Phase 3
Completed N=389
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)
Source: ClinicalTrials.gov NCT02005471 ↗Enrolled (actual)
389
Serious AEs
48.8%
Results posted
Oct 2018
Primary outcomePrimary: Percentage of Participants With PD as Assessed by the Investigator Using Standard International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Guidelines or Death — 88.7; 70.1 percentage of participants
◆ Published Evidence
Highly cited
300citations · ~43 / year
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.
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).
Linked Publications (5)
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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.
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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.
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Enduring undetectable MRD and updated outcomes in relapsed/refractory CLL after fixed-duration venetoclax-rituximab.
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The MURANO study: final analysis and retreatment/crossover substudy results of VenR for patients with relapsed/refractory CLL.
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Bioavailability Evaluation of Venetoclax Lower-Strength Tablets and Oral Powder Formulations to Establish Interchangeability with the 100 mg Tablet.
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Percentage of Participants With PD as Assessed by the Investigator Using Standard International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Guidelines or Death |
88.7; 70.1 | — |
| PRIMARY Progression-Free Survival (PFS) as Assessed by the Investigator Using Standard iwCLL Guidelines |
17.0; 54.7 | <.0001 sig |
| SECONDARY Percentage of Participants With PD or Death as Assessed by the Independent Review Committee (IRC) Using Standard iwCLL Guidelines |
54.4; 18.0 | — |
| SECONDARY PFS as Assessed by the IRC Using Standard iwCLL Guidelines |
18.1; NA | <.0001 sig |
| SECONDARY 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 |
80.4; 80.4 | — |
| SECONDARY PFS as Assessed by the Investigator Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test |
15.4; 47.9 | <.0001 sig |
| SECONDARY 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 |
47.8; 19.6 | — |
| SECONDARY PFS as Assessed by the IRC Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test |
16.1; NA | <.0001 sig |
| SECONDARY 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 |
8.2; 26.3; 0.5; 1.5; 6.2; 3.6 | <.0001 sig |
| SECONDARY Percentage of Participants With Best Overall Response of CR, CRi, nPR, or PR as Assessed by the IRC Using iwCLL Guidelines |
67.7; 93.3 | <.0001 sig |
| SECONDARY 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 |
63.1; 88.1 | <.0001 sig |
| SECONDARY 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 |
62.6; 87.1 | <.0001 sig |
| SECONDARY Percentage of Participants Who Died |
43.1; 30.9 | — |
| SECONDARY Overall Survival (OS) |
87.8; NA | 0.0002 sig |
| SECONDARY 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 |
89.2; 71.1 | — |
| SECONDARY Event-Free Survival (EFS) as Assessed by the Investigator Using iwCLL Guidelines |
16.4; 53.7 | <.0001 sig |
| SECONDARY 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 |
95.5; 68.5 | — |
| SECONDARY Duration of Responses (DOR) as Assessed by the Investigator Using iwCLL Guidelines |
19.1; 53.6 | — |
| SECONDARY Percentage of Participants With Start of New Anti-CLL Treatment or Death as Assessed by the Investigator |
81.5; 62.4 | — |
| SECONDARY Time to New Anti-CLL Treatment (TTNT) as Assessed by the Investigator |
24.0; 63.0 | <.0001 sig |
| SECONDARY Percentage of Participants With Minimal Residual Disease (MRD) Negativity in Peripheral Blood |
13.3; 62.4 | <.0001 sig |
| SECONDARY Percentage of Participants With MRD Negativity in Bone Marrow |
1.0; 14.4 | <.0001 sig |
| SECONDARY Plasma Venetoclax Concentrations |
0.626; 1.34; 0.681; 1.34 | — |
| SECONDARY Change From Baseline in Monroe Dunaway (MD) Anderson Symptom Inventory (MDASI) Core Symptom Severity, Module Symptom Severity, and Interference Scores |
1.76; 1.55; 0.00; -0.08; 0.26; -0.30 | — |
| SECONDARY 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 |
82.59; 83.77; 0.0; 1.39; 0.31; 2.99 | — |
| SECONDARY Change From Baseline in HRQoL as Measured by Quality of Life Questionnaire Associated CLL Module (QLQ-CLL16) Multi-Item Scales Score |
14.29; 9.42; 0.0; 0.12; 1.62; 0.62 | — |
| SECONDARY Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) |
185; 194; 84; 101 | — |
| SECONDARY Number of Participants With Grade 3 or Higher Tumor Lysis Syndrome (TLS) and Infusion-related Reactions (IRRs) |
2; 6; 10; 4 | — |
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 ( /=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
Data sourced from ClinicalTrials.gov (NCT02005471) and the linked publication. Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication. Informational only — not medical advice.