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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

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2017 by Janssen Research & Development, LLC
Sponsor:
Collaborator:
Bristol Meyers Squibb (BMS)
Information provided by (Responsible Party):
Janssen Research & Development, LLC
ClinicalTrials.gov Identifier:
NCT02329847
First received: December 30, 2014
Last updated: February 20, 2017
Last verified: February 2017
  Purpose
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 Intervention Phase
Hematologic Neoplasms
Drug: Ibrutinib
Drug: Nivolumab
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: No masking
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

Resource links provided by NLM:


Further study details as provided by Janssen Research & Development, LLC:

Primary Outcome Measures:
  • 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:
  • 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.

  • 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).

  • 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 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.

  • 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.

  • 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.

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

Estimated Enrollment: 158
Study Start Date: March 2015
Estimated Study Completion Date: May 2018
Estimated Primary Completion Date: February 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.
  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
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
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02329847

Contacts
Contact: Use link at the bottom of the page to see if you qualify for an enrolling site (see list). If you still have questions: JNJ.CT@sylogent.com

Locations
United States, Georgia
Withdrawn
Atlanta, Georgia, United States
United States, New York
Recruiting
New York, New York, United States
United States, Pennsylvania
Withdrawn
Pittsburgh, Pennsylvania, United States
Australia
Recruiting
Bedford Park, Australia
Recruiting
Darlinghurst, Australia
Withdrawn
Heidelberg, Australia
Recruiting
Woolloongabba, Australia
Israel
Recruiting
Haifa, Israel
Recruiting
Jeursalem, Israel
Recruiting
Ramat Gan, Israel
Recruiting
Tel Aviv, Israel
Poland
Completed
Chorzow, Poland
Recruiting
Gdansk, Poland
Recruiting
Krakow, Poland
Recruiting
Wroclaw, Poland
Spain
Recruiting
Barcelona, Spain
Recruiting
Madrid, Spain
Recruiting
Salamanca, Spain
Turkey
Recruiting
Ankara, Turkey
Recruiting
Istanbul, Turkey
Recruiting
İzmir, Turkey
Sponsors and Collaborators
Janssen Research & Development, LLC
Bristol Meyers Squibb (BMS)
Investigators
Study Director: Janssen Research & Development, LLC Clinical Trial Janssen Research & Development, LLC
  More Information

Additional Information:
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 )
Study First Received: December 30, 2014
Last Updated: February 20, 2017

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

ClinicalTrials.gov processed this record on March 24, 2017