Ibrutinib, Bortezomib and Rituximab-CHOP for the Treatment of Elderly Patients With CD20+ DLBCL, IPI ≥ 2

NCT03129828 | Completed Phase 1

• 1 other identifier: EudraCT-Nr.: 2015-003429-32
• Study Type: interventional
• Target: 38
• Locations: 1 country
• Sites: 1

Brief Summary

The ImbruVeRCHOP-Trials is an Investigator-initiated, single-arm, multi-center, prospective, open phase I/II trial to evaluate the efficacy and feasibility of Ibrutinib and Bortezomib in the therapy of higher-risk DLBCL patients of different molecular subtypes and to correlate outcome with clinical, molecular and imaging-guided response parameters. The protocol includes a safety run-in phase, i.e. the phase I part of the study, to uncover unexpected toxicities that may arise in the context of Ibrutinib and Bortezomib co-administered with the R-CHOP backbone. The safety run-in phase is followed by the phase II part of the trial. About 34 patients will be included. Additional 8-11 German university centers and 1-5 in Austria will participate in this trial. The study treatment includes a pre-phase therapy with Prednisone and 6 cycles of a combined immuno-chemotherapy with the anti-CD20 antibody Rituximab together with 6 cycles of a chemotherapy consisting of Cyclophosphamide, Doxorubicin, Vincristine and Prednisone plus Bortezomib and Ibrutinib followed by two additional 3-week cycles of Rituximab. Secondary endpoints are the predictive power of subtypes (such as GCB/ABC-"cell-of-origin"), markers of minimal residual disease over time and during-the-study-determined markers (e.g. gene signatures) to identify patients who benefit from this treatment addition.

Conditions

Diffuse Large B Cell Lymphoma

Keywords

Diffuse Large B Cell Lymphoma; Ibrutinib; Bortezomib

Outcome Measures

Primary Outcomes (1)

• 2-year progression-free survival

  progression-free survival after 2 years after end of treatment

  2 years after completion of treatment

Secondary Outcomes (7)

• Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

  through study completion, an average of 3 years

• 1y- and 2y-PFS for patients based on cell-of-origin (COO, i.e. GCB vs. ABC subtype)

  1 and 2 years after end of treatment

• number of patients with complete remission in all patients and based on cell-of-origin

  2 years after end of treatment

• Predictive power of markers for Minimal Residual Disease (MRD) over time

  2 years after end of treatment

• Objective Response Rate (ORR) in all patients and based on cell-of-origin

  2 years after end of treatment

Study Arms (1)

Ibrutinib and Bortezomib + R-CHOP

EXPERIMENTAL

A pre-phase therapy with Prednisone 100 mg p.o. is mandatory from d-4 until d0. Patients receive 6 cycles of a combined immunochemotherapy with the anti-CD20 antibody Rituximab (375 mg/m2 d0 or d1) together with 6 cycles of a chemotherapy consisting of Cyclophosphamide (750 mg/m2 d1), Doxorubicin (50 mg/m2 d1), Vincristine 1 mg absolute d1), Prednisone (100 mg absolute p.o. d1-5) and Bortezomib s.c. (1.3 mg/m2 C1 on d3 and 8, other cycles d1 and d8), in 21-day intervals and Ibrutinib 560 mg p.o. for individuals \< 65 years and 420 mg p.o. for individuals ≥ 65 years (from d6 of C1 until d21 of C6), followed by two additional 3-week cycles of Rituximab (375 mg/m2).

Drug: Ibrutinib and Bortezomib + R-CHOP

Interventions

Ibrutinib and Bortezomib + R-CHOP DRUG

A pre-phase therapy with Prednisone 100 mg p.o. is mandatory from d-4 until d0. Patients receive 6 cycles of a combined immunochemotherapy with the anti-CD20 antibody Rituximab (375 mg/m2 d0 or d1) together with 6 cycles of a chemotherapy consisting of Cyclophosphamide (750 mg/m2 d1), Doxorubicin (50 mg/m2 d1), Vincristine 1 mg absolute d1), Prednisone (100 mg absolute p.o. d1-5) and Bortezomib s.c. (1.3 mg/m2 C1 on d3 and 8, other cycles d1 and d8), in 21-day intervals and Ibrutinib 560 mg p.o. for individuals \< 65 years and 420 mg p.o. for individuals ≥ 65 years (from d6 of C1 until d21 of C6), followed by two additional 3-week cycles of Rituximab (375 mg/m2).

Also known as: Ibrutinib (Imbruvica®), Bortezomib (Velcade®)

Ibrutinib and Bortezomib + R-CHOP

Eligibility Criteria

• Age: 61 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent indicating that they understand the purpose of and procedures required for the study, including biomarkers and are willing to participate in the study
• Age ≥ 61 years and ≤ 80 years
• CD20-positive diffuse large B-cell lymphoma (DLBCL); including T-cell-rich large B-cell lymphoma, anaplastic large B-cell lymphoma, plasmablastic lymphoma; follicular lymphoma grade 3b or primary transformed follicular lymphoma at initial diagnosis or highgrade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements or high-grade B-cell lymphoma NOS
• Lymphoma biopsy native, fresh-frozen for genome-wide transcriptome array or RNA-Seq analyses (gene expression profiling \[GEP\]) for molecular subtype diagnosis
• Willingness to consent to a re-biopsy in C1/day d2, and - in case of a residual lesion by interim CT - in C3/d2 if it can be obtained without inadequate risk
• Unfavorable risk profile according to the IPI score (IPI ≥ 2)
• Performance status (ECOG) 0-2
• Bi-dimensionally measurable disease (measurable by CT scan or MRI)
• Cardiac ejection fraction ≥ 50 % without clinically significant abnormalities
• Adequate hematological function: hemoglobin ≥ 9 g/dL absolute neutrophil count ≥ 1,00/μL independent of growth factor support and platelet count ≥ 100,000/μL or ≥ 50,000/μL if bone marrow involvement independent of transfusion support in either situation
• Adequate renal function as documented by serum creatinine level \< 2 x ULN or estimated GFR ≥ 40 ml/min/1,73m²
• Adequate hepatic function (total bilirubin ≤ 1,5 x ULN unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin, alanine aminotransferase ALT and aspartate aminotransferase AST ≤ 3 x ULN)
• Life expectancy \> 6 months
• Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin \[ß-hCG\]) or urine pregnancy test at screening. Women who are pregnant or breastfeeding are ineligible for this study.
• 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 month after the last dose of study drug.

You may not qualify if:

• Unable to sign informed consent
• Secondary transformed B-NHL or types of NHL other than DLBCL and its subtypes according to WHO classification
• Prior therapy for DLBCL
• Known central nervous system lymphoma
• CNS involvement by lymphoma or any evidence of spinal cord compression. Brain CT/MRI is only mandatory (within 4 weeks prior to study entrance) in case of clinical suspicion of CNS involvement by lymphoma
• Major surgery within 4 weeks of study entrance
• History of stroke or intracranial hemorrhage within 6 months prior to study entrance
• Anticoagulation with Warfarin or equivalent vitamin K antagonists (e.g, Phenprocoumon)
• 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 or 4 cardiac disease as defined by NYHA
• treatment with strong CYP3A inhibitors
• 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
• Vaccination with live, attenuated vaccines within 3 weeks of study entrance
• History of solid organ transplantation
• Pregnant or nursing females
• Prior malignancy (except adequately treated basal cell carcinoma and squamous cell carcinoma of the skin, cervical cancer in situ, or any other cancer for which the patient has been in remission for at least 5 years)

Sponsors & Collaborators

• Prof. Dr. Clemens Schmitt: lead
• Charite University, Berlin, Germany: collaborator
• Janssen-Cilag Ltd.: collaborator

Study Sites (1)

Charité - Universitätsmedizin Berlin, Hematology, Oncology and Tumor Immunology, Campus Virchow Klinikum

Berlin, 13353, Germany

Location

Related Publications (2)

• Denker S, Bittner A, Na IK, Kase J, Frick M, Anagnostopoulos I, Hummel M, Schmitt CA. A Phase I/II first-line study of R-CHOP plus B-cell receptor/NF-kappaB-double-targeting to molecularly assess therapy response. Int J Hematol Oncol. 2019 Dec 19;8(4):IJH20. doi: 10.2217/ijh-2019-0010.

  PMID: 31903182 BACKGROUND

• Vernava I, Schmitt CA. Daratumumab as a novel treatment option in refractory ITP. Blood Cells Mol Dis. 2023 Mar;99:102724. doi: 10.1016/j.bcmd.2023.102724. Epub 2023 Jan 13.

  PMID: 36669360 DERIVED

MeSH Terms

Conditions

Lymphoma, Large B-Cell, Diffuse

Interventions

ibrutinib; Bortezomib

Condition Hierarchy (Ancestors)

Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Organic Chemicals; Pyrazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Clemens Schmitt, Prof. Dr.

  Representative of the Sponsor, National Coordinator, Principal Investigator

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator, Representative of the Sponsor, National Coordinator

Study Record Dates

• First Submitted: April 20, 2017
• First Posted: April 26, 2017
• Study Start: March 17, 2017
• Primary Completion: November 12, 2024
• Study Completion: November 12, 2024
• Last Updated: December 13, 2024

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will not share

Locations

DE (1)