Clinical trial NCT02329847: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Hematologic Neoplasms
Keywords: Hematologic Neoplasms
JNJ54179060
Ibrutinib
Nivolumab
Lead sponsor: Janssen Research & Development, LLC
Sponsor class: INDUSTRY
Collaborators: name: Bristol-Myers Squibb
First posted: 2015-01-01
Enrollment: 144
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Overall Response Rate (ORR) as Assessed International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008: Disease Cohort
timeFrame: Up to 6 years 11 months
measure: Overall Response Rate (ORR) as Assessed Non-Hodgkin Lymphoma (NHL), Cheson 2014: Disease Cohort
timeFrame: Up to 6 years 11 months
measure: Percentage of Participants With Treatment-emergent Adverse Event (TEAEs): Study Cohort
timeFrame: Up to 6 years 10 months
Secondary outcomes:
measure: Duration of Response (DoR): Study Cohort
timeFrame: Up to 6 years 11 months
measure: Duration of Stable Disease or Better: Study Cohort
timeFrame: Up to 6 years and 11 months
measure: Progression-free Survival (PFS): Study Cohort
timeFrame: Up to 6 years 11 months
measure: Overall Survival (OS): Study Cohort
timeFrame: Up to 6 years 11 months
measure: Percentage of Participants With Lymphoma-related Symptoms: Study Cohort
timeFrame: Up to 6 years 11 months
Other outcomes:
Locations:
city: New York
country: United States
state: New York
city: Bedford Park
country: Australia
city: Darlinghurst
country: Australia
city: Woolloongabba
country: Australia
city: Haifa
country: Israel
city: Jeursalem
country: Israel
city: Ramat Gan
country: Israel
city: Tel Aviv
country: Israel
city: Chorzow
country: Poland
city: Gdansk
country: Poland
city: Krakow
country: Poland
city: Wroclaw
country: Poland
city: Barcelona
country: Spain
city: Madrid
country: Spain
city: Salamanca
country: Spain
city: Ankara
country: Turkey
city: Istanbul
country: Turkey
city: Izmir
country: Turkey
Study officials:
affiliation: Janssen Research & Development, LLC
name: Janssen Research & Development, LLC Clinical Trial
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.