællands Universitetshospital, Roskilde
Sygehus Lillebælt, Vejle
Hôpital Morvan
Centre Hospitalier Départemental Les Oudairies
Hopital Claude Huriez - CHU Lille
Hopital Saint Eloi
CHU Nantes - Hôtel Dieu; Service Assistance Medicale à la Procreation
Hopital Robert Debre
Centre Hospitalier Lyon Sud
CHU Poitiers - Hopital La Miletrie
CHU de Rennes - Hopital de Pontchaillo
Centre Henri Becquerel
Institut Universitaire du Cancer - Oncopole Toulouse (IUCT-O)
CHU Tours - Hôpital Bretonneau
Hôpital de Brabois Adultes
Universitätsklinikum "Carl Gustav Carus" der Technischen Universität Dresden
Universitaetsklinikum Freiburg
Universitätsklinikum Tübingen
Semmelweis Egyetem
Orszagos Onkologiai Intezet
Debreceni Egyetem Klinikai Központ; B?rgyógyászati Klinika
Somogy Megyei Kaposi Mor Oktato Korhaz
Szegedi Tud.Egyetem Szent-Gyorgyi Albert Klin.Kozp.
Azienda Ospedaliera Città della Salute e della Scienza di Torino; Radiology
Azienda Ospedaliero Universitaria San Martino
Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII (Presidio Papa Giovanni XXIII)
Ospedale San Raffaele
Asst Grande Ospedale Metropolitano Niguarda; SC Farmacia Ospedale
Azienda Ospedaliero Universitaria Ospedali Riuniti
Istituto Tumori Giovanni Paolo II IRCCS Ospedale Oncologico Bari
Azienda Ospedaliera Universitaria Careggi
Azienda Ospedaliera Di Padova
Seoul National University Bundang Hospital
Severance Hospital, Yonsei University Health System
Konkuk University Medical Center
The Catholic University of Korea Seoul St. Mary?s Hospital
Amsterdam UMC, Locatie VUMC; Neurology
Amsterdam UMC Location AMC
Albert Schweitzer Ziekenhuis, Dordwijk; Internal Medicine, Hemato-Oncology
Medisch Spectrum Twente
Leids Universitair Medisch Centrum; Cardiology
Erasmus Medisch Centrum
UMC Utrecht
North Shore Hospital; Haematolgy
Middlemore Hospital
Christchurch Hospital NZ
Baxter Healthcare
SP ZOZ Zespol Szpitali Miejskich w Chorzowie
Uniwersyteckie Centrum Kliniczne
Wojewódzkie Wielospecjalistyczne Centrum Onkologii i Traumatologii im. M. Kopernika w Lodzi
Szpital Wojewodzki w Opolu
MTZ Clinical Research Sp. z o.o.
Samodzielny Publiczny Szpital Kliniczny nr 1
FSBSI "Russian Oncological Scientific Center n.a. N.N. Blokhin"
SRI of Hematology and Transfusiology
North-West Federal Medical Research Center n.a. V.A. Almazov
Kemerovo Regional Clinical Hospital
BHI of Omsk region Clinical Oncology Dispensary
Complejo Hospitalario de Navarra
Hospital Universitari Vall d'Hebron
Hospital Clinic i Provincial de Barcelona; Hematology
Hospital Universitario 12 de Octubre
Hospital Clinico Universitario de Salamanca
Skånes Universitetssjukhus
Akademiska Sjukhuset
National Taiwan University Hospital
Bristol Haematology and Oncology centre
The Christie
Southampton General Hospital
Singleton Hospital; Pharmacy Department

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

Experimental

Arm Label

Bendamustine + Rituximab

Venetoclax + Rituximab

Bendamustine + Rituximab Crossover Substudy

Venetoclax + Rituximab Re-Treatment

Arm Description

Participants will receive bendamustine 70 milligrams per meter square (mg/m^2) via intravenous (IV) infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 followed by 500 mg/m^2 on Day 1 of Cycles 2-6.

Participants will be initially placed on a venetoclax 5 weeks ramp-up period, and will receive an initial dose of 20 milligrams (mg) via tablet orally once daily (QD). Then the dose will be incremented weekly up to a maximum dose of 400 mg. Participants will then continue receiving venetoclax 400 mg QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards, as directed by the investigator, in combination with rituximab 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 followed by 500 mg/m^2 on Day 1 of Cycles 2-6.

Participants entering the Crossover Substudy will have a 5-week venetoclax dose ramp-up period to reach the target dose of 400 mg QD. Following the venetoclax ramp-up period, Participants will receive 6 cycles of rituximab consisting of a single infusion on the first day of each 28-day cycle. Participants will continue to take their daily dose of venetoclax during the rituximab cycles. Participants who have not progressed following the completion of the 6 cycles will continue to receive venetoclax monotherapy until disease progression or for a maximum of 2 years from Cycle 1 Crossover Day 1 of the Substudy.

Participants entering the Re-Treatment Substudy will have a 5-week venetoclax dose ramp-up period to reach the target dose of 400 mg QD. Following the venetoclax ramp-up period, Participants will receive 6 cycles of rituximab consisting of a single infusion on the first day of each 28-day cycle. Participants will continue to take their daily dose of venetoclax during the rituximab cycles. Participants who have not progressed following the completion of the 6 cycles will continue to receive venetoclax monotherapy until disease progression or for a maximum of 2 years from Cycle 1 Re-Treatment Day 1 of the Substudy.

Outcomes

Primary Outcome Measures

Percentage of Participants With PD as Assessed by the Investigator Using Standard International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Guidelines or Death

Assessment of response was performed by the investigator according to the iwCLL guidelines. PD was defined as occurrence of one of the following events: appearance of any new extra nodal lesion; new palpable lymph node (greater than [>] 1.5 centimeters [cm]); unequivocal progression of non-target lesion; an increase of greater than or equal to (>/=) 50 percent (%) compared to baseline in splenomegaly, hepatomegaly, number of blood lymphocytes with lymphocyte count >/=5000 per microliter (mcL), or in longest diameter of any extra nodal lesion; transformation to a more aggressive histology; decrease of >/=50% compared to baseline in platelet or neutrophil count; or decrease in hemoglobin level by >2 grams per deciliter (g/dL) or to less than [<] 10 g/dL. Percentages are rounded off.

Progression-Free Survival (PFS) as Assessed by the Investigator Using Standard iwCLL Guidelines

PFS was defined as the time from randomization until first occurrence of PD/relapse as assessed by the investigator using iwCLL guidelines, or death from any cause, whichever occurred first. PD: occurrence of one of the following: new lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; increase of >/=50% in splenomegaly, hepatomegaly, blood lymphocytes with count >/=5000/mcL, longest diameter of any lesion; transformation to more aggressive histology; decrease of >/=50% in platelet or neutrophil count, or hemoglobin level by >2 g/dL or to <10 g/dL. Participants who had not progressed, relapsed, or died at the time of analysis, were censored on the date of last assessment. In case of no disease assessment after baseline, PFS was censored at the time of randomization+1 day. The median PFS was estimated using Kaplan-Meier method and the 95% confidence interval (CI) was computed using method of Brookmeyer and Crowley.

Secondary Outcome Measures

Percentage of Participants With PD or Death as Assessed by the Independent Review Committee (IRC) Using Standard iwCLL Guidelines

Assessment of response was performed by the IRC according to the iwCLL guidelines. PD was defined as occurrence of one of the following events: appearance of any new extra nodal lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; an increase of >/=50% compared to baseline in splenomegaly, hepatomegaly, number of blood lymphocytes with lymphocyte count >/=5000/mcL, or in longest diameter of any extra nodal lesion; transformation to a more aggressive histology; decrease of >/=50% compared to baseline in platelet or neutrophil count; or decrease in hemoglobin level by >2 g/dL or to <10 g/dL. No new IRC data was generated post the primary analysis.

PFS as Assessed by the IRC Using Standard iwCLL Guidelines

PFS was defined as the time from randomization until first occurrence of PD/relapse as assessed by the IRC using iwCLL guidelines, or death from any cause, whichever occurred first. PD: occurrence of one of the following: new lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; increase of >/=50% in splenomegaly, hepatomegaly, blood lymphocytes with count >/=5000/mcL, longest diameter of any lesion; transformation to more aggressive histology; decrease of >/=50% in platelet or neutrophil count, or hemoglobin level by >2 g/dL or to <10 g/dL. Participants who had not progressed, relapsed, or died at the time of analysis, were censored on the date of last assessment. In case of no disease assessment after baseline, PFS was censored at the time of randomization+1 day. The median PFS was estimated using Kaplan-Meier method and the 95% CI was computed using method of Brookmeyer and Crowley. No new IRC data was generated post the primary analysis.

Percentage of Participants With PD or Death as Assessed by the Investigator Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by Fluorescence In-situ Hybridization (FISH) Test

Assessment of response was performed by the investigator according to the iwCLL guidelines. PD was defined as occurrence of one of the following events: appearance of any new extra nodal lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; an increase of >/=50% compared to baseline in splenomegaly, hepatomegaly, number of blood lymphocytes with lymphocyte count >/=5000/mcL, or in longest diameter of any extra nodal lesion; transformation to a more aggressive histology; decrease of >/=50% compared to baseline in platelet or neutrophil count; or decrease in hemoglobin level by >2 g/dL or to <10 g/dL. Percentages are rounded off.

PFS as Assessed by the Investigator Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test

PFS was defined as the time from randomization until first occurrence of PD/relapse as assessed by the investigator using iwCLL guidelines, or death from any cause, whichever occurred first. PD: occurrence of one of the following: new lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; increase of >/=50% in splenomegaly, hepatomegaly, blood lymphocytes with count >/=5000/mcL, longest diameter of any lesion; transformation to more aggressive histology; decrease of >/=50% in platelet or neutrophil count, or hemoglobin level by >2 g/dL or to <10 g/dL. Participants who had not progressed, relapsed, or died at the time of analysis, were censored on the date of last assessment. In case of no disease assessment after baseline, PFS was censored at the time of randomization+1 day. The median PFS was estimated using Kaplan-Meier method and the 95% CI was computed using method of Brookmeyer and Crowley.

Percentage of Participants With PD or Death as Assessed by the IRC Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test

PFS as Assessed by the IRC Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test

Percentage of Participants With Best Overall Response of Complete Response (CR), CR With Incomplete Bone Marrow Recovery (CRi), Nodular Partial Response (nPR), or Partial Response (PR) as Assessed by the Investigator Using iwCLL Guidelines

Response was assessed by investigator according to iwCLL guidelines and was confirmed by repeat assessment >/=4 weeks after initial documentation. CR: peripheral blood lymphocytes <4000/mcL; absence of any new lesion, nodal disease, lymphadenopathy, hepatomegaly, splenomegaly, and constitutional symptoms; neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL without need for transfusion or exogenous growth factors; normocellular bone marrow with <30% lymphocytes; no lymphoid nodules. CRi: fulfilling all CR criteria but persistent cytopenia. PR: >/=50% reduction in two of following: peripheral blood lymphocytes, lymphadenopathy, spleen and/or liver enlargement; and 1 of following: neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL or >/=50% improvement without need for transfusion or exogenous growth factors. nPR: fulfilling all CR criteria but presence of lymphoid nodules. 95% CI was computed using Pearson-Clopper method.Percentages are rounded off.

Percentage of Participants With Best Overall Response of CR, CRi, nPR, or PR as Assessed by the IRC Using iwCLL Guidelines

Response was assessed by IRC according to iwCLL guidelines and was confirmed by repeat assessment >/=4 weeks after initial documentation. CR: peripheral blood lymphocytes <4000/mcL; absence of any new lesion, nodal disease, lymphadenopathy, hepatomegaly, splenomegaly, constitutional symptoms; neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL without need for transfusion or exogenous growth factors; normocellular bone marrow with <30% lymphocytes; no lymphoid nodules. CRi: fulfilling all CR criteria but persistent cytopenia. PR: >/=50% reduction in 2 of following: peripheral blood lymphocytes, lymphadenopathy, spleen and/or liver enlargement; 1 of following: neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL or >/=50% improvement without need for transfusion or exogenous growth factors. nPR: fulfilling all CR criteria but presence of lymphoid nodules. 95% CI was computed using Pearson-Clopper method.No new IRC data was generated post primary analysis.

Percentage of Participants With Overall Response of CR, Cri, nPR, or PR at End of Combination Treatment Visit as Assessed by the Investigator Using iwCLL Guidelines

Response was assessed by investigator according to iwCLL guidelines and was confirmed by repeat assessment >/=4 weeks after initial documentation. CR: peripheral blood lymphocytes <4000/mcL; absence of any new lesion, nodal disease, lymphadenopathy, hepatomegaly, splenomegaly, and constitutional symptoms; neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL without need for transfusion or exogenous growth factors; normocellular bone marrow with <30% lymphocytes; no lymphoid nodules. CRi: fulfilling all CR criteria but persistent cytopenia. PR: >/=50% reduction in 2 of following: peripheral blood lymphocytes, lymphadenopathy, spleen and/or liver enlargement; and 1 of following: neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL or >/=50% improvement without need for transfusion or exogenous growth factors. nPR: fulfilling all CR criteria but presence of lymphoid nodules. 95% CI was computed using Pearson-Clopper method. Percentages are rounded off.

Percentage of Participants With Overall Response of CR, Cri, nPR, or PR at End of Combination Treatment Visit as Assessed by the IRC Using iwCLL Guidelines

Response was assessed by the IRC according to the iwCLL guidelines and was confirmed by repeat assessment >/=4 weeks after initial documentation. CR: peripheral blood lymphocytes <4000/mcL; absence of any new lesion, nodal disease, lymphadenopathy, hepatomegaly, splenomegaly, and constitutional symptoms; neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL without need for transfusion or exogenous growth factors; normocellular bone marrow with <30% lymphocytes; no lymphoid nodules. CRi: fulfilling all CR criteria but persistent cytopenia. PR: >/=50% reduction in two of the following: peripheral blood lymphocytes, lymphadenopathy, spleen and/or liver enlargement; and one of the following: neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL or >/=50% improvement without need for transfusion or exogenous growth factors. nPR: fulfilling all CR criteria but presence of lymphoid nodules. The 95% CI was computed using Pearson-Clopper method.

Percentage of Participants Who Died

Percentage of participants who died from any cause, during the study, was reported. Percentage is rounded off.

Overall Survival (OS)

OS was defined as the time from the date of randomization to the date of death from any cause. Participants alive at the time of the analysis were censored at the date when they were last known to be alive as documented by the investigator. The median OS was estimated using Kaplan-Meier method and the 95% CI was computed using method of Brookmeyer and Crowley.

Percentage of Participants With PD/Relapse, Start of a New Anti-Chronic Lymphocytic Leukemia (CLL) Therapy, or Death as Assessed by the Investigator Using iwCLL Guidelines

Percentage of participants with PD/relapse, death from any cause, or start of a new non-protocol-specified anti-CLL therapy as assessed by the investigator, during the study, was reported. PD was defined as occurrence of one of the following events: appearance of any new extra nodal lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; an increase of >/=50% compared to baseline in splenomegaly, hepatomegaly, number of blood lymphocytes with lymphocyte count >/=5000/mcL, or in longest diameter of any extra nodal lesion; transformation to a more aggressive histology; decrease of >/=50% compared to baseline in platelet or neutrophil count; or decrease in hemoglobin level by >2 g/dL or to <10 g/dL. Percentages are rounded off.

Event-Free Survival (EFS) as Assessed by the Investigator Using iwCLL Guidelines

EFS was defined as the time from date of randomization until the date of PD/relapse, start of a new non-protocol-specified anti-CLL therapy, or death from any cause, whichever occurred first, as assessed by the investigator. PD: occurrence of one of the following: new lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; increase of >/=50% in splenomegaly, hepatomegaly, blood lymphocytes with count >/=5000/mcL, longest diameter of any lesion; transformation to more aggressive histology; decrease of >/=50% in platelet or neutrophil count, or hemoglobin level by >2 g/dL or to <10 g/dL. Participants without any of the specified event at the time of analysis were censored at the date of last adequate response assessment. In case of no post-baseline response assessment, participants were censored at the randomization date. The median EFS was estimated using Kaplan-Meier method and the 95% CI was computed using method of Brookmeyer and Crowley.

Percentage of Participants With PD or Death Among Participants With Best Overall Response of CR, CRi, nPR, or PR as Assessed by the Investigator Using iwCLL Guidelines

Percentage of participants with PD as assessed by the investigator according to the iwCLL guidelines or death from any cause during the study was reported. PD was defined as occurrence of one of the following events: appearance of any new extra nodal lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; an increase of >/=50% compared to baseline in splenomegaly, hepatomegaly, number of blood lymphocytes with lymphocyte count >/=5000/mcL, or in longest diameter of any extra nodal lesion; transformation to a more aggressive histology; decrease of >/=50% compared to baseline in platelet or neutrophil count; or decrease in hemoglobin level by >2 g/dL or to <10 g/dL. CR, CRi, nPR, and PR have been defined in previous outcomes, and are not repeated here due to space constraint. Percentage is rounded off.

Duration of Responses (DOR) as Assessed by the Investigator Using iwCLL Guidelines

DOR was defined as the time from first occurrence of a documented response of CR, CRi, nPR, or PR until PD/relapse, as assessed by the investigator according to the iwCLL guidelines, or death from any cause. PD: occurrence of one of the following: new lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; increase of >/=50% in splenomegaly, hepatomegaly, blood lymphocytes with count >/=5000/mcL, longest diameter of any lesion; transformation to more aggressive histology; decrease of >/=50% in platelet or neutrophil count, or hemoglobin level by >2 g/dL or to <10 g/dL. Participants without PD or death after response were censored at the last date of adequate response assessment. The median DOR was estimated using Kaplan-Meier method and the 95% CI was computed using method of Brookmeyer and Crowley. CR, CRi, nPR, and PR have been defined in previous outcomes, and are not repeated here due to space constraint.

Percentage of Participants With Start of New Anti-CLL Treatment or Death as Assessed by the Investigator

Percentage of participants with start of new non-protocol-specified anti-CLL therapy, as assessed by the investigator, or death from any cause, during the study, was reported. Percentage is rounded off.

Time to New Anti-CLL Treatment (TTNT) as Assessed by the Investigator

TTNT was defined as the time from randomization until start of new non-protocol-specified anti-CLL treatment or death from any cause. Participants without the event at the time of analysis were censored at the last visit date for this outcome measure analysis. The median TTNT was estimated using Kaplan-Meier method and the 95% CI was computed using method of Brookmeyer and Crowley.

Percentage of Participants With Minimal Residual Disease (MRD) Negativity in Peripheral Blood

MRD-negativity was defined as the presence of <1 malignant B-cell per 10000 normal B-cells in a sample of at least 200000 B-cells, as assessed by the allele specific oligonucleotide polymerase chain reaction (ASO-PCR) and/or flow cytometry technique. Percentage of participants with MRD-negativity was reported. The 95% CI was computed using Pearson-Clopper method. Percentage is rounded off.

Percentage of Participants With MRD Negativity in Bone Marrow

MRD-negativity was defined as the presence of <1 malignant B-cell per 10000 normal B-cells in a sample of at least 200000 B-cells, as assessed flow cytometry technique. Percentage of participants with MRD-negativity was reported. The 95% CI was computed using Pearson-Clopper method. Percentages are rounded off.

Plasma Venetoclax Concentrations

Change From Baseline in Monroe Dunaway (MD) Anderson Symptom Inventory (MDASI) Core Symptom Severity, Module Symptom Severity, and Interference Scores

MDASI is a 25-item validated questionnaire consisting of 2 parts. Part 1: 19-items divided into 2 scales, Core Symptom Severity (average of Questions 1 to 13; total 13 items: pain, fatigue, nausea, disturbed sleep, distress, shortness of breath, remembering things, lack of appetite, drowsiness, dry mouth, sadness, vomiting, and numbness) and Module Symptom Severity (average of Questions 14 to 19; total 6 items: night sweats, fevers and chills, lymph node swelling, diarrhea, bruising easy or bleeding, and constipation). Part 2: 6-items to assess Interference (symptom distress) (average of Questions 20 to 25; total 6 items: general activity, walking, work, mood, relations with other people, and enjoyment of life). Each item was rated from 0 to 10, with lower scores indicating better outcome. Total score for Core Symptom Severity, Module Symptom Severity, and Interference are reported which range from 0 to 10, with lower scores indicating better health-related quality of life (HRQoL).

Change From Baseline in HRQoL as Measured by European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scales Score and Global Health Status/Global Quality-of-Life (QoL) Scale Score

EORTC QLQ-C30 is a validated self-report measure consisting of 30 questions incorporated into 5 functional scales (Physical, Role, Cognitive, Emotional, and Social), 3 symptom scales (fatigue, pain, nausea, and vomiting), a global health status/global QoL scale, and single items (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea). Most questions used 4-point scale (1='Not at all' to 4='Very much'), while 2 questions used 7-point scale (1='very poor' to 7='Excellent'). Scores were averaged, transformed to 0-100 scale; where higher score for functional scales=poor level of functioning; higher score for global health status/global QoL=better HRQoL.

Change From Baseline in HRQoL as Measured by Quality of Life Questionnaire Associated CLL Module (QLQ-CLL16) Multi-Item Scales Score

The EORTC QLQ-CLL16 module is designed for participants with Stage 0 to Stage 4 CLL. It is composed of 16 questions and there are four multi-item scales on Fatigue (2 items), Treatment-related side effects (TRSE, 4 items), Disease-related symptoms (DRS, 4 items), and Infection (4 items); and two single-item scales on social activities and future health worries. Multi-item scales score are reported and the total score for each multi-item scale was transformed to result in a total score range of 0 to 100, where higher score = poor HRQoL.

Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

An AE was defined as any untoward medical occurrence in a participant administered with Mircera and which does not necessarily have a causal relationship with Mircera. A Serious Adverse Event (SAE) is any significant hazard, contraindication, side effect that is fatal or life threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is medically significant or requires intervention to prevent one or other of the outcomes listed above. AEs were assessed using National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI CTCAE, v4.0)

Number of Participants With Grade 3 or Higher Tumor Lysis Syndrome (TLS) and Infusion-related Reactions (IRRs)

An AE was defined as any untoward medical occurrence in a participant administered with Mircera and which does not necessarily have a causal relationship with Mircera. A SAE is any significant hazard, contraindication, side effect that is fatal or life threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is medically significant or requires intervention to prevent one or other of the outcomes listed above. TLS and IRRs were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v4.0). Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe or medically significant; Grade 4 = Life-threatening; Grade 5 = Death. A higher grade indicates a worse outcome.

Full Information

NCT ID

NCT02005471

First Posted

December 4, 2013

Last Updated

September 22, 2023

Sponsor

Hoffmann-La Roche

Collaborators

AbbVie

1. Study Identification

Unique Protocol Identification Number

NCT02005471

Brief Title

A Study to Evaluate the Benefit of Venetoclax Plus Rituximab Compared With Bendamustine Plus Rituximab in Participants With Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)

Acronym

MURANO

Official Title

A Multicenter, Phase III, Open-Label, Randomized Study in Relapsed/Refractory Patients With Chronic Lymphocytic Leukemia to Evaluate the Benefit of Venetoclax (GDC-0199/ABT-199) Plus Rituximab Compared With Bendamustine Plus Rituximab

Study Type

Interventional

2. Study Status

Record Verification Date

September 2023

Overall Recruitment Status

Completed

Study Start Date

March 17, 2014 (Actual)

Primary Completion Date

May 8, 2017 (Actual)

Study Completion Date

August 3, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Hoffmann-La Roche

Collaborators

AbbVie

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The purpose of this open-label, multicenter, randomized, Phase III study is to evaluate the benefit of venetoclax in combination with rituximab compared with bendamustine in combination with rituximab in participants with relapsed or refractory CLL. Participants will be randomly assigned in 1:1 ratio to receive either venetoclax + rituximab (Arm A) or bendamustine + rituximab (Arm B).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Chronic Lymphocytic Leukemia

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

389 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Bendamustine + Rituximab

Arm Type

Active Comparator

Arm Description

Arm Title

Venetoclax + Rituximab

Arm Type

Experimental

Arm Description

Arm Title

Bendamustine + Rituximab Crossover Substudy

Arm Type

Experimental

Arm Description

Arm Title

Venetoclax + Rituximab Re-Treatment

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Bendamustine

Intervention Description

Bendamustine will be administered at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle, for 6 cycles.

Intervention Type

Drug

Intervention Name(s)

Venetoclax

Other Intervention Name(s)

GDC-0199, ABT-199

Intervention Description

Venetoclax will be administered at an initial dose of 20 mg via tablet orally QD, incremented weekly up to a maximum dose of 400 mg during a 5-week ramp-up period. Venetoclax will be continued at 400 mg QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to disease progression (PD) or 2 years, whichever occurs first. R/C Substudy: venetoclax will be administered for 5-week dose ramp-up period to reach the target dose of 400 mg QD. Venetoclax will continue to be administered during the rituximab cycles until disease progression or for a maximum of 2 years from Cycle 1R/C Day 1 of the R/C Substudy.

Intervention Type

Drug

Intervention Name(s)

Rituximab

Intervention Description

Rituximab will be administered at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. R/C Substudy: Following the venetoclax ramp-up period, rituximab will be administered for 6 cycles consisting of a single infusion on the first day of each 28-day cycle.

Primary Outcome Measure Information:

Title

Percentage of Participants With PD as Assessed by the Investigator Using Standard International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Guidelines or Death

Description

Time Frame

Baseline up to PD or death from any cause, whichever occurred first (up to approximately 8 years 5 months)

Title

Progression-Free Survival (PFS) as Assessed by the Investigator Using Standard iwCLL Guidelines

Description

Time Frame

Baseline up to PD or death, whichever occurred first (up to approximately 8 years 5 months)

Secondary Outcome Measure Information:

Title

Percentage of Participants With PD or Death as Assessed by the Independent Review Committee (IRC) Using Standard iwCLL Guidelines

Description

Time Frame

Baseline up to PD or death, whichever occurred first (up to approximately 3 years)

Title

PFS as Assessed by the IRC Using Standard iwCLL Guidelines

Description

Time Frame

Baseline up to PD or death, whichever occurred first (up to approximately 3 years)

Title

Description

Assessment of response was performed by the investigator according to the iwCLL guidelines. PD was defined as occurrence of one of the following events: appearance of any new extra nodal lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; an increase of >/=50% compared to baseline in splenomegaly, hepatomegaly, number of blood lymphocytes with lymphocyte count >/=5000/mcL, or in longest diameter of any extra nodal lesion; transformation to a more aggressive histology; decrease of >/=50% compared to baseline in platelet or neutrophil count; or decrease in hemoglobin level by >2 g/dL or to <10 g/dL. Percentages are rounded off.

Time Frame

Baseline up to PD or death, whichever occurred first (up to approximately 8 years 5 months)

Title

PFS as Assessed by the Investigator Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test

Description

PFS was defined as the time from randomization until first occurrence of PD/relapse as assessed by the investigator using iwCLL guidelines, or death from any cause, whichever occurred first. PD: occurrence of one of the following: new lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; increase of >/=50% in splenomegaly, hepatomegaly, blood lymphocytes with count >/=5000/mcL, longest diameter of any lesion; transformation to more aggressive histology; decrease of >/=50% in platelet or neutrophil count, or hemoglobin level by >2 g/dL or to <10 g/dL. Participants who had not progressed, relapsed, or died at the time of analysis, were censored on the date of last assessment. In case of no disease assessment after baseline, PFS was censored at the time of randomization+1 day. The median PFS was estimated using Kaplan-Meier method and the 95% CI was computed using method of Brookmeyer and Crowley.

Time Frame

Baseline up to PD or death, whichever occurred first (up to approximately 8 years 5 months)

Title

Percentage of Participants With PD or Death as Assessed by the IRC Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test

Description

Time Frame

Baseline up to PD or death, whichever occurred first (up to approximately 3 years)

Title

PFS as Assessed by the IRC Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test

Description

Time Frame

Baseline up to PD or death, whichever occurred first (up to approximately 3 years)

Title

Description

Time Frame

Baseline up to approximately 8 years 5 months

Title

Percentage of Participants With Best Overall Response of CR, CRi, nPR, or PR as Assessed by the IRC Using iwCLL Guidelines

Description

Time Frame

Baseline up to last FUV (up to approximately 3 years)

Title

Percentage of Participants With Overall Response of CR, Cri, nPR, or PR at End of Combination Treatment Visit as Assessed by the Investigator Using iwCLL Guidelines

Description

Response was assessed by investigator according to iwCLL guidelines and was confirmed by repeat assessment >/=4 weeks after initial documentation. CR: peripheral blood lymphocytes <4000/mcL; absence of any new lesion, nodal disease, lymphadenopathy, hepatomegaly, splenomegaly, and constitutional symptoms; neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL without need for transfusion or exogenous growth factors; normocellular bone marrow with <30% lymphocytes; no lymphoid nodules. CRi: fulfilling all CR criteria but persistent cytopenia. PR: >/=50% reduction in 2 of following: peripheral blood lymphocytes, lymphadenopathy, spleen and/or liver enlargement; and 1 of following: neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL or >/=50% improvement without need for transfusion or exogenous growth factors. nPR: fulfilling all CR criteria but presence of lymphoid nodules. 95% CI was computed using Pearson-Clopper method. Percentages are rounded off.

Time Frame

End of combination treatment response (EoCTR) visit (8 to 12 weeks after Cycle [C] 6 Day [1]); Cycle length = 28 days

Title

Percentage of Participants With Overall Response of CR, Cri, nPR, or PR at End of Combination Treatment Visit as Assessed by the IRC Using iwCLL Guidelines

Description

Time Frame

EoCTR visit (8 to 12 weeks after C6D1); Cycle length = 28 days

Title

Percentage of Participants Who Died

Description

Percentage of participants who died from any cause, during the study, was reported. Percentage is rounded off.

Time Frame

Baseline up to approximately 8 years 5 months

Title

Overall Survival (OS)

Description

Time Frame

Baseline up to approximately 8 years 5 months

Title

Percentage of Participants With PD/Relapse, Start of a New Anti-Chronic Lymphocytic Leukemia (CLL) Therapy, or Death as Assessed by the Investigator Using iwCLL Guidelines

Description

Time Frame

Baseline up to PD/relapse, start of a new anti-CLL therapy, or death from any cause, whichever occurred first (approximately 8 years 5 months)

Title

Event-Free Survival (EFS) as Assessed by the Investigator Using iwCLL Guidelines

Description

Time Frame

Baseline up to PD/relapse, start of a new anti-CLL therapy, or death from any cause, whichever occurred first (approximately 8 years 5 months)

Title

Percentage of Participants With PD or Death Among Participants With Best Overall Response of CR, CRi, nPR, or PR as Assessed by the Investigator Using iwCLL Guidelines

Description

Time Frame

From time of achieving best overall response until PD or death from any cause, whichever occurred first (up to approximately 8 years 5 months)

Title

Duration of Responses (DOR) as Assessed by the Investigator Using iwCLL Guidelines

Description

Time Frame

From time of achieving best overall response until PD or death from any cause, whichever occurred first (up to approximately 8 years 5 months)

Title

Percentage of Participants With Start of New Anti-CLL Treatment or Death as Assessed by the Investigator

Description

Time Frame

Baseline up to start of new ani-CLL therapy or death, whichever occurred first (up to approximately 8 years 5 months)

Title

Time to New Anti-CLL Treatment (TTNT) as Assessed by the Investigator

Description

Time Frame

Baseline up to start of new ani-CLL therapy or death, whichever occurred first (up to approximately 8 years 5 months)

Title

Percentage of Participants With Minimal Residual Disease (MRD) Negativity in Peripheral Blood

Description

Time Frame

EoCTR visit (8 to 12 weeks after C6D1); Cycle length = 28 days

Title

Percentage of Participants With MRD Negativity in Bone Marrow

Description

Time Frame

EoCTR visit (8 to 12 weeks after C6D1); Cycle length = 28 days

Title

Plasma Venetoclax Concentrations

Time Frame

Pre-dose (0 hour, anytime before venetoclax administration) and 4 hours post-dose on D1 of Cycles 1 and 4; Cycle length = 28 days

Title

Change From Baseline in Monroe Dunaway (MD) Anderson Symptom Inventory (MDASI) Core Symptom Severity, Module Symptom Severity, and Interference Scores

Description

Time Frame

Baseline, Days 1, 8, and 15 of Cycles 1, 2, and 3; Cycle length = 28 days

Title

Description

Time Frame

Baseline, D1 of Cycles 1, 2, 3, 4, 5, 6, STC/EW visit (up to C6D28), EoCTR visit (8 to 12 weeks after C6D1), and FUVs (every 12 weeks after EoCTR up to 3 years); Cycle length = 28 days

Title

Change From Baseline in HRQoL as Measured by Quality of Life Questionnaire Associated CLL Module (QLQ-CLL16) Multi-Item Scales Score

Description

Time Frame

Baseline, D1 of Cycles 1, 2, 3, 4, 5, 6, STC/EW visit (up to C6D28), EoCTR visit (8 to 12 weeks after C6D1), and FUVs (every 12 weeks after EoCTR up to 3 years); Cycle length = 28 days

Title

Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

Description

Time Frame

From signing of informed consent form up to approximately 8 years 5 months

Title

Number of Participants With Grade 3 or Higher Tumor Lysis Syndrome (TLS) and Infusion-related Reactions (IRRs)

Description

Time Frame

From signing of informed consent form up to approximately 8 years 5 months

Other Pre-specified Outcome Measures:

Title

Change From Baseline in Lymphocyte Subset Counts at Specified Time Points

Time Frame

Baseline, C4D14-28, Study Treatment Completion/Early Withdrawal (STC/EW, up to C6D28), EoCTR visit (8 to 12 weeks after C6D1), and at FUVs (every 12 weeks after EoCTR up to 3 years); Cycle length = 28 days

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Diagnosis of CLL per diagnostic criteria for relapsed or refractory CLL per the international workshop on chronic lymphocytic leukemia (iwCLL) guidelines Previously treated with 1-3 lines of therapy (example: completed greater than or equal to [>/=] 2 treatment cycles per therapy), including at least one standard chemotherapy-containing regimen Participants previously treated with bendamustine only if their duration of response was >/= 24 months Eastern Cooperative Oncology Group (ECOG) performance score of less than or equal to (</=) 1 Adequate bone marrow function Adequate renal and hepatic function Participants must use effective birth control throughout study until at least 30 days after study treatment or 1 year after rituximab treatment, whichever is later; female participants must not be pregnant or breast-feeding For participants with the 17p deletion, previously treated with 1-3 lines of therapy, including at least one prior standard chemotherapy-containing regimen or at least one prior alemtuzumab-containing therapy Inclusion Criteria R/C Substudy: Participants randomized to Arm A or Arm B with a confirmed disease progression of CLL per iwCLL criteria Participants who have not received new anti-CLL therapy following disease progression in Arm A or Arm B Adequate renal and hepatic function per laboratory reference range Exclusion Criteria: Transformation of CLL to aggressive non-Hodgkin lymphoma or central nervous system (CNS) involvement by CLL Undergone an allogenic stem cell transplant A history of significant renal, neurologic, psychiatric, endocrine, metabolic, immunologic, cardiovascular or hepatic disease Hepatitis B or C or known human immunodeficiency virus (HIV) positive Receiving warfarin treatment Received an anti-CLL monoclonal antibody within 8 weeks prior to the first dose of study drug Received any anti-cancer or investigational therapy within 28 days prior to the first dose of study drug or has not recovered to less than Grade 2 clinically significant adverse effect(s)/toxicity(ies) of any previous therapy Received cytochrome P450 3A4 (CYP3A4) inhibitors (such as fluconazole, ketoconazole and clarithromycin) or inducers (such as rifampin, carbamazapine, phenytoin, St. John's Wort) within 7 days prior to the first dose of venetoclax History of prior venetoclax treatment Participants with another cancer, history of another cancer considered uncured on in complete remission for <5 years, or currently under treatment for another suspected cancer except non-melanoma skin cancer or carcinoma in situ of the cervix that has been treated or excised and is considered resolved Malabsorption syndrome or other condition that precludes enteral route of administration Other clinically significant uncontrolled condition(s) including, but not limited to, systemic infection (viral, bacterial or fungal) Vaccination with a live vaccine within 28 days prior to randomization Consumed grapefruit or grapefruit products, seville oranges (including marmalade containing seville oranges), or star fruit within 3 days prior to the first dose of study treatment A cardiovascular disability status of New York Heart Association Class >/=3. Class 3 is defined as cardiac disease in which participants are comfortable at rest but have marked limitation of physical activity due to fatigue, palpitations, dyspnea, or anginal pain Major surgery within 30 days prior to the first dose of study treatment A participant who is pregnant or breastfeeding Known allergy to both xanthine oxidase inhibitors and rasburicase Exclusion Criteria R/C Substudy: Transformation of CLL to aggressive NHL (e.g., Richter's transformation, prolymphocytic leukemia, or DLBCL) or CNS involvement by CLL Evidence of other clinically significant uncontrolled condition(s) including, but not limited to, uncontrolled systemic infection (viral, bacterial, or fungal) Development of other malignancy since enrollment into the study, with the exception of curatively treated basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma in situ of the cervix Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia History of severe (i.e., requiring permanent discontinuation of prior rituximab therapy) prior allergic or anaphylactic reactions to rituximab Known HIV positivity Positive test results for chronic hepatitis B infection (defined as positive hepatitis B surface antigen [HbsAg] serology) Positive test results for hepatitis C virus (HCV; HCV antibody serology testing) Requires the use of warfarin (due to potential drug interactions that may potentially increase the exposure of warfarin) Has not recovered to less than Grade 2 clinically significant adverse effect(s)/toxicity(ies) of any previous therapy Received potent CYP3A4 inhibitors (such as fluconazole, ketoconazole, and clarithromycin) within 7 days prior to the first dose of study treatment Received potent CYP3A4 inducers (such as rifampin, carbamazepine, phenytoin, St. John's wort) within 7 days prior to the first dose of study treatment Consumed grapefruit or grapefruit products, Seville oranges (including marmalade containing Seville oranges), or star fruit within 3 days prior to the first dose of study treatment A cardiovascular disability status of New York Heart Association Class >/= 3 A significant history of renal, neurologic, psychiatric, endocrine, metabolic, immunologic, cardiovascular, or hepatic disease that, in the opinion of the investigator, would adversely affect the participants's participation in this study or interpretation of study outcomes Major surgery within 30 days prior to the first dose of study treatment A participant who is pregnant or breastfeeding Malabsorption syndrome or other condition that precludes enteral route of administration Known allergy to both xanthine oxidase inhibitors and rasburicase Vaccination with a live vaccine within 28 days prior to randomization

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Clinical Trials

Organizational Affiliation

Hoffmann-La Roche

Official's Role

Study Director

Facility Information:

Facility Name

University of California San Diego Medical Center

City

La Jolla

State/Province

California

ZIP/Postal Code

92093-5354

Country

United States

Facility Name

Henry Ford Health System

City

Detroit

State/Province

Michigan

ZIP/Postal Code

48202

Country

United States

Facility Name

Memorial Sloan Kettering Cancer Center; Clinical Trials Office

City

New York

State/Province

New York

ZIP/Postal Code

10021

Country

United States

Facility Name

Perlmutter Cancer Center NYU Langone Health

City

New York

State/Province

New York

ZIP/Postal Code

10032

Country

United States

Facility Name

Huntsman Cancer Institute; University of Utah

City

Salt Lake City

State/Province

Utah

ZIP/Postal Code

84112

Country

United States

Facility Name

The Canberra Hospital

City

Garran

State/Province

Australian Capital Territory

ZIP/Postal Code

2065

Country

Australia

Facility Name

Concord Repatriation General Hospital

City

Concord

State/Province

New South Wales

ZIP/Postal Code

2139

Country

Australia

Facility Name

St George Hospital

City

Kogarah, New South Wales

State/Province

New South Wales

ZIP/Postal Code

2217

Country

Australia

Facility Name

Princess Alexandra Hospital

City

Woolloongabba

State/Province

Queensland

ZIP/Postal Code

4102

Country

Australia

Facility Name

Royal Adelaide Hospital

City

Adelaide

State/Province

South Australia

ZIP/Postal Code

5000

Country

Australia

Facility Name

Flinders Medical Centre

City

Bedford Park

State/Province

South Australia

ZIP/Postal Code

5042

Country

Australia

Facility Name

Royal Hobart Hospital

City

Hobart

State/Province

Tasmania

ZIP/Postal Code

7000

Country

Australia

Facility Name

Frankston Hospital

City

Frankston

State/Province

Victoria

ZIP/Postal Code

3199

Country

Australia

Facility Name

Monash Medical Centre; Haematology

City

Melbourne

State/Province

Victoria

ZIP/Postal Code

3168

Country

Australia

Facility Name

Slade Health Pharmacy

City

Mount Waverley

State/Province

Victoria

ZIP/Postal Code

3149

Country

Australia

Facility Name

Peter MacCallum Cancer Center

City

North Melbourne

State/Province

Victoria

ZIP/Postal Code

3051

Country

Australia

Facility Name

Royal Melbourne Hospital

City

Parkville

State/Province

Victoria

ZIP/Postal Code

3050

Country

Australia

Facility Name

The Perth Blood Institute

City

Nedlands

State/Province

Western Australia

ZIP/Postal Code

6009

Country

Australia

Facility Name

Medizinische Universität Innsbruck

City

Innsbruck

ZIP/Postal Code

6020

Country

Austria

Facility Name

LKH - Universitätsklinikum der PMU Salzburg

City

Salzburg

ZIP/Postal Code

5020

Country

Austria

Facility Name

Medizinische Universität Wien

City

Wien

ZIP/Postal Code

1090

Country

Austria

Facility Name

Klinik Ottakring

City

Wien

ZIP/Postal Code

1160

Country

Austria

Facility Name

ZNA Antwerpen; Department Hematology

City

Antwerpen

ZIP/Postal Code

2060

Country

Belgium

Facility Name

Cliniques Universitaires Saint-Luc; Hematology

City

Bruxelles

ZIP/Postal Code

1200

Country

Belgium

Facility Name

AZ Groeninge

City

Kortrijk

ZIP/Postal Code

8500

Country

Belgium

Facility Name

UZ Leuven; Department Hematology

City

Leuven

ZIP/Postal Code

3000

Country

Belgium

Facility Name

CHU UCL Mont-Godinne

City

Mont-godinne

ZIP/Postal Code

5530

Country

Belgium

Facility Name

AZ Delta (Campus Rumbeke)

City

Roeselare

ZIP/Postal Code

8800

Country

Belgium

Facility Name

Foothills Medical Centre; Centre Dept of Medical Clinical Neuroscience

City

Calgary

State/Province

Alberta

ZIP/Postal Code

T2N 2T9

Country

Canada

Facility Name

Juravinski Cancer Clinic

City

Hamilton

State/Province

Ontario

ZIP/Postal Code

L8N 3Z5

Country

Canada

Facility Name

Jewish General Hospital

City

Montreal

State/Province

Quebec

ZIP/Postal Code

H3T 1E2

Country

Canada

Facility Name

Saskatoon City Hospital;Saskatchewan Cancer Centre

City

Saskatoon

State/Province

Saskatchewan

ZIP/Postal Code

S7N 4H4

Country

Canada

Facility Name

Fakultni nemocnice Brno

City

Brno

ZIP/Postal Code

613 00

Country

Czechia

Facility Name

Fakultni nemocnice Hradec Kralove

City

Hradec Kralove

ZIP/Postal Code

500 05

Country

Czechia

Facility Name

Fakultní nemocnice Olomouc

City

Olomouc

ZIP/Postal Code

775 20

Country

Czechia

Facility Name

Fakultni nemocnice Ostrava

City

Ostrava - Poruba

ZIP/Postal Code

708 52

Country

Czechia

Facility Name

Vseobecna fakultni nemocnice v Praze

City

Praha 2

ZIP/Postal Code

128 08

Country

Czechia

Facility Name

Fakultni nemocnice Kralovske Vinohrady

City

Praha

ZIP/Postal Code

100 34

Country

Czechia

Facility Name

Herlev Hospital

City

Herlev

ZIP/Postal Code

2730

Country

Denmark

Facility Name

Rigshospitalet

City

København Ø

ZIP/Postal Code

2100

Country

Denmark

Facility Name

Odense Universitetshospital

City

Odense C

ZIP/Postal Code

5000

Country

Denmark

Facility Name

Sjællands Universitetshospital, Roskilde

City

Roskilde

ZIP/Postal Code

4000

Country

Denmark

Facility Name

Sygehus Lillebælt, Vejle

City

Vejle

ZIP/Postal Code

7100

Country

Denmark

Facility Name

Hôpital Morvan

City

Brest

ZIP/Postal Code

29609

Country

France

Facility Name

Centre Hospitalier Départemental Les Oudairies

City

La Roche sur Yon

ZIP/Postal Code

85925

Country

France

Facility Name

Hopital Claude Huriez - CHU Lille

City

Lille

ZIP/Postal Code

59037

Country

France

Facility Name

Hopital Saint Eloi

City

Montpellier

ZIP/Postal Code

34295

Country

France

Facility Name

CHU Nantes - Hôtel Dieu; Service Assistance Medicale à la Procreation

City

Nantes

ZIP/Postal Code

44093

Country

France

Facility Name

Hopital Robert Debre

City

Paris

ZIP/Postal Code

75019

Country

France

Facility Name

Centre Hospitalier Lyon Sud

City

Pierre Benite

ZIP/Postal Code

69495

Country

France

Facility Name

CHU Poitiers - Hopital La Miletrie

City

Poitiers

ZIP/Postal Code

86000

Country

France

Facility Name

CHU de Rennes - Hopital de Pontchaillo

City

Rennes

ZIP/Postal Code

35033

Country

France

Facility Name

Centre Henri Becquerel

City

Rouen

ZIP/Postal Code

76038

Country

France

Facility Name

Institut Universitaire du Cancer - Oncopole Toulouse (IUCT-O)

City

Toulouse

ZIP/Postal Code

31059

Country

France

Facility Name

CHU Tours - Hôpital Bretonneau

City

Tours

ZIP/Postal Code

37044

Country

France

Facility Name

Hôpital de Brabois Adultes

City

Vandoeuvre-les-nancy

ZIP/Postal Code

54511

Country

France

Facility Name

Universitätsklinikum "Carl Gustav Carus" der Technischen Universität Dresden

City

Dresden

ZIP/Postal Code

01307

Country

Germany

Facility Name

Universitaetsklinikum Freiburg

City

Freiburg

ZIP/Postal Code

79106

Country

Germany

Facility Name

Universitätsklinikum Tübingen

City

Tübingen

ZIP/Postal Code

72076

Country

Germany

Facility Name

Semmelweis Egyetem

City

Budapest

ZIP/Postal Code

1088

Country

Hungary

Facility Name

Orszagos Onkologiai Intezet

City

Budapest

ZIP/Postal Code

1122

Country

Hungary

Facility Name

Debreceni Egyetem Klinikai Központ; B?rgyógyászati Klinika

City

Debrecen

ZIP/Postal Code

4012

Country

Hungary

Facility Name

Somogy Megyei Kaposi Mor Oktato Korhaz

City

Pecs

ZIP/Postal Code

7624

Country

Hungary

Facility Name

Szegedi Tud.Egyetem Szent-Gyorgyi Albert Klin.Kozp.

City

Szeged

ZIP/Postal Code

6720

Country

Hungary

Facility Name

Azienda Ospedaliera Città della Salute e della Scienza di Torino; Radiology

City

Torino

State/Province

Abruzzo

ZIP/Postal Code

10126

Country

Italy

Facility Name

Azienda Ospedaliero Universitaria San Martino

City

Genova

State/Province

Liguria

ZIP/Postal Code

16132

Country

Italy

Facility Name

Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII (Presidio Papa Giovanni XXIII)

City

Bergamo

State/Province

Lombardia

ZIP/Postal Code

24127

Country

Italy

Facility Name

Ospedale San Raffaele

City

Milano

State/Province

Lombardia

ZIP/Postal Code

20132

Country

Italy

Facility Name

Asst Grande Ospedale Metropolitano Niguarda; SC Farmacia Ospedale

City

Milano

State/Province

Lombardia

ZIP/Postal Code

20162

Country

Italy

Facility Name

Azienda Ospedaliero Universitaria Ospedali Riuniti

City

Torrette Di Ancona

State/Province

Marche

ZIP/Postal Code

60126

Country

Italy

Facility Name

Istituto Tumori Giovanni Paolo II IRCCS Ospedale Oncologico Bari

City

Bari

State/Province

Puglia

ZIP/Postal Code

70124

Country

Italy

Facility Name

Azienda Ospedaliera Universitaria Careggi

City

Florence

State/Province

Toscana

ZIP/Postal Code

50134

Country

Italy

Facility Name

Azienda Ospedaliera Di Padova

City

Padova

State/Province

Veneto

ZIP/Postal Code

35128

Country

Italy

Facility Name

Seoul National University Bundang Hospital

City

Seongnam-si

ZIP/Postal Code

463-707

Country

Korea, Republic of

Facility Name

Severance Hospital, Yonsei University Health System

City

Seoul

ZIP/Postal Code

03722

Country

Korea, Republic of

Facility Name

Konkuk University Medical Center

City

Seoul

ZIP/Postal Code

05030

Country

Korea, Republic of

Facility Name

The Catholic University of Korea Seoul St. Mary?s Hospital

City

Seoul

ZIP/Postal Code

6591

Country

Korea, Republic of

Facility Name

Amsterdam UMC, Locatie VUMC; Neurology

City

Amsterdam

ZIP/Postal Code

1081 HV

Country

Netherlands

Facility Name

Amsterdam UMC Location AMC

City

Amsterdam

ZIP/Postal Code

1105 AZ

Country

Netherlands

Facility Name

Albert Schweitzer Ziekenhuis, Dordwijk; Internal Medicine, Hemato-Oncology

City

Dordrecht

ZIP/Postal Code

3318 AT

Country

Netherlands

Facility Name

Medisch Spectrum Twente

City

Enschede

ZIP/Postal Code

7512 KZ

Country

Netherlands

Facility Name

Leids Universitair Medisch Centrum; Cardiology

City

Leiden

ZIP/Postal Code

2333 ZA

Country

Netherlands

Facility Name

Erasmus Medisch Centrum

City

Rotterdam

ZIP/Postal Code

3000 CA

Country

Netherlands

Facility Name

UMC Utrecht

City

Utrecht

ZIP/Postal Code

3508

Country

Netherlands

Facility Name

North Shore Hospital; Haematolgy

City

Auckland

ZIP/Postal Code

1309

Country

New Zealand

Facility Name

Middlemore Hospital

City

Auckland

Country

New Zealand

Facility Name

Christchurch Hospital NZ

City

Christchurch

ZIP/Postal Code

8011

Country

New Zealand

Facility Name

Baxter Healthcare

City

Mount Wellington

ZIP/Postal Code

1060

Country

New Zealand

Facility Name

SP ZOZ Zespol Szpitali Miejskich w Chorzowie

City

Chorzow

ZIP/Postal Code

41-500

Country

Poland

Facility Name

Uniwersyteckie Centrum Kliniczne

City

Gdansk

Country

Poland

Facility Name

Wojewódzkie Wielospecjalistyczne Centrum Onkologii i Traumatologii im. M. Kopernika w Lodzi

City

Lodz

ZIP/Postal Code

93-513

Country

Poland

Facility Name

Szpital Wojewodzki w Opolu

City

Opole

ZIP/Postal Code

45-061

Country

Poland

Facility Name

MTZ Clinical Research Sp. z o.o.

City

Warszawa

ZIP/Postal Code

02-106

Country

Poland

Facility Name

Samodzielny Publiczny Szpital Kliniczny nr 1

City

Zabrze

ZIP/Postal Code

44803

Country

Poland

Facility Name

FSBSI "Russian Oncological Scientific Center n.a. N.N. Blokhin"

City

Moscow

State/Province

Moskovskaja Oblast

ZIP/Postal Code

115478

Country

Russian Federation

Facility Name

SRI of Hematology and Transfusiology

City

Sankt-peterburg

State/Province

Sankt Petersburg

ZIP/Postal Code

191024

Country

Russian Federation

Facility Name

North-West Federal Medical Research Center n.a. V.A. Almazov

City

St. Petersburg

State/Province

Sankt Petersburg

ZIP/Postal Code

197341

Country

Russian Federation

Facility Name

Kemerovo Regional Clinical Hospital

City

Kemerovo

ZIP/Postal Code

650066

Country

Russian Federation

Facility Name

BHI of Omsk region Clinical Oncology Dispensary

City

Omsk

ZIP/Postal Code

644013

Country

Russian Federation

Facility Name

Complejo Hospitalario de Navarra

City

Pamplona

State/Province

Navarra

ZIP/Postal Code

31008

Country

Spain

Facility Name

Hospital Universitari Vall d'Hebron

City

Barcelona

ZIP/Postal Code

08035

Country

Spain

Facility Name

Hospital Clinic i Provincial de Barcelona; Hematology

City

Barcelona

ZIP/Postal Code

08036

Country

Spain

Facility Name

Hospital Universitario 12 de Octubre

City

Madrid

ZIP/Postal Code

28041

Country

Spain

Facility Name

Hospital Clinico Universitario de Salamanca

City

Salamanca

ZIP/Postal Code

37007

Country

Spain

Facility Name

Skånes Universitetssjukhus

City

Lund

ZIP/Postal Code

221 85

Country

Sweden

Facility Name

Akademiska Sjukhuset

City

Uppsala

ZIP/Postal Code

751 85

Country

Sweden

Facility Name

National Taiwan University Hospital

City

Taipei

ZIP/Postal Code

10002

Country

Taiwan

Facility Name

Bristol Haematology and Oncology centre

City

Bristol

ZIP/Postal Code

BS2 8ED

Country

United Kingdom

Facility Name

The Christie

City

Manchester

ZIP/Postal Code

M20 4BX

Country

United Kingdom

Facility Name

Southampton General Hospital

City

Southampton

ZIP/Postal Code

SO16 6YD

Country

United Kingdom

Facility Name

Singleton Hospital; Pharmacy Department

City

Swansea

ZIP/Postal Code

SA2 8QA

Country

United Kingdom

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/ourmember/roche/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

Citations:

PubMed Identifier

35829925

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.

Results Reference

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PubMed Identifier

35605176

Citation

Seymour JF, Kipps TJ, Eichhorst BF, D'Rozario J, Owen CJ, Assouline S, Lamanna N, Robak T, de la Serna J, Jaeger U, Cartron G, Montillo M, Mellink C, Chyla B, Panchal A, Lu T, Wu JQ, Jiang Y, Lefebure M, Boyer M, Kater AP. Enduring undetectable MRD and updated outcomes in relapsed/refractory CLL after fixed-duration venetoclax-rituximab. Blood. 2022 Aug 25;140(8):839-850. doi: 10.1182/blood.2021015014.

Results Reference

derived

PubMed Identifier

32986498

Citation

Kater AP, Wu JQ, Kipps T, Eichhorst B, Hillmen P, D'Rozario J, Assouline S, Owen C, Robak T, de la Serna J, Jaeger U, Cartron G, Montillo M, Dubois J, Eldering E, Mellink C, Van Der Kevie-Kersemaekers AM, Kim SY, Chyla B, Punnoose E, Bolen CR, Assaf ZJ, Jiang Y, Wang J, Lefebure M, Boyer M, Humphrey K, Seymour JF. Venetoclax Plus Rituximab in Relapsed Chronic Lymphocytic Leukemia: 4-Year Results and Evaluation of Impact of Genomic Complexity and Gene Mutations From the MURANO Phase III Study. J Clin Oncol. 2020 Dec 1;38(34):4042-4054. doi: 10.1200/JCO.20.00948. Epub 2020 Sep 28.

Results Reference

derived

PubMed Identifier

30523712

Citation

Kater AP, Seymour JF, Hillmen P, Eichhorst B, Langerak AW, Owen C, Verdugo M, Wu J, Punnoose EA, Jiang Y, Wang J, Boyer M, Humphrey K, Mobasher M, Kipps TJ. Fixed Duration of Venetoclax-Rituximab in Relapsed/Refractory Chronic Lymphocytic Leukemia Eradicates Minimal Residual Disease and Prolongs Survival: Post-Treatment Follow-Up of the MURANO Phase III Study. J Clin Oncol. 2019 Feb 1;37(4):269-277. doi: 10.1200/JCO.18.01580. Epub 2018 Dec 3.

Results Reference

derived

PubMed Identifier

29562156

Citation

Seymour JF, Kipps TJ, Eichhorst B, Hillmen P, D'Rozario J, Assouline S, Owen C, Gerecitano J, Robak T, De la Serna J, Jaeger U, Cartron G, Montillo M, Humerickhouse R, Punnoose EA, Li Y, Boyer M, Humphrey K, Mobasher M, Kater AP. Venetoclax-Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. N Engl J Med. 2018 Mar 22;378(12):1107-1120. doi: 10.1056/NEJMoa1713976.

Results Reference

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PubMed Identifier

27233802

Citation

Jones AK, Freise KJ, Agarwal SK, Humerickhouse RA, Wong SL, Salem AH. Clinical Predictors of Venetoclax Pharmacokinetics in Chronic Lymphocytic Leukemia and Non-Hodgkin's Lymphoma Patients: a Pooled Population Pharmacokinetic Analysis. AAPS J. 2016 Sep;18(5):1192-1202. doi: 10.1208/s12248-016-9927-9. Epub 2016 May 27.

Results Reference

derived

Learn more about this trial

A Study to Evaluate the Benefit of Venetoclax Plus Rituximab Compared With Bendamustine Plus Rituximab in Participants With Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)

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