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

• ClinicalTrials.gov Identifier: NCT02329847
• Recruitment Status: Completed
• First Posted: January 1, 2015
• Results First Posted: June 15, 2023
• Last Update Posted: June 15, 2023
• Sponsor: Janssen Research & Development, LLC
• Collaborator: Bristol-Myers Squibb
• Information provided by (Responsible Party): Janssen Research & Development, LLC

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Hematologic Neoplasms	Drug: Ibrutinib; Drug: Nivolumab	Phase 1; Phase 2

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 144 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: March 11, 2015
• Actual Primary Completion Date: February 9, 2022
• Actual Study Completion Date: February 9, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cohort A1; 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; 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.; Other Name: JNJ54179060; Drug: Nivolumab; Participants will receive nivolumab intravenously as 3 mg/kg on Day 1 every cycle of 14 days.; Other Name: BMS-936558
Experimental: Cohort A2; 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; 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.; Other Name: JNJ54179060; Drug: Nivolumab; Participants will receive nivolumab intravenously as 3 mg/kg on Day 1 every cycle of 14 days.; Other Name: BMS-936558
Experimental: Cohort B1; 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; 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.; Other Name: JNJ54179060; Drug: Nivolumab; Participants will receive nivolumab intravenously as 3 mg/kg on Day 1 every cycle of 14 days.; Other Name: BMS-936558
Experimental: Cohort B2; 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; 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.; Other Name: JNJ54179060; Drug: Nivolumab; Participants will receive nivolumab intravenously as 3 mg/kg on Day 1 every cycle of 14 days.; Other Name: BMS-936558
Experimental: Cohort B3; 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; 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.; Other Name: JNJ54179060; Drug: Nivolumab; Participants will receive nivolumab intravenously as 3 mg/kg on Day 1 every cycle of 14 days.; Other Name: BMS-936558
Experimental: Cohort B4; 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; 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.; Other Name: JNJ54179060; Drug: Nivolumab; Participants will receive nivolumab intravenously as 3 mg/kg on Day 1 every cycle of 14 days.; Other Name: BMS-936558

Outcome Measures

Primary Outcome Measures :

1. Overall Response Rate (ORR) as Assessed International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008: Disease Cohort [ Time Frame: 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/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.
2. Overall Response Rate (ORR) as Assessed Non-Hodgkin Lymphoma (NHL), Cheson 2014: Disease Cohort [ Time Frame: 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 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.
3. Percentage of Participants With Treatment-emergent Adverse Event (TEAEs): Study Cohort [ Time Frame: 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.

Secondary Outcome Measures :

1. Duration of Response (DoR): Study Cohort [ Time Frame: 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 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.
2. Duration of Stable Disease or Better: Study Cohort [ Time Frame: 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 cytopenia (Hemoglobin b or platelets) attributable to CLL; transformation to a more aggressive histology.
3. Progression-free Survival (PFS): Study Cohort [ Time Frame: 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 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.
4. Overall Survival (OS): Study Cohort [ Time Frame: 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.
5. Percentage of Participants With Lymphoma-related Symptoms: Study Cohort [ Time Frame: 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, New York

New York, New York, United States

Australia

Bedford Park, Australia

Darlinghurst, Australia

Woolloongabba, Australia

Israel

Haifa, Israel

Jeursalem, Israel

Ramat Gan, Israel

Tel Aviv, Israel

Poland

Chorzow, Poland

Gdansk, Poland

Krakow, Poland

Wroclaw, Poland

Spain

Barcelona, Spain

Madrid, Spain

Salamanca, Spain

Turkey

Ankara, Turkey

Istanbul, Turkey

Izmir, Turkey

Sponsors and Collaborators

Janssen Research & Development, LLC

Bristol-Myers Squibb

Investigators

• Study Director: Janssen Research & Development, LLC Clinical Trial; Janssen Research & Development, LLC

  Study Documents (Full-Text)

Documents provided by Janssen Research & Development, LLC:

Study Protocol  [PDF] October 12, 2020

Statistical Analysis Plan  [PDF] August 9, 2017

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Bruscaggin A, di Bergamo LT, Spina V, Hodkinson B, Forestieri G, Bonfiglio F, Condoluci A, Wu W, Pirosa MC, Faderl MR, Koch R, Schaffer M, Alvarez JD, Fourneau N, Gerber B, Stussi G, Zucca E, Balasubramanian S, Rossi D. Circulating tumor DNA for comprehensive noninvasive monitoring of lymphoma treated with ibrutinib plus nivolumab. Blood Adv. 2021 Nov 23;5(22):4674-4685. doi: 10.1182/bloodadvances.2021004528. Erratum In: Blood Adv. 2023 Jan 10;7(1):159-161.

Younes A, Brody J, Carpio C, Lopez-Guillermo A, Ben-Yehuda D, Ferhanoglu B, Nagler A, Ozcan M, Avivi I, Bosch F, Caballero Barrigon MD, Hellmann A, Kuss B, Ma DDF, Demirkan F, Yagci M, Horowitz NA, Marlton P, Cordoba R, Wrobel T, Buglio D, Streit M, Hodkinson BP, Schaffer M, Alvarez J, Ceulemans R, Balasubramanian S, de Jong J, Wang SS, Fourneau N, Jurczak W. 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. Lancet Haematol. 2019 Feb;6(2):e67-e78. doi: 10.1016/S2352-3026(18)30217-5. Epub 2019 Jan 11.

• Responsible Party: Janssen Research & Development, LLC
• ClinicalTrials.gov Identifier: NCT02329847
• Other Study ID Numbers: CR106681; PCI-32765LYM1002 ( Other Identifier: Janssen Research & Development, LLC ); 2014-005191-28 ( EudraCT Number )
• First Posted: January 1, 2015
• Results First Posted: June 15, 2023
• Last Update Posted: June 15, 2023
• Last Verified: May 2023

• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Janssen Research & Development, LLC:

Hematologic Neoplasms; JNJ54179060; Ibrutinib; Nivolumab

Additional relevant MeSH terms:

Hematologic Neoplasms; Neoplasms; Neoplasms by Site; Hematologic Diseases; Nivolumab; Ibrutinib; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action; Tyrosine Kinase Inhibitors; Protein Kinase Inhibitors; Enzyme Inhibitors