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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT02329847
Registration number
NCT02329847
Ethics application status
Date submitted
30/12/2014
Date registered
1/01/2015
Date last updated
15/06/2023
Titles & IDs
Public title
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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Scientific 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
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Secondary ID [1]
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PCI-32765LYM1002
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Secondary ID [2]
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CR106681
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Hematologic Neoplasms
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Condition category
Condition code
Cancer
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Leukaemia - Acute leukaemia
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Cancer
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Leukaemia - Chronic leukaemia
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Ibrutinib
Treatment: Drugs - Nivolumab
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.
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.
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.
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.
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.
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.
Treatment: Drugs: 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.
Treatment: Drugs: Nivolumab
Participants will receive nivolumab intravenously as 3 mg/kg on Day 1 every cycle of 14 days.
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Overall Response Rate (ORR) as Assessed International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008: Disease Cohort
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Assessment method [1]
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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.
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Timepoint [1]
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Up to 6 years 11 months
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Primary outcome [2]
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Overall Response Rate (ORR) as Assessed Non-Hodgkin Lymphoma (NHL), Cheson 2014: Disease Cohort
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Assessment method [2]
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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.
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Timepoint [2]
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Up to 6 years 11 months
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Primary outcome [3]
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Percentage of Participants With Treatment-emergent Adverse Event (TEAEs): Study Cohort
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Assessment method [3]
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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.
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Timepoint [3]
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Up to 6 years 10 months
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Secondary outcome [1]
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Duration of Response (DoR): Study Cohort
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Assessment method [1]
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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.
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Timepoint [1]
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Up to 6 years 11 months
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Secondary outcome [2]
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Duration of Stable Disease or Better: Study Cohort
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Assessment method [2]
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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.
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Timepoint [2]
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Up to 6 years and 11 months
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Secondary outcome [3]
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Progression-free Survival (PFS): Study Cohort
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Assessment method [3]
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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.
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Timepoint [3]
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Up to 6 years 11 months
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Secondary outcome [4]
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Overall Survival (OS): Study Cohort
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Assessment method [4]
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OS was defined as duration from the date of first dose of study drug to the date of the participant's death.
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Timepoint [4]
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Up to 6 years 11 months
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Secondary outcome [5]
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Percentage of Participants With Lymphoma-related Symptoms: Study Cohort
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Assessment method [5]
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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.
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Timepoint [5]
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Up to 6 years 11 months
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Eligibility
Key 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
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key 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
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Non-randomised trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 1/Phase 2
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
11/03/2015
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
9/02/2022
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Sample size
Target
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Accrual to date
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Final
144
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Recruitment in Australia
Recruitment state(s)
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Recruitment hospital [1]
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- Bedford Park
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Recruitment hospital [2]
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- Darlinghurst
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Recruitment hospital [3]
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- Woolloongabba
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Recruitment postcode(s) [1]
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- Bedford Park
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Recruitment postcode(s) [2]
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- Darlinghurst
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Recruitment postcode(s) [3]
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- Woolloongabba
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Recruitment outside Australia
Country [1]
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United States of America
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State/province [1]
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New York
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Country [2]
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Israel
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State/province [2]
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Haifa
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Country [3]
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Israel
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State/province [3]
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Jeursalem
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Country [4]
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Israel
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State/province [4]
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Ramat Gan
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Country [5]
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Israel
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State/province [5]
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Tel Aviv
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Country [6]
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Poland
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State/province [6]
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Chorzow
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Country [7]
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Poland
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State/province [7]
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Gdansk
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Country [8]
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Poland
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State/province [8]
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Krakow
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Country [9]
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Poland
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State/province [9]
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Wroclaw
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Country [10]
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Spain
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State/province [10]
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Barcelona
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Country [11]
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Spain
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State/province [11]
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Madrid
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Country [12]
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Spain
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State/province [12]
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Salamanca
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Country [13]
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Turkey
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State/province [13]
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Ankara
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Country [14]
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Turkey
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State/province [14]
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Istanbul
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Country [15]
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Turkey
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State/province [15]
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Izmir
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Janssen Research & Development, LLC
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Address
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Country
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Other collaborator category [1]
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Commercial sector/Industry
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Name [1]
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Bristol-Myers Squibb
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Address [1]
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Ethics approval
Ethics application status
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Summary
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.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT02329847
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Janssen Research & Development, LLC Clinical Trial
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Address
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Janssen Research & Development, LLC
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Country
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Address
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Country
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Phone
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Fax
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Email
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT02329847
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