A Study of Ibrutinib in Combination With Bendamustine and Rituximab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
Randomized, Double-blind, Placebo-controlled Phase 3 Study of Ibrutinib, a Bruton's Tyrosine Kinase (BTK) Inhibitor, in Combination With Bendamustine and Rituximab (BR) in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
4 other identifiers
interventional
578
21 countries
155
Brief Summary
The purpose of this study is to examine the safety and efficacy of Ibrutinib administered in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_3
Started Sep 2012
Longer than P75 for phase_3
155 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
May 15, 2012
CompletedFirst Posted
Study publicly available on registry
June 4, 2012
CompletedStudy Start
First participant enrolled
September 19, 2012
CompletedPrimary Completion
Last participant's last visit for primary outcome
January 23, 2019
CompletedStudy Completion
Last participant's last visit for all outcomes
January 23, 2019
CompletedResults Posted
Study results publicly available
March 3, 2020
CompletedMarch 3, 2020
February 1, 2020
6.3 years
May 15, 2012
January 23, 2020
February 20, 2020
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
Progression-free Survival (PFS)
PFS was defined as the interval between the date of randomization and the date of disease progression or death, whichever was first reported. IWCLL 2008 criteria for PD: New enlarged nodes \>1.5 cm, new hepatomegaly or splenomegaly, or other new organ infiltrates, bone lesion, ascites, or pleural effusion confirmed due to chronic lymphocytic leukemia (CLL); \>=50% increase in existing lymph nodes; \>=50% increase in enlargement of liver or spleen; \>=50% increase from baseline in lymphocyte count (and to \>=5\*10\^9/L) or \>=50% increase from nadir count confirmed on \>=2 serial assessments if absolute lymphocyte count (ALC) \>=30,000 per microliter and lymphocyte doubling time is rapid, unless considered treatment-related lymphocytosis; new cytopenia (Hemoglobin b \[Hgb\] or platelets) attributable to CLL; and transformation to a more aggressive histology.
Up to 5 years
Secondary Outcomes (13)
Overall Response Rate (ORR)
Up to 5 years
Overall Survival (OS)
Up to 5 years
Percentage of Participants With Minimal Residual Disease (MRD)-Negative Response
Up to 5 years
Percentage of Participants With Sustained Hematologic Improvement
Up to 5 years
Median Time to Clinically Meaningful Improvement in FACIT-Fatigue Scale
Up to 2 years
- +8 more secondary outcomes
Study Arms (2)
Ibrutinib + BR
EXPERIMENTALIbrutinib 420 mg will be administered orally once daily on a continuous schedule. All subjects will receive background therapy with bendamustine and rituximab (BR) for a maximum of 6 cycles (a cycle is defined as 28 days, with the exception of Cycle 1, which will be 29 days to allow for rituximab dosing prior to bendamustine and study medication).
Placebo + BR
PLACEBO COMPARATORMatching placebo will be administered orally once daily on a continuous schedule. All subjects will receive background therapy with BR for a maximum of 6 cycles (a cycle is defined as 28 days, with the exception of Cycle 1, which will be 29 days to allow for rituximab dosing prior to bendamustine and study medication).
Interventions
Type=exact number, unit=mg, number=420 , form=capsule, route=oral use. Capsule is taken once daily continuously.
Type=exact number, unit=mg, number=70 mg/m2, route=intravenous use. Administered intravenously on Cycle 1, Days 2-3 and Cycles 2-6, Days 1-2.
Type=exact number, unit=mg, number=375 mg/m2 and 500 mg/m2, route=intravenous use. Administered intravenously on Cycle 1, Day 1, and Cycles 2-6, Day 1, respectively.
Eligibility Criteria
You may qualify if:
- Diagnosis of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) that meets protocol-defined criteria
- Active disease meeting at least 1 of the International Workshop on Chronic Lymphocytic Leukemia 2008 criteria for requiring treatment
- Measurable nodal disease by computed tomography
- Relapsed or refractory CLL or SLL following at least 1 prior line of systemic therapy consisting of at least 2 cycles of a chemotherapy-containing regimen
- Eastern Cooperative Oncology Group Performance Status score of 0 or 1
- Hematology and biochemical values within protocol-defined limits
- Agrees to protocol-defined use of effective contraception
- Women of childbearing potential must have negative blood or urine pregnancy test at screening
You may not qualify if:
- Recent therapeutic interventions within 3 (chemotherapy/radiotherapy) to 10 weeks (immunotherapy)
- Prior treatment with ibrutinib or other Bruton's tyrosine kinase inhibitors or prior randomization in any other clinical study evaluating ibrutinib
- The presence of deletion of the short arm of chromosome 17
- Patients previously treated with a bendamustine-containing regimen who did not achieve a response or who relapsed and required treatment within 24 months of treatment with that regimen
- Patients for whom the goal of therapy is tumor debulking prior to stem cell transplant
- Received a hematopoietic stem cell transplant
- Known central nervous system leukemia/lymphoma or Richter's transformation
- Patients with uncontrolled autoimmune hemolytic anemia or autoimmune thrombocytopenia
- Chronic use of corticosteroids
- History of prior malignancy, except: malignancy treated with curative intent and with no known active disease present for \>=3 years before randomization; adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease; adequately treated cervical carcinoma in situ without evidence of disease
- History of stroke or intracranial hemorrhage within 6 months prior to randomization; or clinically significant cardiovascular disease
- Requires anticoagulation with warfarin or equivalent vitamin K antagonists or treatment with strong CYP3A4/5 inhibitors
- Known history of human immunodeficiency virus or hepatitis C, or active infection with hepatitis B or C
- Any uncontrolled active systemic infection or any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the patient's safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk
- A woman who is pregnant or breast feeding, or a man who plans to father a child while enrolled in this study or within 3 months after the last dose of study drug
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- Janssen Research & Development, LLClead
- Pharmacyclics LLC.collaborator
Study Sites (155)
Unknown Facility
Birmingham, Alabama, United States
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Phoenix, Arizona, United States
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Berkeley, California, United States
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Duarte, California, United States
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Greenbrae, California, United States
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Stamford, Connecticut, United States
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Washington D.C., District of Columbia, United States
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Boca Raton, Florida, United States
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Jacksonville, Florida, United States
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Atlanta, Georgia, United States
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Marietta, Georgia, United States
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Chicago, Illinois, United States
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Springfield, Illinois, United States
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Fort Wayne, Indiana, United States
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Goshen, Indiana, United States
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Indianapolis, Indiana, United States
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Iowa City, Iowa, United States
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Westwood, Kansas, United States
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Louisville, Kentucky, United States
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Paducah, Kentucky, United States
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Marrero, Louisiana, United States
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Baltimore, Maryland, United States
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Worcester, Massachusetts, United States
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Ann Arbor, Michigan, United States
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Battle Creek, Michigan, United States
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Detroit, Michigan, United States
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Lansing, Michigan, United States
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St Louis, Missouri, United States
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Lincoln, Nebraska, United States
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Lebanon, New Hampshire, United States
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Hackensack, New Jersey, United States
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Albuquerque, New Mexico, United States
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Dunkirk, New York, United States
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Hawthorne, New York, United States
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New York, New York, United States
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Bismarck, North Dakota, United States
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Cleveland, Ohio, United States
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Portland, Oregon, United States
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Charleston, South Carolina, United States
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Sioux Falls, South Dakota, United States
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Temple, Texas, United States
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Morgantown, West Virginia, United States
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Buenos Aires, Argentina
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Ciudad Autonoma Buenos Aires, Argentina
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Córdoba, Argentina
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Aalst, Belgium
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Bruges, Belgium
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Brussels, Belgium
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Ghent, Belgium
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Leuven, Belgium
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Rio de Janeiro, Brazil
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Salvador, Brazil
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São Paulo, Brazil
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Edmonton, Alberta, Canada
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Vancouver, British Columbia, Canada
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Hamilton, Ontario, Canada
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London, Ontario, Canada
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Ottawa, Ontario, Canada
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Toronto, Ontario, Canada
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Montreal, Quebec, Canada
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Bogotá, Colombia
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Floridablanca, Colombia
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Brno, Czechia
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Prague, Czechia
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Créteil, France
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Montpellier, France
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Paris, France
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Pessac, France
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Pierre-Bénite, France
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Tours, France
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Villejuif, France
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Aschaffenburg, Germany
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Augsburg, Germany
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Cologne, Germany
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Dresden, Germany
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Erlangen, Germany
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Essen, Germany
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Frankfurt, Germany
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Frechen, Germany
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Hamm, Germany
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Heidelberg, Germany
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Homburg/Saar, Germany
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Kassel, Germany
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Kiel, Germany
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Koblenz, Germany
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Kÿln N/a, Germany
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Lebach, Germany
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Magdeburg, Germany
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Mannheim, Germany
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Marburg, Germany
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Mutlangen, Germany
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Ulm, Germany
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Würzburg, Germany
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Athens, Greece
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Thessalonikis, Greece
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Haifa, Israel
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Jerusalem, Israel
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Nahariya, Israel
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Netanya, Israel
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Petah Tikva, Israel
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Ramat Gan, Israel
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Tel Aviv, Israel
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México, Mexico
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Monterrey, Mexico
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Oaxaca City, Mexico
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Brzozów, Poland
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Chorzów, Poland
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Krakow, Poland
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Opole, Poland
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Słupsk, Poland
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Coimbra, Portugal
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Lisbon, Portugal
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Ponta Delgada, Portugal
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Porto, Portugal
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Arkhangelsk, Russia
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Dzerzhinsk, Russia
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Krasnodar, Russia
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Moscow, Russia
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Nizhny Novgorod, Russia
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Obninsk, Russia
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Perm, Russia
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Rostov-on-Don, Russia
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Ryazan, Russia
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Saint Petersburg, Russia
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Samara, Russia
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Sochi, Russia
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Syktyvkar, Russia
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Yekaterinburg, Russia
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Seoul, South Korea
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Barcelona, Spain
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L'Hospitalet de Llobregat, Spain
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Madrid, Spain
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Salamanca, Spain
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Valencia, Spain
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Gothenburg, Sweden
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Huddinge, Sweden
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Stockholm, Sweden
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Umeå, Sweden
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Ankara, Turkey (Türkiye)
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Istanbul, Turkey (Türkiye)
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Izmir, Turkey (Türkiye)
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Kayseri, Turkey (Türkiye)
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Cherkassy, Ukraine
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Dnipro, Ukraine
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Donetsk, Ukraine
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Khakhiv, Ukraine
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Khmelnitskiy, Ukraine
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Kiev, Ukraine
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Lviv, Ukraine
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Vinnitsa, Ukraine
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Birmingham, United Kingdom
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Harrow, United Kingdom
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Plymouth, United Kingdom
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Sheffield Yorks, United Kingdom
Unknown Facility
Sutton, United Kingdom
Related Publications (5)
Abuhelwa AY, Almansour SA, Brown JR, Al-Shamsi HO, Abuhelwa Z, Kharaba Z, Bustanji Y, Semreen MH, Ali S, Alhuraiji A, McKinnon RA, Sorich MJ, Alzoubi KH, Hopkins AM. Statin use and survival in CLL/SLL treated with ibrutinib: pooled analysis of 4 randomized controlled trials. Blood Adv. 2025 Jul 22;9(14):3566-3575. doi: 10.1182/bloodadvances.2024015287.
PMID: 40266025DERIVEDFraser GAM, Chanan-Khan A, Demirkan F, Santucci Silva R, Grosicki S, Janssens A, Mayer J, Bartlett NL, Dilhuydy MS, Loscertales J, Avigdor A, Rule S, Samoilova O, Pavlovsky MA, Goy A, Mato A, Hallek M, Salman M, Tamegnon M, Sun S, Connor A, Nottage K, Schuier N, Balasubramanian S, Howes A, Cramer P. Final 5-year findings from the phase 3 HELIOS study of ibrutinib plus bendamustine and rituximab in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Leuk Lymphoma. 2020 Dec;61(13):3188-3197. doi: 10.1080/10428194.2020.1795159. Epub 2020 Aug 6.
PMID: 32762271DERIVEDLavezzi SM, de Jong J, Neyens M, Cramer P, Demirkan F, Fraser G, Bartlett N, Dilhuydy MS, Loscertales J, Avigdor A, Rule S, Samoilova O, Goy A, Ganguly S, Salman M, Howes A, Mahler M, De Nicolao G, Poggesi I. Systemic Exposure of Rituximab Increased by Ibrutinib: Pharmacokinetic Results and Modeling Based on the HELIOS Trial. Pharm Res. 2019 May 1;36(7):93. doi: 10.1007/s11095-019-2605-8.
PMID: 31044267DERIVEDBrown JR, Moslehi J, O'Brien S, Ghia P, Hillmen P, Cymbalista F, Shanafelt TD, Fraser G, Rule S, Kipps TJ, Coutre S, Dilhuydy MS, Cramer P, Tedeschi A, Jaeger U, Dreyling M, Byrd JC, Howes A, Todd M, Vermeulen J, James DF, Clow F, Styles L, Valentino R, Wildgust M, Mahler M, Burger JA. Characterization of atrial fibrillation adverse events reported in ibrutinib randomized controlled registration trials. Haematologica. 2017 Oct;102(10):1796-1805. doi: 10.3324/haematol.2017.171041. Epub 2017 Jul 27.
PMID: 28751558DERIVEDChanan-Khan A, Cramer P, Demirkan F, Fraser G, Silva RS, Grosicki S, Pristupa A, Janssens A, Mayer J, Bartlett NL, Dilhuydy MS, Pylypenko H, Loscertales J, Avigdor A, Rule S, Villa D, Samoilova O, Panagiotidis P, Goy A, Mato A, Pavlovsky MA, Karlsson C, Mahler M, Salman M, Sun S, Phelps C, Balasubramanian S, Howes A, Hallek M; HELIOS investigators. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol. 2016 Feb;17(2):200-211. doi: 10.1016/S1470-2045(15)00465-9. Epub 2015 Dec 5.
PMID: 26655421DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Limitations and Caveats
Study was planned to end when 80% of randomized participants died or 5 years after last participant randomized, whichever was first. Sponsor terminated study on 23-Jan-2019 (5 year after last participant randomized) and study was considered completed
Results Point of Contact
- Title
- Medical Director Clinical Research
- Organization
- Janssen Research & Development, LLC
Study Officials
- STUDY DIRECTOR
Janssen Research & Development, LLC Clinical Trial
Janssen Research & Development, LLC
Publication Agreements
- PI is Sponsor Employee
- No
- Restriction Type
- OTHER
- Restrictive Agreement
- Yes
Study Design
- Study Type
- interventional
- Phase
- phase 3
- Allocation
- RANDOMIZED
- Masking
- TRIPLE
- Who Masked
- PARTICIPANT, CARE PROVIDER, INVESTIGATOR
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- INDUSTRY
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
May 15, 2012
First Posted
June 4, 2012
Study Start
September 19, 2012
Primary Completion
January 23, 2019
Study Completion
January 23, 2019
Last Updated
March 3, 2020
Results First Posted
March 3, 2020
Record last verified: 2020-02