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

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:

MedlinePlus related topics: Chronic Lymphocytic Leukemia Leukemia Lymphoma

Drug Information available for: Tyrosine Bendamustine hydrochloride Bendamustine Rituximab

U.S. FDA Resources

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 ]

Estimated Enrollment:	580
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.

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 (individuals will be assigned by chance to study treatments), double-blind (individuals 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 and 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. 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 within 7 days prior to randomization
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 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

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

Contacts

Contact: Use link at the bottom of the page to see if you qualify for an enrolling site (see list). If you still have questions:

JNJ.CT@sylogent.com

Show 177 Study Locations

Sponsors and Collaborators

Janssen Research & Development, LLC

Pharmacyclics

Investigators

Study Director:

Janssen Research & Development, LLC Clinical Trial

Janssen Research & Development, LLC

More Information

Additional Information:

To learn how to participate in this trial please click here. This link exits the ClinicalTrials.gov site

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:	May 10, 2013
Health Authority:	United States: Food and Drug Administration Turkey: Ministry of Health Czech Republic: State Institute for Drug Control United States: Federal Government Germany: Ethics Commission

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
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Lymphoid
Lymphoma
Neoplasms by Histologic Type
Neoplasms
Leukemia, B-Cell
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Bendamustine

Rituximab
Nitrogen Mustard Compounds
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents

ClinicalTrials.gov processed this record on May 21, 2013