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

Tracking Information

• First Submitted Date: December 30, 2014
• First Posted Date: January 1, 2015
• Results First Submitted Date: February 9, 2023
• Results First Posted Date: June 15, 2023
• Last Update Posted Date: June 15, 2023
• Actual Study Start Date: March 11, 2015
• Actual Primary Completion Date: February 9, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 19, 2023)

• 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.
• 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.
• 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.

Original Primary Outcome Measures (submitted: December 30, 2014)

Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: 2 years ]

An AE was any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in-patient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.

Current Secondary Outcome Measures (submitted: May 19, 2023)

• 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.
• 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.
• 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.
• 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.
• 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.

Original Secondary Outcome Measures (submitted: December 30, 2014)

• Overall Response Rate (ORR) [ Time Frame: 2 years ]
  ORR is defined as the proportion of participants who achieve complete response (CR) or partial response (PR) per International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 and International Working Group (IWG) 2014 criteria over the course of the study.
• Duration of response [ Time Frame: 2 years ]
  Duration of response will be calculated from the date of initial documentation of a response (CR, or PR) to the date of first documented evidence of progressive disease (or relapse for participants who experience CR during the study) or death. participants who are progression-free and alive or have unknown status will be censored at the last tumor assessment.
• Progression-Free Survival (PFS) [ Time Frame: From the date of randomization until disease progression or death, whichever occurred first, as assessed up to the last efficacy assessment for disease progression (approximately 2 years) ]
  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 are progression-free and alive or have unknown status will be censored at the last tumor assessment.
• Overall survival [ Time Frame: From the date of randomization until disease progression or death, whichever occurred first, as assessed up to the last efficacy assessment for disease progression (approximately 2 years) ]
  Overall survival is defined as the time interval in days between the date of randomization and the participant's death from any cause.
• 1-year Progression-Free Survival (PFS) Rate [ Time Frame: 1 year ]
  The 1-year PFS rate is defined as the percentage of participants surviving 1 year after randomization without disease progression or death.
• Plasma and serum concentration of Ibrutinib and nivolumab [ Time Frame: 2 years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study to Evaluate Safety, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy of the Combination of Ibrutinib With Nivolumab in Participants With Hematologic Malignancies
• 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
• 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.
• 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 Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Hematologic Neoplasms

Intervention

• 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

Study Arms

• 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.
  Interventions:

  • Drug: Ibrutinib
  • Drug: Nivolumab
• 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.
  Interventions:

  • Drug: Ibrutinib
  • Drug: Nivolumab
• 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.
  Interventions:

  • Drug: Ibrutinib
  • Drug: Nivolumab
• 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.
  Interventions:

  • Drug: Ibrutinib
  • Drug: Nivolumab
• 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.
  Interventions:

  • Drug: Ibrutinib
  • Drug: Nivolumab
• 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.
  Interventions:

  • Drug: Ibrutinib
  • Drug: Nivolumab

Publications *

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 28, 2020): 144
• Original Estimated Enrollment (submitted: December 30, 2014): 108
• Actual Study Completion Date: February 9, 2022
• Actual Primary Completion Date: February 9, 2022 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Israel, Poland, Spain, Turkey, United States

Administrative Information

• NCT Number: NCT02329847
• Other Study ID Numbers: CR106681; PCI-32765LYM1002 ( Other Identifier: Janssen Research & Development, LLC ); 2014-005191-28 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

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

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Janssen Research & Development, LLC
• Original Responsible Party: Same as current
• Current Study Sponsor: Janssen Research & Development, LLC
• Original Study Sponsor: Same as current
• Collaborators: Bristol-Myers Squibb

Investigators

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

• PRS Account: Janssen Research & Development, LLC
• Verification Date: May 2023