Study of Ibrutinib in Combination With Bendamustine and Rituximab for Patients With Relapsed/Refractory Aggressive BCL

April 21, 2019 updated by: Meirav Kedmi MD

A Phase II Study of the Bruton's Tyrosine Kinase Inhibitor, PCI-32765 (Ibrutinib), in Combination With Bendamustine and Rituximab (BR) for Patients With Relapsed/Refractory Aggressive B Cell Lymphomas

This is a phase 2 study of the Bruton's Tyrosine Kinase Inhibitor, PCI-32765 (ibrutinib), in combination with bendamustine and rituximab (BR) in subjects with previously treated aggressive B cell non Hodgkin lymphoma (aB-NHL) including any subtype of diffuse large B cell lymphoma (DLBCL) primary mediastinal B cell lymphoma (PMBCL), double and triple hit DLBCL, transformed indolent lymphoma, unclassifiable aggressive B cell lymphoma between DLBCL and Burkitt lymphoma. Patients with CNS involvement (primary or secondary) will be excluded. Ibrutinib (IMBRUVICA®; PCI-32765; JNJ-54179060) is a first-in-class, potent, orally-administered covalently-binding small molecule inhibitor of Bruton's tyrosine kinase currently FDA approved for the treatment of relapsed Mantle cell lymphoma (MCL), Chronic Lymphocytic Leukemia (CLL) and waldenstrom Macroglobulinemia (WM).It is under constant investigation for the treatment of other B-cell malignancies. The initial approval of ibrutinib was received on 13 November 2013 by the United States Food and Drug Administration for the treatment of adult patients with MCL who have received at least 1 prior therapy. Ibrutinib has not been approved for marketing for the treatment of aggressive B cell lymphoma although Phase I trial in this setting has already been published. In Israel ibrutinib is registered for the treatment of MCL and CLL.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Unknown

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

This is a phase II single arm clinical trial that is designed to test the efficacy of ibrutinib in combination with BR in relapsed aB-NHL either as third line post ASCT or as second or third line in non-transplant eligible patients. Patients will be referred for this study from all medical centers in Israel through the Israeli Lymphoma Working Group, but will be treated only in Chaim Sheba Medical center.

The study will include a Screening Phase, Treatment Phase, and Post- treatment Follow-up Phase.

Subject eligibility will be determined up to 30 days prior to therapy initiation. The treatment Phase will extend from cycle 1 day 1 until study drug discontinuation, either due to progression, toxicity, or due to referral to allo- SCT.

Approximately 72 eligible subjects will be stratified by background chemotherapy treatment refractory versus relapsed disease aB-NHL histology, and number of prior lines of therapy. All subject will receive BR protocol and ibrutinib 560mg per day. Ibrutinib will be administered orally once

daily starting on cycle 1, day 1, on a continuous schedule until disease progression, referral for allo-SCT, unacceptable toxicity whichever comes first. The post-treatment Follow-up Phase will begin at the end of 6 cycles of BR. Subjects who discontinue for reasons other than disease progression must continue disease evaluations.

The Post-treatment Follow-up Phase will continue until death, loss to follow up, consent withdrawal, or study end, whichever occurs first.

Assessment of tumor response and progression will be conducted in accordance with the Lugano criteria for Malignant Lymphoma. The investigator will evaluate sites of disease by radiological imaging, physical examination, or other procedures as necessary. The primary efficacy analysis of ORR will be based on investigator assessment.

At each site visit, subjects will be evaluated for toxicity. Safety evaluations will include adverse event monitoring, physical examinations, concomitant medication usage, and clinical laboratory parameters.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Anticipated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
72

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Adult patients over the age of 18.
  2. Histologically confirmed DLBCL, Transformed low grade lymphoma to DLBCL, primary mediastinal B cell lymphoma or unclassifiable lymphoma between DLBCL and Burkitt Lymphoma, either in first or second relapse/progression in patients who are not candidates for ASCT or in second relapse/progression post ASCT (as first salvage therapy following relapse/progression post ASCT).
  3. Pathology must be confirmed by a local hemato-pathologist. Patients with pathology sample over 1 year old will have to undergo a new diagnostic biopsy.
  4. At least 1 prior line of therapy with rituximab containing regimen.
  5. At least 1 site of measurable disease according to the Lugano criteria [1]

  6. Hematology laboratory values must be within the following limits:

    1. Absolute neutrophil count (ANC)≥1000/mm3 independent of growth factor support
    2. Platelets ≥100,000/mm3 or ≥50,000/mm3 if bone marrow involvement independent of transfusion support in either situation.

  7. Biochemical values within the following limits:

    1. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x upper limit of normal (ULN)
    2. Total bilirubin ≤ 1.5 x ULN unless the increase is due to Gilbert's syndrome or of non-hepatic origin
    3. Serum creatinine ≤ 2 x ULN or estimated Glomerular Filtration Rate (Cockroft-Gault) ≥ 40 mL/min/1.73m2
  8. Women of childbearing potential and men who are sexually active must be practicing a highly effective method of birth control during and after the study consistent with local regulations regarding the use of birth control methods for subjects participating in clinical trials. Men must agree to not donate sperm during and after the study. For females, these restrictions apply for 1 month after the last dose of study drug. For males, these restrictions apply for 3 months after the last dose of study drug.
  9. Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin [beta-hCG]) or urine pregnancy test at screening. Women who are pregnant or breastfeeding are ineligible for this study.
  10. ECOG performance status 0-2.
  11. Sign (or their legally-acceptable representatives must sign) an informed consent document indicating that they understand the purpose of and procedures required for the study, including biomarkers, and are willing to participate in the study.

Exclusion Criteria:

Prior chemotherapy radiotherapy or major surgery within 4 weeks of cycle 1 day 1.

2. Previous treatment with either bendamustine or Ibrutinib. 3. Prior allogeneic stem cell transplantation. 4. Known central nervous system lymphoma. 5. History of stroke or intracranial hemorrhage within 6 months prior to randomization.

6. Requires anticoagulation with warfarin or equivalent vitamin K antagonists. 7. Requires treatment with strong CYP3A inhibitors. 8. Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification.

9. Vaccinated with live, attenuated vaccines within 4 weeks of randomization. 10. Known history of human immunodeficiency virus (HIV) or active Hepatitis C Virus or active Hepatitis B Virus infection or any uncontrolled active systemic infection requiring intravenous (IV) antibiotics. Hbcore positive HBs negative patients will be eligible but will need to be treated with lamivudine 100 mg/day throughout the treatment phase and 6 months after it.

11. Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk.

12. Diagnosed or treated for malignancy other than DLBCL, except:

  1. Malignancy treated with curative intent and with no known active disease present for 3 years before randomization
  2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
  3. Adequately treated carcinoma in situ without evidence of disease

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: one arm

Therapy initiation 30 days max from screening.

Bendamustine 90 mg/m2 IV on Days 1-2, Cycles 1-6 Rituximab 375 mg/m2 IV Day 1, Cycles 1-6; a cycle is defined as 28 days Ibrutinib, 560 mg orally, once daily, continuously starting on Cycle 1, Day 1 until disease progression, toxicity or referral for allo-SCT
Drug: Bendamustine 90 mg/m2 IV on Days 1-2, Cycles 1-6

Therapy initiation 30 days max from screening.

Bendamustine 90 mg/m2 IV on Days 1-2, Cycles 1-6 Rituximab 375 mg/m2 IV Day 1, Cycles 1-6; a cycle is defined as 28 days Ibrutinib, 560 mg orally, once daily, continuously starting on Cycle 1, Day 1 until disease progression, toxicity or referral for allo-SCT

Other Names:
  • Rituximab 375 mg/m2 IV Day 1, Cycles 1-6;
  • Ibrutinib, 560 mg orally, once daily

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
overall response rate (ORR) of the combination of ibrutinib, bendamustine and rituximab (IBR)
Time Frame: 5 years
ORR is defined as the proportion of patients having at least partial repose (PR) in interim imaging or end of chemo-immunotherapy.
5 years

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Time Frame
overall survival (OS)
Time Frame: 5 years
5 years
progression free survival (PFS)
Time Frame: 5 years
5 years
duration of response.
Time Frame: 5 years
5 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Meirav Kedmi MD

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Johnson & Johnson

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: MEIRAV KEDMI, Sheba Medical Center

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
December 1, 2016

Primary Completion (Anticipated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
June 1, 2020

Study Completion (Anticipated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
October 1, 2021

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
April 20, 2016

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 21, 2016

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
April 22, 2016

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
April 23, 2019

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 21, 2019

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
April 1, 2019

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • Bruton's Tyrosine_Meirav Kedmi

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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Conditions

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