A Study of Ibrutinib in Combination With Bendamustine and Rituximab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

NCT ID: NCT01611090

Last Updated: 2020-03-03

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 578 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-09-19
• Study Completion Date: 2019-01-23

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).

Detailed Description

This is a randomized (patients will be assigned by chance to study treatments), double-blind (patients and study personnel will not know the identity of study treatments), placebo (an inactive substance that is compared with a drug to test whether the drug has a real effect in a clinical trial)-controlled study to determine the benefits and risks of combining ibrutinib with bendamustine and rituximab (BR) in patients with relapsed or refractory CLL/SLL following at least 1 line of prior systemic therapy. Approximately 580 patients will be randomized in a 1:1 ratio to either treatment arm A (placebo) or treatment arm B (ibrutinib 420 mg).

Study medication will be administered orally once daily on a continuous schedule. All patients will receive BR as the background therapy plus either ibrutinib or placebo for a maximum of 6 cycles, after which treatment with ibrutinib or placebo will continue until disease progression or unacceptable toxicity.

A treatment cycle will be defined as 28 days. The study will include a screening phase, a treatment phase, and a follow-up phase. Study end is defined as when either 80% of the patients have died or 5 years after the last patient is randomized into the study, whichever occurs first.

Patients in treatment arm A (placebo) who complete the treatment phase, with disease progression or (after interim analysis) meet International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria for treatment, may crossover to ibrutinib treatment (as in treatment arm B), at the investigators discretion. This open-label, next-line treatment with ibrutinib will continue until disease progression, unacceptable toxicity, withdrawal from study, or until the study end, whichever occurs earlier. One interim analysis is planned for the study. Efficacy evaluations will include computed tomography scans, laboratory testing, focused physical examinations, bone marrow biopsy and aspirate, and assessment of patient-reported outcomes. In both treatment arms, samples for the development of a population-based pharmacokinetic (PK; study of what the body does to a drug) approach will be collected. Safety will be assessed throughout the study.

Conditions

Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Ibrutinib + BR

Ibrutinib 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).

Group Type: EXPERIMENTAL

Ibrutinib

Intervention Type: DRUG

Type=exact number, unit=mg, number=420 , form=capsule, route=oral use. Capsule is taken once daily continuously.

Bendamustine hydrochloride

Intervention Type: DRUG

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.

Rituximab

Intervention Type: DRUG

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.

Placebo + BR

Matching 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).

Group Type: PLACEBO_COMPARATOR

Bendamustine hydrochloride

Intervention Type: DRUG

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.

Rituximab

Intervention Type: DRUG

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.

Placebo

Intervention Type: DRUG

Form=capsule, route=oral use. Capsule is taken once daily continuously.

Interventions

Ibrutinib

Type=exact number, unit=mg, number=420 , form=capsule, route=oral use. Capsule is taken once daily continuously.

Intervention Type: DRUG

Bendamustine hydrochloride

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.

Intervention Type: DRUG

Rituximab

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.

Intervention Type: DRUG

Placebo

Form=capsule, route=oral use. Capsule is taken once daily continuously.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• 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

Exclusion Criteria

• 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Pharmacyclics LLC.

INDUSTRY

Sponsor Role: collaborator

Janssen Research & Development, LLC

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Janssen Research & Development, LLC Clinical Trial

Role: STUDY_DIRECTOR

Janssen Research & Development, LLC

Locations

Birmingham, Alabama, United States

Phoenix, Arizona, United States

Berkeley, California, United States

Duarte, California, United States

Greenbrae, California, United States

Stamford, Connecticut, United States

Washington D.C., District of Columbia, United States

Boca Raton, Florida, United States

Jacksonville, Florida, United States

Atlanta, Georgia, United States

Marietta, Georgia, United States

Chicago, Illinois, United States

Springfield, Illinois, United States

Fort Wayne, Indiana, United States

Goshen, Indiana, United States

Indianapolis, Indiana, United States

Iowa City, Iowa, United States

Westwood, Kansas, United States

Louisville, Kentucky, United States

Paducah, Kentucky, United States

Marrero, Louisiana, United States

Baltimore, Maryland, United States

Worcester, Massachusetts, United States

Ann Arbor, Michigan, United States

Battle Creek, Michigan, United States

Detroit, Michigan, United States

Lansing, Michigan, United States

St Louis, Missouri, United States

Lincoln, Nebraska, United States

Lebanon, New Hampshire, United States

Hackensack, New Jersey, United States

Albuquerque, New Mexico, United States

Dunkirk, New York, United States

Hawthorne, New York, United States

New York, New York, United States

Bismarck, North Dakota, United States

Cleveland, Ohio, United States

Portland, Oregon, United States

Charleston, South Carolina, United States

Sioux Falls, South Dakota, United States

Temple, Texas, United States

Morgantown, West Virginia, United States

Buenos Aires, , Argentina

Ciudad Autonoma Buenos Aires, , Argentina

Córdoba, , Argentina

Aalst, , Belgium

Bruges, , Belgium

Brussels, , Belgium

Ghent, , Belgium

Leuven, , Belgium

Rio de Janeiro, , Brazil

Salvador, , Brazil

São Paulo, , Brazil

Edmonton, Alberta, Canada

Vancouver, British Columbia, Canada

Hamilton, Ontario, Canada

London, Ontario, Canada

Ottawa, Ontario, Canada

Toronto, Ontario, Canada

Montreal, Quebec, Canada

Bogotá, , Colombia

Floridablanca, , Colombia

Brno, , Czechia

Prague, , Czechia

Créteil, , France

Montpellier, , France

Paris, , France

Pessac, , France

Pierre-Bénite, , France

Tours, , France

Villejuif, , France

Aschaffenburg, , Germany

Augsburg, , Germany

Cologne, , Germany

Dresden, , Germany

Erlangen, , Germany

Essen, , Germany

Frankfurt, , Germany

Frechen, , Germany

Hamm, , Germany

Heidelberg, , Germany

Homburg/Saar, , Germany

Kassel, , Germany

Kiel, , Germany

Koblenz, , Germany

Kÿln N/a, , Germany

Lebach, , Germany

Magdeburg, , Germany

Mannheim, , Germany

Marburg, , Germany

Mutlangen, , Germany

Ulm, , Germany

Würzburg, , Germany

Athens, , Greece

Thessalonikis, , Greece

Haifa, , Israel

Jerusalem, , Israel

Nahariya, , Israel

Netanya, , Israel

Petah Tikva, , Israel

Ramat Gan, , Israel

Tel Aviv, , Israel

México, , Mexico

Monterrey, , Mexico

Oaxaca City, , Mexico

Brzozów, , Poland

Chorzów, , Poland

Krakow, , Poland

Opole, , Poland

Słupsk, , Poland

Coimbra, , Portugal

Lisbon, , Portugal

Ponta Delgada, , Portugal

Porto, , Portugal

Arkhangelsk, , Russia

Dzerzhinsk, , Russia

Krasnodar, , Russia

Moscow, , Russia

Nizhny Novgorod, , Russia

Obninsk, , Russia

Perm, , Russia

Rostov-on-Don, , Russia

Ryazan, , Russia

Saint Petersburg, , Russia

Samara, , Russia

Sochi, , Russia

Syktyvkar, , Russia

Yekaterinburg, , Russia

Seoul, , South Korea

Barcelona, , Spain

L'Hospitalet de Llobregat, , Spain

Madrid, , Spain

Salamanca, , Spain

Valencia, , Spain

Gothenburg, , Sweden

Huddinge, , Sweden

Stockholm, , Sweden

Umeå, , Sweden

Ankara, , Turkey (Türkiye)

Istanbul, , Turkey (Türkiye)

Izmir, , Turkey (Türkiye)

Kayseri, , Turkey (Türkiye)

Cherkassy, , Ukraine

Dnipro, , Ukraine

Donetsk, , Ukraine

Khakhiv, , Ukraine

Khmelnitskiy, , Ukraine

Kiev, , Ukraine

Lviv, , Ukraine

Vinnitsa, , Ukraine

Birmingham, , United Kingdom

Harrow, , United Kingdom

Plymouth, , United Kingdom

Sheffield Yorks, , United Kingdom

Sutton, , United Kingdom

Countries

United States; Argentina; Belgium; Brazil; Canada; Colombia; Czechia; France; Germany; Greece; Israel; Mexico; Poland; Portugal; Russia; South Korea; Spain; Sweden; Turkey (Türkiye); Ukraine; United Kingdom

References

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.

Reference Type: DERIVED

PMID: 40266025 (View on PubMed)

Fraser 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.

Reference Type: DERIVED

PMID: 32762271 (View on PubMed)

Lavezzi 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.

Reference Type: DERIVED

PMID: 31044267 (View on PubMed)

Brown 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.

Reference Type: DERIVED

PMID: 28751558 (View on PubMed)

Chanan-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.

Reference Type: DERIVED

PMID: 26655421 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

PCI-32765CLL3001

Identifier Type: OTHER

Identifier Source: secondary_id

2012-000600-15

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

U1111-1135-3745

Identifier Type: OTHER

Identifier Source: secondary_id

CR100840

Identifier Type: -

Identifier Source: org_study_id