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

NCT02747732 | Unknown Phase 2

• 1 other identifier: Bruton's Tyrosine_Meirav Kedmi
• Study Type: interventional
• Target: 72
• Locations: 1 country
• Sites: 2

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.

Conditions

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

Outcome Measures

Primary Outcomes (1)

• 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.

  5 years

Secondary Outcomes (3)

• progression free survival (PFS)

  5 years

• overall survival (OS)

  5 years

• duration of response.

  5 years

Study Arms (1)

one arm

EXPERIMENTAL

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

Interventions

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

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

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

one arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

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

Sponsors & Collaborators

• Meirav Kedmi MD: lead
• Johnson & Johnson: collaborator

Study Sites (2)

Dr. Meirav Kedmi

Ramat Gan, 5262179, Israel

NOT YET RECRUITING

Sheba medical organization

Ramat Gan, Israel

RECRUITING

Related Publications (1)

• Kedmi M, Ribakovsy E, Benjamini O, Schiby G, Barshack I, Raskin S, Eshet Y, Mehr R, Horowitz N, Gurion R, Goldschmidt N, Perry C, Levi I, Aviv A, Herzog-Tzarfati K, Nagler A, Avigdor A. Ibrutinib With Bendamustine and Rituximab for Treatment of Patients With Relapsed/Refractory Aggressive B-Cell Lymphoma. Hematol Oncol. 2024 Nov;42(6):e70001. doi: 10.1002/hon.70001.

  PMID: 39572395 DERIVED

MeSH Terms

Conditions

Lymphoma, Large B-Cell, Diffuse; Recurrence; Neoplasms

Interventions

Bendamustine Hydrochloride; Rituximab; ibrutinib

Condition Hierarchy (Ancestors)

Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Butyrates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• MEIRAV KEDMI

  Sheba Medical Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

MEIRAV KEDMI, MD

CONTACT

meirav.Kedmi@sheba.health.gov.il

Aliza Ackerstein

CONTACT

972546853835; Aliza.Ackerstein@sheba.health.gov.il

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Dr.

Study Record Dates

• First Submitted: April 20, 2016
• First Posted: April 22, 2016
• Study Start: December 1, 2016
• Primary Completion: June 1, 2020
• Study Completion: October 1, 2021
• Last Updated: April 23, 2019

Record last verified: 2019-04

Data Sharing

• IPD Sharing: Will not share

Locations

IL (2)