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NCT02329847

A Study to Evaluate Safety, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy of the Combination of Ibrutinib With Nivolumab in Participants With Hematologic Malignancies

Completed Phase 1, PHASE2 Results posted Last updated 25 May 2025
What this trial tests

Phase 1, PHASE2 trial testing Ibrutinib in Hematologic Neoplasms in 144 participants. Completed in 9 February 2022.

Timeline
11 March 2015
Primary endpoint
9 February 2022
9 February 2022

Quick facts

Lead sponsorJanssen Research & Development, LLC
PhasePhase 1, PHASE2
StatusCompleted
Study typeINTERVENTIONAL
Allocationnon randomized
Designparallel
Maskingnone
Primary purposetreatment
Enrollment144
Start date11 March 2015
Primary completion9 February 2022
Estimated completion9 February 2022
Sites18 locations across Israel, Poland, Australia, United States, Turkey (Türkiye), Spain

Drugs / interventions tested

Conditions studied

Sponsor

Janssen Research & Development, LLC — full company profile →

Who can join

18 and older, any sex, with Hematologic Neoplasms. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Overall Response Rate (ORR) as Assessed International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008: Disease Cohort Primary · Up to 6 years 11 months

ORR is percentage of participants achieving a complete response (CR), CR with incomplete marrow recovery (CRi), nodular partial response (nPR) or PR. IWCLL 2008 criteria: CR- No lymphadenopathy and hepatosplenomegaly, no constitutional symptoms, neutrophils \>1.5\*10\^9/L, platelets \>100\*10\^9/L, Hgb \>11 g/dL and absolute lymphocyte count \<4000/mcL; CRi- CR with incomplete recovery of bone marrow; nPR- participants meet criteria for CR, but the bone marrow biopsy shows B-lymphoid nodules, may represent a clonal infiltrate; PR- \>=50% drop in lymphocyte count from baseline or \<=4.0\*10\^9/

GroupValue95% CI
Ibrutinib and Nivolumab: Chronic Lymphocytic Leukemia (CLL)63.3
Overall Response Rate (ORR) as Assessed Non-Hodgkin Lymphoma (NHL), Cheson 2014: Disease Cohort Primary · Up to 6 years 11 months

ORR defined as percentage of participants achieving a CR, CRi, nPR or PR. As per Non-Hodgkin Lymphoma, Cheson 2014, CR is complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. PR is \>= 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses. Progressive disease (PD) \>= 50% increase from nadir in the sum of the products of at least two lymph nodes, or appearance of a new lesion greater than 1.5 cm in any axis even if other lesions are decreasing in size. SD is nei

GroupValue95% CI
Ibrutinib and Nivolumab: Small Lymphocytic Lymphoma (SLL)50.0
Ibrutinib and Nivolumab: Follicular Lymphoma (FL)32.5
Ibrutinib and Nivolumab: Diffuse Large B-cell Lymphoma (DLBCL)37.8
Ibrutinib and Nivolumab: Richter65.0
Percentage of Participants With Treatment-emergent Adverse Event (TEAEs): Study Cohort Primary · Up to 6 years 10 months

An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/ biological agent under study. TEAEs for the treatment phase included events with an onset date/time on or after the start of study intervention through end of study were considered as treatment-emergent.

GroupValue95% CI
Cohort A1 (CLL/FL/DLBCL): Ibrutinib 420 mg + Nivolumab 3 mg/kg100
Cohort A2 (FL/DLBCL): Ibrutinib 560 mg + Nivolumab 3 mg/kg100
Cohort B1 (CLL/SLL): Ibrutinib 420 mg + Nivolumab 3 mg/kg100
Cohort B2 (FL): Ibrutinib 560 mg + Nivolumab 3 mg/kg100
Cohort B3 (DLBCL): Ibrutinib 560 mg + Nivolumab 3 mg/kg97.3
Cohort B4 (Richter Syndrome): Ibrutinib 560 mg + Nivolumab 3 mg/kg95.0
Duration of Response (DoR): Study Cohort Secondary · Up to 6 years 11 months

DOR is defined as the interval between the date of initial documentation of a response including partial response with lymphocytosis (PRL) and date of first documented evidence of progressive disease or death or date of censoring. iWCLL 2008 criteria for progressive disease: New enlarged nodes \>1.5 cm, new hepatomegaly or splenomegaly, or other organ infiltrates; \>= 50% increase from nadir in existing lymph node or \>=50% increase from nadir in sum of product of diameters of multiple nodes; \>=50% increase from nadir in enlargement of liver or spleen; \>=50% increase from baseline in lymphoc

GroupValue95% CI
Cohort A1 (CLL/FL/DLBCL): Ibrutinib 420 mg + Nivolumab 3 mg/kg11.52.4 – 20.7
Cohort A2 (FL/DLBCL): Ibrutinib 560 mg + Nivolumab 3 mg/kgNANA – NA
Cohort B1 (CLL/SLL): Ibrutinib 420 mg + Nivolumab 3 mg/kg19.29.4 – 19.4
Cohort B2 (FL): Ibrutinib 560 mg + Nivolumab 3 mg/kg10.25.1 – 17.8
Cohort B3 (DLBCL): Ibrutinib 560 mg + Nivolumab 3 mg/kgNA4.6 – NA
Cohort B4 (Richter Syndrome): Ibrutinib 560 mg + Nivolumab 3 mg/kg6.91.3 – NA
Duration of Stable Disease or Better: Study Cohort Secondary · Up to 6 years and 11 months

Duration of stable disease or better was defined as duration from the start of the treatment until the criteria for progression were met. IWCLL 2008 criteria for progressive disease: New enlarged nodes \>1.5 cm, new hepatomegaly or splenomegaly, or other organ infiltrates; \>= 50% increase from nadir in existing lymph node or \>=50% increase from nadir in sum of product of diameters of multiple nodes; \>=50% increase from nadir in enlargement of liver or spleen; \>=50% increase from baseline in lymphocyte count (and to \>=5\*10\^9/L) unless considered treatment-related lymphocytosis; new cytop

GroupValue95% CI
Cohort A1 (CLL/FL/DLBCL): Ibrutinib 420 mg + Nivolumab 3 mg/kg24.824.8 – 24.8
Cohort A2 (FL/DLBCL): Ibrutinib 560 mg + Nivolumab 3 mg/kg20.820.8 – 20.8
Cohort B1 (CLL/SLL): Ibrutinib 420 mg + Nivolumab 3 mg/kg17.3814.0 – 21.6
Cohort B2 (FL): Ibrutinib 560 mg + Nivolumab 3 mg/kg14.5512.7 – 20.4
Cohort B3 (DLBCL): Ibrutinib 560 mg + Nivolumab 3 mg/kg14.114.1 – 14.1
Progression-free Survival (PFS): Study Cohort Secondary · Up to 6 years 11 months

PFS is defined as the duration from the date of first dose of study drug until the date of first documented evidence of progressive disease (or relapse for participants who experience CR during the study) or death, whichever comes first. Participants who were progression-free and alive or had unknown status were censored at the last tumor assessment. IWCLL 2008 criteria for progressive disease: New enlarged nodes \>1.5 cm, new hepatomegaly or splenomegaly, or other organ infiltrates; \>= 50% increase from nadir in existing lymph node or \>=50% increase from nadir in sum of product of diameters

GroupValue95% CI
Cohort A1 (CLL/FL/DLBCL): Ibrutinib 420 mg + Nivolumab 3 mg/kg2.01.1 – 24.8
Cohort A2 (FL/DLBCL): Ibrutinib 560 mg + Nivolumab 3 mg/kg9.10.7 – 20.8
Cohort B1 (CLL/SLL): Ibrutinib 420 mg + Nivolumab 3 mg/kg21.612.0 – 21.6
Cohort B2 (FL): Ibrutinib 560 mg + Nivolumab 3 mg/kg7.62.9 – 12.7
Cohort B3 (DLBCL): Ibrutinib 560 mg + Nivolumab 3 mg/kg3.22.1 – NA
Cohort B4 (Richter Syndrome): Ibrutinib 560 mg + Nivolumab 3 mg/kg5.02.4 – NA
Overall Survival (OS): Study Cohort Secondary · Up to 6 years 11 months

OS was defined as duration from the date of first dose of study drug to the date of the participant's death.

GroupValue95% CI
Cohort A1 (CLL/FL/DLBCL): Ibrutinib 420 mg + Nivolumab 3 mg/kg12.42.0 – 28.8
Cohort A2 (FL/DLBCL): Ibrutinib 560 mg + Nivolumab 3 mg/kgNA0.8 – NA
Cohort B1 (CLL/SLL): Ibrutinib 420 mg + Nivolumab 3 mg/kgNA21.6 – NA
Cohort B2 (FL): Ibrutinib 560 mg + Nivolumab 3 mg/kgNANA – NA
Cohort B3 (DLBCL): Ibrutinib 560 mg + Nivolumab 3 mg/kg19.07.7 – NA
Cohort B4 (Richter Syndrome): Ibrutinib 560 mg + Nivolumab 3 mg/kg10.34.8 – NA
Percentage of Participants With Lymphoma-related Symptoms: Study Cohort Secondary · Up to 6 years 11 months

Percentage of participants with lymphoma-related symptoms were reported. These symptoms included B-symptoms, recurrent fever, night sweats, weight loss, other disease-related symptoms, itching, fatigue, physical discomfort and any other.

GroupValue95% CI
Cohort A1 (CLL/FL/DLBCL): Ibrutinib 420 mg + Nivolumab 3 mg/kg14.3
Cohort A2 (FL/DLBCL): Ibrutinib 560 mg + Nivolumab 3 mg/kg42.9
Cohort B1 (CLL/SLL): Ibrutinib 420 mg + Nivolumab 3 mg/kg74.3
Cohort B2 (FL): Ibrutinib 560 mg + Nivolumab 3 mg/kg25.7
Cohort B3 (DLBCL): Ibrutinib 560 mg + Nivolumab 3 mg/kg54.1
Cohort B4 (Richter Syndrome): Ibrutinib 560 mg + Nivolumab 3 mg/kg60.0

Adverse events — posted to ClinicalTrials.gov

Time frame: Up to 6 years 11 months. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Cohort A1 (CLL/FL/DLBCL): Ibrutinib 420 mg + Nivolumab 3 mg/kg
Serious: 4/7 (57%)
Deaths: 4/7
Cohort A2 (FL/DLBCL): Ibrutinib 560 mg + Nivolumab 3 mg/kg
Serious: 3/7 (43%)
Deaths: 4/7
Cohort B1 (CLL/SLL): Ibrutinib 420 mg + Nivolumab 3 mg/kg
Serious: 23/35 (66%)
Deaths: 22/36
Cohort B2 (FL): Ibrutinib 560 mg + Nivolumab 3 mg/kg
Serious: 15/35 (43%)
Deaths: 12/35
Cohort B3 (DLBCL): Ibrutinib 560 mg + Nivolumab 3 mg/kg
Serious: 23/37 (62%)
Deaths: 20/39
Cohort B4 (Richter Syndrome): Ibrutinib 560 mg + Nivolumab 3 mg/kg
Serious: 15/20 (75%)
Deaths: 13/20

Serious adverse events (104 terms)

ReactionSystemCohort A1 (CLL/FL/DLBCL): …Cohort A2 (FL/DLBCL): Ibru…Cohort B1 (CLL/SLL): Ibrut…Cohort B2 (FL): Ibrutinib …Cohort B3 (DLBCL): Ibrutin…Cohort B4 (Richter Syndrom…
AnaemiaBlood and lymphatic system disorders
Febrile NeutropeniaBlood and lymphatic system disorders
LymphadenopathyBlood and lymphatic system disorders
Cardiac FailureCardiac disorders
Abdominal PainGastrointestinal disorders
PyrexiaGeneral disorders
PneumoniaInfections and infestations
Pneumonia BacterialInfections and infestations
HydronephrosisRenal and urinary disorders
DyspnoeaRespiratory, thoracic and mediastinal disorders
PneumonitisRespiratory, thoracic and mediastinal disorders
NeutropeniaBlood and lymphatic system disorders
PancytopeniaBlood and lymphatic system disorders
SplenomegalyBlood and lymphatic system disorders
Atrial FibrillationCardiac disorders
CardiotoxicityCardiac disorders
Myocardial InfarctionCardiac disorders
CataractEye disorders
Abdominal DiscomfortGastrointestinal disorders
ColitisGastrointestinal disorders
DiarrhoeaGastrointestinal disorders
EnterocolitisGastrointestinal disorders
Gastric HaemorrhageGastrointestinal disorders
GastritisGastrointestinal disorders
Gastrointestinal HaemorrhageGastrointestinal disorders
Other adverse events (207 terms — click to expand)

ReactionSystemCohort A1 (CLL/FL/DLBCL): …Cohort A2 (FL/DLBCL): Ibru…Cohort B1 (CLL/SLL): Ibrut…Cohort B2 (FL): Ibrutinib …Cohort B3 (DLBCL): Ibrutin…Cohort B4 (Richter Syndrom…
NeutropeniaBlood and lymphatic system disorders
FatigueGeneral disorders
DiarrhoeaGastrointestinal disorders
AnaemiaBlood and lymphatic system disorders
ThrombocytopeniaBlood and lymphatic system disorders
Upper Respiratory Tract InfectionInfections and infestations
CoughRespiratory, thoracic and mediastinal disorders
RashSkin and subcutaneous tissue disorders
PyrexiaGeneral disorders
ArthralgiaMusculoskeletal and connective tissue disorders
NauseaGastrointestinal disorders
Muscle SpasmsMusculoskeletal and connective tissue disorders
Lipase IncreasedInvestigations
HypokalaemiaMetabolism and nutrition disorders
Oedema PeripheralGeneral disorders
VomitingGastrointestinal disorders
Pain in ExtremityMusculoskeletal and connective tissue disorders
Abdominal PainGastrointestinal disorders
ConstipationGastrointestinal disorders
AstheniaGeneral disorders
PneumoniaInfections and infestations
Alanine Aminotransferase IncreasedInvestigations
Amylase IncreasedInvestigations
Blood Creatinine IncreasedInvestigations
HypomagnesaemiaMetabolism and nutrition disorders
Back PainMusculoskeletal and connective tissue disorders
MyalgiaMusculoskeletal and connective tissue disorders
HeadacheNervous system disorders
PneumonitisRespiratory, thoracic and mediastinal disorders
HaematomaVascular disorders
Non-Cardiac Chest PainGeneral disorders
BronchitisInfections and infestations
Lower Respiratory Tract InfectionInfections and infestations
NasopharyngitisInfections and infestations
SinusitisInfections and infestations
Aspartate Aminotransferase IncreasedInvestigations
Decreased AppetiteMetabolism and nutrition disorders
HyperglycaemiaMetabolism and nutrition disorders
ArthritisMusculoskeletal and connective tissue disorders
DyspnoeaRespiratory, thoracic and mediastinal disorders

Most-reported serious reactions: Anaemia, Febrile Neutropenia, Lymphadenopathy, Cardiac Failure, Abdominal Pain, Pyrexia, Pneumonia, Pneumonia Bacterial.

Data from ClinicalTrials.gov NCT02329847 adverse events section.

Sponsor's own description

The purpose of this study is to determine the safety and to establish the recommended phase 2 dose (RP2D) for the combination of ibrutinib and nivolumab in participants with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), follicular cell lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Once the dose is optimized, the combination will be assessed for Pharmacokinetics, Pharmacodynamics, and preliminary efficacy, further safety in participants with CLL/SLL, FL or DLBCL and in participants with Richter syndrome.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Safety and activity of ibrutinib in combination with nivolumab in patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukaemia: a phase 1/2a study.
    Younes A, Brody J, Carpio C, Lopez-Guillermo A, et al · · 2019 · cited 166× · PMID 30642819 · DOI 10.1016/s2352-3026(18)30217-5
  2. Immunotherapy in hematologic malignancies: achievements, challenges and future prospects.
    Tang L, Huang Z, Mei H, Hu Y. · · 2023 · cited 98× · PMID 37591844 · DOI 10.1038/s41392-023-01521-5
  3. T-cells in chronic lymphocytic leukemia: Guardians or drivers of disease?
    Roessner PM, Seiffert M. · · 2020 · cited 93× · PMID 32457353 · DOI 10.1038/s41375-020-0873-2
  4. Advances in targeted therapy for malignant lymphoma.
    Wang L, Qin W, Huo YJ, Li X, et al · · 2020 · cited 88× · PMID 32296035 · DOI 10.1038/s41392-020-0113-2
  5. PD-1/PD-L1 Based Combinational Cancer Therapy: Icing on the Cake.
    Zhang JY, Yan YY, Li JJ, Adhikari R, et al · · 2020 · cited 72× · PMID 32528284 · DOI 10.3389/fphar.2020.00722
  6. Non-Hodgkin lymphoma across the pediatric and adolescent and young adult age spectrum.
    Sandlund JT, Martin MG. · · 2016 · cited 59× · PMID 27913533 · DOI 10.1182/asheducation-2016.1.589
  7. Combining targeted therapy with immunotherapy. Can 1+1 equal more than 2?
    Robert L, Ribas A, Hu-Lieskovan S. · · 2016 · cited 58× · PMID 26861544 · DOI 10.1016/j.smim.2016.01.001
  8. Immune Dysfunctions and Immune-Based Therapeutic Interventions in Chronic Lymphocytic Leukemia.
    Griggio V, Perutelli F, Salvetti C, Boccellato E, et al · · 2020 · cited 54× · PMID 33312177 · DOI 10.3389/fimmu.2020.594556

Verify or expand the search:

Other trials of Ibrutinib

Trials testing the same drug.

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Trials by the same sponsor.

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Primary sources · FDA · ClinicalTrials.gov · EMA · SEC EDGAR · ChEMBL · Wikidata · full sourcing