Neoplasms

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Diffuse Large B-Cell Lymphoma

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Protein Kinase Inhibitors

Tyrosine

Treatment-naive high-risk DLBCL patients will be enrolled. R/R2-CHOP were allowed in cycle 1 due to poor physical condition or liver and renal failure caused by lymphoma progression. Patients achieving Complete Remission (CR) or Partial Remission (PR) after 2 cycles will receive another 2 cycles. Patients achieving CR or PR after 4 cycles will finish 6 cycles. Patients achieving CR after 6 cycles with double-hit/triple-hit/double-expression/median to high risk aaIPI will undergo Autologous Stem Cell Transplantation (ASCT). Other patients will be administered rituximab for another 2 cycles and then turn to follow-up. After completion of study treatment, patients are followed up every 3 months for 2 years, and then every 6 months for another 3 years. Patients achieving Stable Disease (SD) or PD (Progression Disease) after 2 or 4 cycles will quit the study. After 6 cycles, patients achieving SD or PD will quit the study and patients achieving PR will receive second-line therapy.

160 mg capsules administered by mouth twice daily (21-day cycles).

25 mg capsules administered by mouth once daily on Day 1 to Day 10 of each cycle (21-day cycles)

375 mg/m2 administered intravenously once on Day 1 of each cycle (21-day cycles)

750 mg/m2 administered intravenously once on Day 1 of each cycle (21-day cycles)

50 mg/m2 administered intravenously once on Day 1 of each cycle (21-day cycles)

1.4 mg/m2 administered intravenously once on Day 1 of each cycle (21-day cycles)

40 mg/m2 capsules administered by mouth once daily on Day 1 to Day 5 of each cycle

Prednisone (or equivalent)

Jianyong Li, Phd, MD

huayuan zhu, PhD

Huayuan Zhu, PhD，MD

Yeqin Sha, MD

This study is a multi-center, open-label, single-arm, non-randomized phase II clinical study in order to evaluate the safety and efficacy of zanubrutinib, lenalidomide plus R-CHOP (ZR2-CHOP) as the first-line therapy for treatment-naive high-risk diffuse large B-cell lymphoma patients.

A Phase II Study of Zanubrutinib, Lenalidomide Plus R-CHOP as the First-line Treatment for Diffused Large B-cell Lymphoma

A Phase II Study of the Bruton's Tyrosine Kinase Inhibitor, Zanubrutinib, in Combination With Lenalidomide Plus Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Patients With Newly Diagnosed Diffuse Large B-Cell Lymphoma

Complete response rate will be assessed by (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET/CT) according to 2014 Lugano Criteria.

PFS was defined as the duration from the date of randomization to the date of progression, relapse from CR, or death, whichever occurred first. Responses were based on 2014 Lugano Criteria.

Overall survival was defined as the duration from the date of randomization to the date of the participant's death. Median Overall Survival was estimated by using the Kaplan-Meier method.

ctDNA will be measured at baseline and after 2, 4, 6 cycles of ZR2-CHOP

Overall response rate will be assessed by FDG-PET/CT or CT scan according to 2014 Lugano Criteria.

Overall response rate will be assessed by FDG-PET/CT according to 2014 Lugano Criteria.

Toxicities will be summarized by grade and by their relationship to treatment according to CTCAE (version 5.0).

The First Affiliated Hospital with Nanjing Medical University

Ibrutinib

Treatment Arm A = placebo + R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone)

560 mg capsules administered by mouth once daily (21-day cycles)

4 matched capsules administered by mouth once daily (21-day cycles)

Placebo

100 mg capsules administered by mouth once daily on Day 1 to Day 5 of each cycle

Janssen Research & Development, LLC Clinical Trial

The purpose of this study is to evaluate if ibrutinib administered in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) improves the clinical outcome in newly diagnosed patients with non-germinal center B-cell subtype (GCB) of diffuse large B-cell lymphoma (DLBCL) selected by immunohistochemistry (IHC) or newly diagnosed patients with activated B cell-like (ABC) subtype of DLBCL identified by gene expression profiling (GEP) or both populations.

This is a randomized (individuals assigned to study treatment by chance), 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 compare the efficacy and safety of ibrutinib in combination with R-CHOP versus R-CHOP alone in adult patients newly diagnosed non-GCB DLBCL selected by IHC or newly diagnosed patients with ABC subtype of DLBCL identified by GEP or both populations. The study will include screening, active treatment, and posttreatment follow-up phases. The study will end when 50% of participants have died or 5 years after the last participant is randomized or the sponsor terminates the study, whichever occurs first. Approximately 800 participants will be randomly assigned in a 1:1 ratio to receive either placebo+R-CHOP (treatment arm A) or ibrutinib+R-CHOP (treatment arm B). All participants will receive R-CHOP as background therapy for 6 or 8 cycles (21 days per cycle) prespecified according to local practice. After 4 treatment cycles, an interim response assessment will be performed to evaluate disease progression for each participant. Participants with progressive disease or relapsed disease after complete response will be discontinued from treatment. Participants who discontinue R-CHOP without disease progression will continue study drug (placebo or ibrutinib) until 6 or 8 cycles are completed, disease progression, or unacceptable toxicity, whichever occurs first. After completion of study drug, participants will undergo assessment of tumor response based on the Revised Response Criteria for Malignant Lymphoma. Participants with documented residual disease upon completion of at least 6 cycles of R-CHOP therapy are considered eligible to initiate subsequent antilymphoma therapy. Serial pharmacokinetic samples will be collected before and after dosing, and safety will be monitored throughout the study.

A Study of the Bruton's Tyrosine Kinase Inhibitor, PCI-32765 (Ibrutinib), in Combination With Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Patients With Newly Diagnosed Non-Germinal Center B-Cell Subtype of Diffuse Large B-Cell Lymphoma

A Randomized, Double-blind, Placebo-controlled Phase 3 Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor, PCI-32765 (Ibrutinib), in Combination With Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) in Subjects With Newly Diagnosed Non-Germinal Center B-Cell Subtype of Diffuse Large B-Cell Lymphoma

EFS: duration from randomization date to disease progression(PD) date, relapse from complete response(CR) assessed by investigator, initiation of subsequent systemic antilymphoma therapy for either positron emission tomography(PET)-positive/ biopsy-proven residual disease upon completion of \>=6 cycles of R-CHOP therapy/death, whichever occurred first. Responses were based on Revised Response Criteria for Malignant Lymphoma. PD: any new lesion or increase by 50% of previously involved sites from nadir; PD criteria: Appearance of new nodal lesion 1.5 cm in any axis, 50% increase in sum of product of diameters(SPD) of \>1 node or 50% increase in longest diameter of previously identified node 1 cm in short axis. CR: disappearance of all evidence of disease; CR criteria: nodal masses PET positive prior to therapy; mass of any size permitted if PET negative; regression to normal size on CT; spleen and liver: not palpable, nodules disappeared; bone marrow: infiltrate cleared on repeat biopsy.

EFS: duration from randomization date to PD date, relapse from CR assessed by investigator, initiation of subsequent systemic antilymphoma therapy for either PET-positive/ biopsy-proven residual disease upon completion of \>=6 cycles of R-CHOP therapy/death, whichever occurred first. Responses were based on Revised Response Criteria for Malignant Lymphoma. PD: any new lesion or increase by 50% of previously involved sites from nadir; PD criteria: Appearance of new nodal lesion 1.5 cm in any axis, 50% increase in SPD of \>1 node or 50% increase in longest diameter of previously identified node 1 cm in short axis. CR: disappearance of all evidence of disease; CR criteria: nodal masses PET positive prior to therapy; mass of any size permitted if PET negative; regression to normal size on CT; spleen and liver: not palpable, nodules disappeared; bone marrow: infiltrate cleared on repeat biopsy.

PFS was defined as the duration from the date of randomization to the date of progression, relapse from CR, or death, whichever occurred first. Responses were based on Revised Response Criteria for Malignant Lymphoma. Progressive Disease (PD): any new lesion or increase by 50% of previously involved sites from nadir; PD criteria: Appearance of new nodal lesion 1.5 centimeter (cm) in any axis, 50% increase in SPD of \>1 node or 50% increase in longest diameter of previously identified node 1 cm in short axis. CR: disappearance of all evidence of disease; CR criteria: nodal masses PET positive prior to therapy; mass of any size permitted if PET negative; regression to normal size on CT; spleen and liver: not palpable, nodules disappeared; bone marrow: infiltrate cleared on repeat biopsy.

Percentage of participants with measurable disease who achieved CR were reported. CR: disappearance of all evidence of disease. CR Criteria: Complete disappearance of all disease-related symptoms; all lymph nodes and nodal masses regressed to normal size (less than or equal to \[\<=\]1.5 cm in greatest transverse diameter \[GTD\] for nodes greater than \[\>\]1.5 cm before therapy). Previous nodes of 1.1 to 1.5 cm in long axis and greater than (\>)1.0 cm in short axis before treatment decreased to \<=1.0 cm in short axis after treatment. Disappearance of all splenic and hepatic nodules and other extranodal disease; a negative positron emission tomography (PET) scan. A posttreatment residual mass of any size but PET-negative; spleen and liver: not palpable, nodules disappeared; bone marrow: infiltrate cleared on repeat biopsy.

Time to worsening in the Lymphoma subscale of the FACT-Lym, defined as the interval from the date of randomization to the start date of worsening of participant symptoms. Worsening was defined by a 5-point decrease from baseline. FACT-Lym Lymphoma subscale contains 15 questions, scores from 0 to 4 for each question (higher the worse). Lymphoma subscale score is the total of reverse scores, range 0 to 60. Higher scores indicate a better quality of life.

Pharmacyclics LLC.

Janssen Research & Development, LLC

Safety population included all randomized participants who received at least 1 dose of study drug.

Participants received ibrutinib 560 milligram (mg) (4\*140 mg) capsules orally once daily (Cycle 1 Day 1 to Day 21 of last cycle; 21-day cycles) along with R-CHOP (Rituximab - Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone) as a background chemotherapy. R-CHOP regimen included rituximab 375 milligram per square meter (mg/m\^2) intravenously (IV), cyclophosphamide 750 mg/m\^2 IV, doxorubicin 50 mg/m\^2 IV, and vincristine 1.4 mg/m\^2 IV, administered on Day 1 and prednisone 100 mg capsules orally on Days 1 to 5 of each cycle. Participants received background chemotherapy plus ibrutinib for 6 or 8 cycles per site preference (21 days per cycle).

Treatment Arm B: Ibrutinib+R-CHOP

Participants received matching placebo (4 capsules) orally once daily (21-day cycles) along with R-CHOP background chemotherapy. R-CHOP regimen included rituximab 375 milligram per square meter (mg/m\^2) intravenously (IV), cyclophosphamide 750 mg/m\^2 IV, doxorubicin 50 mg/m\^2 IV, and vincristine 1.4 mg/m\^2 IV, administered on Day 1 and prednisone 100 mg capsules orally on Days 1 to 5 of each cycle. Participants received background chemotherapy plus matching placebo for 6 or 8 cycles per site preference (21 days per cycle).

Treatment Arm A: Placebo+R-CHOP

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race/Ethnicity, Customized

Argentina

Australia

Belgium

Brazil

Canada

China

Czech Republic

Denmark

Finland

France

Germany

Hungary

Israel

Italy

Japan

Mexico

Netherlands

Norway

Poland

Russia

Korea, Republic Of

Spain

Sweden

Taiwan, Province Of China

Turkey

Ukraine

United Kingdom

United States

Region of Enrollment

Sponsor decided to stop the study as all participants had concluded study treatment and outcomes were not expected to change and study was considered as completed.

Medical Officer

Intent-to-Treat (ITT) population included all randomized participants, enrolled with non-germinal center B-cell (GCB) of diffuse large B-cell lymphoma (DLBCL) subtype by immunohistochemistry (IHC), and were analyzed according to treatment to which they were randomized.

Event-Free Survival (EFS) - Intent-to-Treat (ITT) Population

ABC population included ITT population (all randomized participants, enrolled with non-GCB of DLBCL subtype by IHC) having ABC subtype determined by gene expression profiling (GEP) (retrospectively determined from available formalin-fixed paraffin-embedded \[FFPE\] tissue specimens). Participants were analyzed according to randomized treatment.

Event-Free Survival (EFS) - Activated B-Cell (ABC) Population

ITT population included all randomized participants, enrolled with non-GCB of DLBCL subtype by IHC, and were analyzed according to treatment to which they were randomized.

Progression-Free Survival (PFS)

ITT population included all randomized participants, who were enrolled with the non-GCB of DLBCL subtype by IHC. Participants in this population were analyzed according to the treatment to which they were randomized.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Phase II Study of Zanubrutinib, Lenalidomide Plus R-CHOP as the First-line Treatment for Diffused Large B-cell Lymphoma	NCT05200312	Non Hodgkin Lym... Diffuse Large B...	Zanubrutinib Lenalidomide Rituximab Cyclophosphamid... Doxorubicin Vincristine Prednisone (or ...	18 Years -	The First Affiliated Hospital with Nanjing Medical University
A Study of the Bruton's Tyrosine Kinase Inhibitor, PCI-32765 (Ibrutinib), in Combination With Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Patients With Newly Diagnosed Non-Germinal Center B-Cell Subtype of Diffuse Large B-Cell Lymphoma	NCT01855750	Lymphoma	Ibrutinib Placebo Rituximab Cyclophosphamid... Doxorubicin Vincristine Prednisone (or ...	18 Years -	Janssen Research & Development, LLC
A Study of the Bruton's Tyrosine Kinase Inhibitor, PCI-32765 (Ibrutinib), in Combination With Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Patients With Newly Diagnosed Non-Germinal Center B-Cell Subtype of Diffuse Large B-Cell Lymphoma	NCT01855750	Lymphoma	Ibrutinib Placebo Rituximab Cyclophosphamid... Doxorubicin Vincristine Prednisone (or ...	18 Years -	Janssen Research & Development, LLC
A Study of the Bruton's Tyrosine Kinase Inhibitor, PCI-32765 (Ibrutinib), in Combination With Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Patients With Newly Diagnosed Non-Germinal Center B-Cell Subtype of Diffuse Large B-Cell Lymphoma	NCT01855750	Lymphoma	Ibrutinib Placebo Rituximab Cyclophosphamid... Doxorubicin Vincristine Prednisone (or ...	18 Years -	Janssen Research & Development, LLC

Spots Global Cancer Trial Database for prednisone (or equivalent)