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

Study Overview
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Brief Summary
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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.

Detailed Description
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This is an open-label study, which consists of Part A (Dose Optimization Cohorts) and Part B (Expansion Cohorts). Part A consists of two dose optimization cohorts (cohort A1 and cohort A2) will determine the RP2D for the combination based on safety, pharmacokinetic, and pharmacodynamic assessments in participants with relapsed/refractory CLL/SLL or B-cell non-Hodgkin lymphoma (B-NHL). Part B consists 3 participant populations to further evaluate the safety and clinical activity of ibrutinib in combination with nivolumab: Cohort B1 (participants with CLL/SLL with del 17p or del 11q), Cohort B2 (participants with FL), Cohort B3 (participants with DLBCL) and Cohort B4 (participants with Richter syndrome). Part A and B will consist of Screening Period (28 days before enrollment), Treatment Period and Follow up Period (every 3 months until death or the end of study). Participants will receive nivolumab intravenously (Day 1 of every cycle) and ibrutinib orally once daily on a 14-day cycle. Efficacy will primarily be evaluated by International Workshop on Chronic Lymphocytic Leukemia (IWCLL) and International Working Group (IWG) for lymphoma guidelines. Participants' safety will be monitored throughout the study. Further exploration of pharmacokinetic/pharmacodynamic and biomarker information will be assessed throughout the trial.

Official Title
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A Phase 1/2a Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of the Combination of Ibrutinib With Nivolumab in Subjects With Hematologic Malignancies

Conditions
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Hematologic Neoplasms

Intervention / Treatment
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* Drug: Ibrutinib
* Drug: Nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) performance status grade 0, 1, or 2 Adequate bone marrow, liver, and renal function defined as: 1) Absolute neutrophil count (ANC) greater than equal to (>=) 1.5* 10^9cells/litre (L); 2) Platelets >=75 x 109cells/L without transfusion support within 7 days prior to test; 3) Hemoglobin >= 8 gram/deciliter (g/dL) without transfusion support within 7 days prior to test 4) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than equal to (<=) 2.5 * upper limit of normal (ULN) 5) Total bilirubin less than (<) 2 milligram/deciliter (mg/dL) 6) Creatinine determined by serum creatinine levels <=1.5 * ULN or a calculated creatinine clearance of >= 50 mL/min/1.73 m^2 Histologically confirmed B-cell non-Hodgkin lymphoma (B-NHL), Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) Relapsed refractory disease after at least 1 but not more than 4 lines of previous systemic therapy Measurable disease (NHL: At least 1 measurable site of disease [>1.5 centimeter [cm] in the long axis regardless of short axis measurement or >1.0 cm in the short axis regardless of long axis measurement, and clearly measurable in 2 perpendicular dimensions]) Cohort B-1: SLL/CLL: 1) Deletion of short arm of chromosome 17 or 11 q based on institutional assessment 2) Relapsed/refractory after at least 1 prior systemic therapy 3) Active disease based in IWCLL criteria Cohort B-2: 1) B- cell follicular lymphoma Grade 1, 2, or 3a (WHO criteria) 2) Relapsed/refractory disease >= 2 lines separated by Progression, prior treatment (or not eligible for receiving) CD20 antibody 3) Measurable disease (IWG -Lugano 2014) Cohort B-3: 1) Histologically-confirmed DLBCL 2) Prior standard rituximab + anthracyclin containing regimen, received or not eligible or considered candidate of HD-ASCT 3) Measurable disease (IWG -Lugano 2014) Cohort B-4: 1) Histologically-confirmed Richter syndrome defined as transformation of CLL or SLL into an aggressive lymphoma 2) Previously treated with at least one line of standard, systemic chemotherapy or not eligible for standard therapy 3) At least 1 measurable site of disease based on the Revised Response Criteria for Malignant Lymphoma Exclusion Criteria: Prior therapy or surgery (3 to 10 weeks depending type) Prior BTK inhibitor or anti PD1, anti PDL1, anti PD-L2 and anti-CD137, anti-cytotoxic T-lymphocyte associated antigen (CTLA-4) antibody 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, or congenital long QT syndrome, or QT interval corrected for heart rate, using Fridericia formula (QTcF) at Screening greater than (>) 470 milliseconds (ms) History of stroke or intracranial hemorrhage within 6 months prior to the first dose of ibrutinib Requires treatment with anticoagulation with warfarin or equivalent vitamin K antagonists Requires treatment with strong cytochrome P450 3A (CYP3A) inhibitors Known history of Human Immunodeficiency Virus (HIV), Hepatitis B or Hepatitis C

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A1<br>Participants will receive ibrutinib 420 milligram (mg) capsule orally once daily and nivolumab intravenously as 3 milligram/kilogram (mg/kg) every 2 weeks for 14-daily dosing cycles and will be continued until disease progression or unacceptable toxicity. | Drug: Ibrutinib<br>* Participants will receive oral capsule of ibrutinib once daily as either 420 mg or 560 mg or at recommended Phase 2 dose in any of the cohort.<br>* Other names: JNJ54179060;Drug: Nivolumab<br>* Participants will receive nivolumab intravenously as 3 mg/kg on Day 1 every cycle of 14 days.<br>* Other names: BMS-936558;|
| Experimental: Cohort A2<br>Participants will receive ibrutinib 560 mg capsule orally once daily and nivolumab intravenously as 3 mg/kg every 2 weeks for 14-daily dosing cycles and will be continued until disease progression or unacceptable toxicity. | Drug: Ibrutinib<br>* Participants will receive oral capsule of ibrutinib once daily as either 420 mg or 560 mg or at recommended Phase 2 dose in any of the cohort.<br>* Other names: JNJ54179060;Drug: Nivolumab<br>* Participants will receive nivolumab intravenously as 3 mg/kg on Day 1 every cycle of 14 days.<br>* Other names: BMS-936558;|
| Experimental: Cohort B1<br>Participants will receive ibrutinib recommended Phase 2 dose (RP2D) orally once daily and nivolumab intravenously as 3 mg/kg every 2 weeks for 14-daily dosing cycles and will be continued until disease progression or unacceptable toxicity. | Drug: Ibrutinib<br>* Participants will receive oral capsule of ibrutinib once daily as either 420 mg or 560 mg or at recommended Phase 2 dose in any of the cohort.<br>* Other names: JNJ54179060;Drug: Nivolumab<br>* Participants will receive nivolumab intravenously as 3 mg/kg on Day 1 every cycle of 14 days.<br>* Other names: BMS-936558;|
| Experimental: Cohort B2<br>Participants will receive ibrutinib recommended Phase 2 dose (RP2D) orally once daily and nivolumab intravenously as 3 mg/kg every 2 weeks for 14-daily dosing cycles and will be continued until disease progression or unacceptable toxicity. | Drug: Ibrutinib<br>* Participants will receive oral capsule of ibrutinib once daily as either 420 mg or 560 mg or at recommended Phase 2 dose in any of the cohort.<br>* Other names: JNJ54179060;Drug: Nivolumab<br>* Participants will receive nivolumab intravenously as 3 mg/kg on Day 1 every cycle of 14 days.<br>* Other names: BMS-936558;|
| Experimental: Cohort B3<br>Participants will receive ibrutinib recommended Phase 2 dose (RP2D) orally once daily and nivolumab intravenously as 3 mg/kg every 2 weeks for 14-daily dosing cycles and will be continued until disease progression or unacceptable toxicity. | Drug: Ibrutinib<br>* Participants will receive oral capsule of ibrutinib once daily as either 420 mg or 560 mg or at recommended Phase 2 dose in any of the cohort.<br>* Other names: JNJ54179060;Drug: Nivolumab<br>* Participants will receive nivolumab intravenously as 3 mg/kg on Day 1 every cycle of 14 days.<br>* Other names: BMS-936558;|
| Experimental: Cohort B4<br>Participants will receive ibrutinib recommended Phase 2 dose (RP2D) orally once daily and nivolumab intravenously as 3 mg/kg every 2 weeks for 14-daily dosing cycles and will be continued until disease progression or unacceptable toxicity. | Drug: Ibrutinib<br>* Participants will receive oral capsule of ibrutinib once daily as either 420 mg or 560 mg or at recommended Phase 2 dose in any of the cohort.<br>* Other names: JNJ54179060;Drug: Nivolumab<br>* Participants will receive nivolumab intravenously as 3 mg/kg on Day 1 every cycle of 14 days.<br>* Other names: BMS-936558;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) as Assessed International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008: Disease Cohort | 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/L with following: >=50% decrease in sum products of up to 6 lymph nodes, no new enlarged lymph nodes, When abnormal, >=50% decrease in enlargement of spleen from baseline or normalization and a response in 1 of following: Neutrophils >1.5*10^9/L, Platelets>100000/mcL and Hgb>11 g/dL or >=50% improvement over baseline in all. This outcome measure was planned to be analyzed for specified arm only. | Up to 6 years 11 months | 
| Overall Response Rate (ORR) as Assessed Non-Hodgkin Lymphoma (NHL), Cheson 2014: Disease Cohort | 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 neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. This outcome measure was planned to be analyzed for specified arms only. | Up to 6 years 11 months | 
| Percentage of Participants With Treatment-emergent Adverse Event (TEAEs): Study Cohort | 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. | Up to 6 years 10 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response (DoR): Study Cohort | 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 lymphocyte count (>=5*10^9/L) unless considered treatment-related lymphocytosis; new cytopenia (Hemoglobin b or platelets) attributable to CLL; transformation to a more aggressive histology. | Up to 6 years 11 months | 
| Duration of Stable Disease or Better: Study Cohort | 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 cytopenia (Hemoglobin b or platelets) attributable to CLL; transformation to a more aggressive histology. | Up to 6 years and 11 months | 
| Progression-free Survival (PFS): Study Cohort | 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 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 cytopenia (Hemoglobin b or platelets) attributable to CLL; transformation to a more aggressive histology. | Up to 6 years 11 months | 
| Overall Survival (OS): Study Cohort | OS was defined as duration from the date of first dose of study drug to the date of the participant's death. | Up to 6 years 11 months | 
| Percentage of Participants With Lymphoma-related Symptoms: Study Cohort | 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. | Up to 6 years 11 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hematologic Neoplasms, JNJ54179060, Ibrutinib, Nivolumab