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

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ClinicalTrials.gov Identifier: NCT02329847
Recruitment Status : Active, not recruiting
First Posted : January 1, 2015
Last Update Posted : July 20, 2018
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Janssen Research & Development, LLC

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 Type : Interventional  (Clinical Trial)
Actual Enrollment : 141 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
Estimated Primary Completion Date : July 15, 2019
Estimated Study Completion Date : July 31, 2019

Resource links provided by the National Library of Medicine


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




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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 or the Lugano Classification by Cheson 2014 over the course of the study.

  2. Duration of Stable Disease [ Time Frame: 2 years ]
    Duration of stable disease is measured from the start of the treatment until the criteria for progression are met. Stable disease: not meeting criteria for complete response (CR), Complete Response with an Incomplete Marrow Recovery (Cri), Nodular Partial Response (nPR), Partial Response (PR), or progressive disease (PD).

  3. 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.

  4. Progression-Free Survival (PFS) [ Time Frame: From the date of first dose of study drug 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.

  5. Overall survival [ Time Frame: From the date of first dose of study drug 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 first dose of study drug and the participant's death from any cause.

  6. 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 first dose of study drug without disease progression or death.

  7. Plasma and serum concentration of Ibrutinib and nivolumab [ Time Frame: 2 years ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02329847


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
İzmir, Turkey
Sponsors and Collaborators
Janssen Research & Development, LLC
Bristol-Myers Squibb
Investigators
Study Director: Janssen Research & Development, LLC Clinical Trial Janssen Research & Development, LLC

Responsible Party: Janssen Research & Development, LLC
ClinicalTrials.gov Identifier: NCT02329847     History of Changes
Other Study ID Numbers: CR106681
PCI-32765LYM1002 ( Other Identifier: Janssen Research & Development, LLC )
2014-005191-28 ( EudraCT Number )
First Posted: January 1, 2015    Key Record Dates
Last Update Posted: July 20, 2018
Last Verified: July 2018

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 by Site
Neoplasms
Hematologic Diseases
Nivolumab
Antibodies, Monoclonal
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs