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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Pharmacyclics
Information provided by (Responsible Party):
Janssen Research & Development, LLC
ClinicalTrials.gov Identifier:
NCT01611090
First received: May 15, 2012
Last updated: August 27, 2014
Last verified: August 2014
  Purpose

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).


Condition Intervention Phase
Chronic Lymphocytic Leukemia
Small Lymphocytic Lymphoma
Drug: Ibrutinib
Drug: Bendamustine hydrochloride
Drug: Rituximab
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Janssen Research & Development, LLC:

Primary Outcome Measures:
  • Progression-free survival [ Time Frame: Up to 4 years after the last patient is randomized ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Number of participants with adverse events [ Time Frame: Up to 30 days following the last dose of study drug ] [ Designated as safety issue: Yes ]
  • Overall response rate [ Time Frame: At disease progression, up to 4 years after the last patient is randomized ] [ Designated as safety issue: No ]
  • Overall survival [ Time Frame: Up to 4 years after the last patient is randomized ] [ Designated as safety issue: No ]
  • Rate of minimal residual disease (MRD)-negative remissions [ Time Frame: At disease progression, up to 4 years after the last patient is randomized ] [ Designated as safety issue: No ]
  • Number of participants with improvement in hematologic values [ Time Frame: At disease progression, up to 4 years after the last patient is randomized ] [ Designated as safety issue: No ]
  • Number of participants with improvement in disease-related symptoms [ Time Frame: At disease progression, up to 4 years after the last patient is randomized ] [ Designated as safety issue: No ]
  • Number of participants with improvement in patient-reported outcome scores [ Time Frame: At disease progression, up to 4 years after the last patient is randomized ] [ Designated as safety issue: No ]
  • Plasma concentrations of ibrutinib [ Time Frame: Up to Day 2, Cycle 6 ] [ Designated as safety issue: No ]
  • Plasma concentrations of bendamustine [ Time Frame: Up to Day 2, Cycle 6 ] [ Designated as safety issue: No ]
  • Plasma concentrations of rituximab [ Time Frame: Up to Day 1, Cycle 12 ] [ Designated as safety issue: No ]
  • Number of participants with biomarkers related to B-cell receptors [ Time Frame: End-of-treatment visit (up to Day 450) ] [ Designated as safety issue: No ]

Enrollment: 578
Study Start Date: September 2012
Estimated Study Completion Date: March 2018
Estimated Primary Completion Date: August 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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).
Drug: Ibrutinib
Type=exact number, unit=mg, number=420 , form=capsule, route=oral use. Capsule is taken once daily continuously.
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.
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.
Placebo Comparator: 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).
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.
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.
Drug: Placebo
Form=capsule, route=oral use. Capsule is taken once daily continuously.

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 4 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 confirmed by independent review committee, may cross over to ibrutinib treatment (as in treatment arm B), at the investigators discretion and with medical monitor approval. 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01611090

  Hide Study Locations
Locations
United States, Alabama
Birmingham, Alabama, United States
United States, Arizona
Phoenix, Arizona, United States
United States, California
Berkeley, California, United States
Duarte, California, United States
Greenbrae, California, United States
United States, Connecticut
Stamford, Connecticut, United States
United States, District of Columbia
Washington, District of Columbia, United States
United States, Florida
Boca Raton, Florida, United States
Jacksonville, Florida, United States
United States, Georgia
Atlanta, Georgia, United States
Marietta, Georgia, United States
United States, Illinois
Chicago, Illinois, United States
Springfield, Illinois, United States
United States, Indiana
Fort Wayne, Indiana, United States
Goshen, Indiana, United States
Indianapolis, Indiana, United States
United States, Iowa
Iowa City, Iowa, United States
United States, Kansas
Westwood, Kansas, United States
United States, Kentucky
Louisville, Kentucky, United States
Paducah, Kentucky, United States
United States, Louisiana
Marrero, Louisiana, United States
United States, Maryland
Baltimore, Maryland, United States
United States, Massachusetts
Worcester, Massachusetts, United States
United States, Michigan
Ann Arbor, Michigan, United States
Battle Creek, Michigan, United States
Detroit, Michigan, United States
Lansing, Michigan, United States
United States, Missouri
St. Louis, Missouri, United States
United States, Nebraska
Lincoln, Nebraska, United States
United States, New Hampshire
Lebanon, New Hampshire, United States
United States, New Jersey
Hackensack, New Jersey, United States
United States, New Mexico
Albuquerque, New Mexico, United States
United States, New York
Dunkirk, New York, United States
Hawthorne, New York, United States
New York, New York, United States
United States, North Dakota
Bismarck, North Dakota, United States
United States, Ohio
Cleveland, Ohio, United States
United States, Oregon
Portland, Oregon, United States
United States, South Carolina
Charleston, South Carolina, United States
United States, South Dakota
Sioux Falls, South Dakota, United States
United States, Texas
Temple, Texas, United States
United States, West Virginia
Morgantown, West Virginia, United States
Argentina
Buenos Aires, Argentina
Ciudad Autonoma Buenos Aires, Argentina
Cordoba, Argentina
Belgium
Aalst, Belgium
Brugge, Belgium
Brussels, Belgium
Gent, Belgium
Leuven, Belgium
Brazil
Rio De Janeiro, Brazil
Salvador, Brazil
Sao Paulo, Brazil
Canada, Alberta
Edmonton, Alberta, Canada
Canada, British Columbia
Vancouver N/A, British Columbia, Canada
Canada, Ontario
Hamilton, Ontario, Canada
London, Ontario, Canada
Ottawa, Ontario, Canada
Toronto, Ontario, Canada
Canada, Quebec
Montreal, Quebec, Canada
Colombia
Bogota, Colombia
Floridablanca, Colombia
Czech Republic
Brno, Czech Republic
Praha 10, Czech Republic
Praha 2, Czech Republic
France
Creteil, France
Montpellier, France
Paris Cedex 13, France
Pessac, France
Pierre Benite, France
Tours, France
Villejuif, France
Germany
Aschaffenburg, Germany
Augsburg, Germany
Dresden, Germany
Erlangen, Germany
Essen, Germany
Frankfurt, Germany
Frechen, Germany
Hamm, Germany
Heidelberg, Germany
Homburg, Germany
Kassel, Germany
Kiel, Germany
Koblenz, Germany
Köln, Germany
Kÿln N/A, Germany
Lebach, Germany
Magdeburg, Germany
Mannheim, Germany
Marburg, Germany
Mutlangen, Germany
Ulm, Germany
Würzburg, Germany
Greece
Athens, Greece
Thessalonikis, Greece
Israel
Haifa, Israel
Jerusalem, Israel
Nahariya, Israel
Netanya, Israel
Petah Tikva, Israel
Ramat-Gan, Israel
Tel Aviv, Israel
Korea, Republic of
Seoul, Korea, Republic of
Mexico
Mexico, Mexico
Monterrey, Mexico
Oaxaca, Mexico
Poland
Brzozow, Poland
Chorzow, Poland
Krakow, Poland
Opole, Poland
Slupsk, Poland
Portugal
Coimbra, Portugal
Lisboa, Portugal
Ponta Delgada, Portugal
Porto, Portugal
Russian Federation
Arkhangelsk, Russian Federation
Dzerzhinsk, Russian Federation
Ekaterinburg, Russian Federation
Krasnodar, Russian Federation
Moscow N/A, Russian Federation
Nizhniy Novgorod, Russian Federation
Obninsk, Russian Federation
Perm, Russian Federation
Rostov-Na-Donu, Russian Federation
Ryazan, Russian Federation
Saint Petersburg, Russian Federation
Samara, Russian Federation
Sochi, Russian Federation
St. Petersburg, Russian Federation
St.-Petersburg, Russian Federation
Syktyvkar, Russian Federation
Spain
Barcelona, Spain
L'Hospitalet De Llobregat, Spain
Madrid, Spain
Salamanca, Spain
Valencia, Spain
Sweden
Göteborg, Sweden
Huddinge, Sweden
Stockholm, Sweden
Umeå, Sweden
Turkey
Ankara, Turkey
Istanbul, Turkey
Izmir, Turkey
Kayseri, Turkey
Ukraine
Cherkassy, Ukraine
Dnepropetrovsk, Ukraine
Donetsk, Ukraine
Kharkiv, Ukraine
Khmelnitskiy, Ukraine
Kiev, Ukraine
Lviv, Ukraine
Vinnitsa, Ukraine
United Kingdom
Birmingham, United Kingdom
Harrow, United Kingdom
Plymouth, United Kingdom
Sheffield Yorks, United Kingdom
Sutton, United Kingdom
Sponsors and Collaborators
Janssen Research & Development, LLC
Pharmacyclics
Investigators
Study Director: Janssen Research & Development, LLC Clinical Trial Janssen Research & Development, LLC
  More Information

No publications provided

Responsible Party: Janssen Research & Development, LLC
ClinicalTrials.gov Identifier: NCT01611090     History of Changes
Other Study ID Numbers: CR100840, PCI-32765CLL3001, 2012-000600-15, U1111-1135-3745
Study First Received: May 15, 2012
Last Updated: August 27, 2014
Health Authority: United States: Food and Drug Administration
Turkey: Ministry of Health
Czech Republic: State Institute for Drug Control
United States: Federal Government
Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica
Belgium: Federal Agency for Medicinal Products and Health Products
Brazil: National Health Surveillance Agency
Canada: Health Canada
Colombia: INVIMA Instituto Nacional de Vigilancia de Medicamentos y Alimentos
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Germany: Federal Institute for Drugs and Medical Devices
Greece: National Organization of Medicines
Israel: Ministry of Health
South Korea: Korea Food and Drug Administration (KFDA)
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Russia: FSI Scientific Center of Expertise of Medical Application
Spain: Agencia Española de Medicamentos y Productos Sanitarios
Sweden: Medical Products Agency
Ukraine: State Pharmacological Center - Ministry of Health
United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Janssen Research & Development, LLC:
Chronic lymphocytic leukemia
Small lymphocytic lymphoma
Relapsed or refractory chronic lymphocytic leukemia
Relapsed or refractory small lymphocytic lymphoma
Ibrutinib
PCI-32765
JNJ-54179060
Bruton's tyrosine kinase inhibitor
Bendamustine
Rituximab

Additional relevant MeSH terms:
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Lymphoid
Lymphoma
Leukemia
Leukemia, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Rituximab
Bendamustine
Nitrogen Mustard Compounds
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 16, 2014