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

Primary Purpose

Diffuse Large B Cell Lymphoma, Primary Mediastinal (Thymic) Large B-cell Lymphoma, Transformed Indolent Lymphoma

Status

Unknown status

Phase

Phase 2

Locations

Israel

Study Type

Interventional

Intervention

Bendamustine 90 mg/m2 IV on Days 1-2, Cycles 1-6

About this trial

This is an interventional treatment trial for Diffuse Large B Cell Lymphoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Adult patients over the age of 18.
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).
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.
At least 1 prior line of therapy with rituximab containing regimen.
At least 1 site of measurable disease according to the Lugano criteria [1]
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.
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
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.
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.
ECOG performance status 0-2.
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:

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 carcinoma in situ without evidence of disease

Sites / Locations

Dr. Meirav Kedmi
Sheba medical organizationRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

one arm

Arm Description

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

Outcomes

Primary Outcome Measures

overall response rate (ORR) of the combination of ibrutinib, bendamustine and rituximab (IBR)

ORR is defined as the proportion of patients having at least partial repose (PR) in interim imaging or end of chemo-immunotherapy.

Secondary Outcome Measures

progression free survival (PFS)

overall survival (OS)

duration of response.

Full Information

NCT ID

NCT02747732

First Posted

April 20, 2016

Last Updated

April 21, 2019

Sponsor

Meirav Kedmi MD

Collaborators

Johnson & Johnson

1. Study Identification

Unique Protocol Identification Number

NCT02747732

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

April 2019

Overall Recruitment Status

Unknown status

Study Start Date

December 2016 (undefined)

Primary Completion Date

June 2020 (Anticipated)

Study Completion Date

October 2021 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Meirav Kedmi MD

Collaborators

Johnson & Johnson

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Diffuse Large B Cell Lymphoma, Primary Mediastinal (Thymic) Large B-cell Lymphoma, Transformed Indolent Lymphoma, Recurrent Disease, Refractory Cancer

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

72 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

one arm

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Bendamustine 90 mg/m2 IV on Days 1-2, Cycles 1-6

Other Intervention Name(s)

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

Intervention Description

Primary Outcome Measure Information:

Title

overall response rate (ORR) of the combination of ibrutinib, bendamustine and rituximab (IBR)

Description

ORR is defined as the proportion of patients having at least partial repose (PR) in interim imaging or end of chemo-immunotherapy.

Time Frame

5 years

Secondary Outcome Measure Information:

Title

progression free survival (PFS)

Time Frame

5 years

Title

overall survival (OS)

Time Frame

5 years

Title

duration of response.

Time Frame

5 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Adult patients over the age of 18. 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). 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. At least 1 prior line of therapy with rituximab containing regimen. At least 1 site of measurable disease according to the Lugano criteria [1] Hematology laboratory values must be within the following limits: Absolute neutrophil count (ANC)≥1000/mm3 independent of growth factor support Platelets ≥100,000/mm3 or ≥50,000/mm3 if bone marrow involvement independent of transfusion support in either situation. Biochemical values within the following limits: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x upper limit of normal (ULN) Total bilirubin ≤ 1.5 x ULN unless the increase is due to Gilbert's syndrome or of non-hepatic origin Serum creatinine ≤ 2 x ULN or estimated Glomerular Filtration Rate (Cockroft-Gault) ≥ 40 mL/min/1.73m2 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. 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. ECOG performance status 0-2. 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: 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 carcinoma in situ without evidence of disease

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

MEIRAV KEDMI, MD

meirav.Kedmi@sheba.health.gov.il

First Name & Middle Initial & Last Name or Official Title & Degree

Aliza Ackerstein

Phone

972546853835

Aliza.Ackerstein@sheba.health.gov.il

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

MEIRAV KEDMI

Organizational Affiliation

Sheba Medical Center

Official's Role

Principal Investigator

Facility Information:

Facility Name

Dr. Meirav Kedmi

City

Ramat Gan

ZIP/Postal Code

5262179

Country

Israel

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Meirav Kedmi, MD

mailto:Meirav.Kedmi@sheba.health.gov.il

First Name & Middle Initial & Last Name & Degree

Aliza Ackerstein, MASTER

Aliza.Ackerstein@sheba.health.gov.il

Facility Name

Sheba medical organization

City

Ramat Gan

Country

Israel

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Meirav Kedmi, MD

Phone

972-3-530-2127

Meirav.kedmi@sheba.health.gov.il

First Name & Middle Initial & Last Name & Degree

Aliza Ackerstein, Msc

Phone

972-3-5308402

aliza.ackerstein@sheba.health.gov.il

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

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

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