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

NCT02329847 | Completed Phase 1 Results

• 3 other identifiers: CR106681PCI-32765LYM10022014-005191-28
• Study Type: interventional
• Target: 144
• Locations: 6 countries
• Sites: 18

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.

Conditions

Hematologic Neoplasms

Keywords

Hematologic Neoplasms; JNJ54179060; Ibrutinib; Nivolumab

Outcome Measures

Primary Outcomes (3)

• Overall Response Rate (ORR) as Assessed International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008: Disease Cohort

  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.

  Up to 6 years 11 months

• Overall Response Rate (ORR) as Assessed Non-Hodgkin Lymphoma (NHL), Cheson 2014: Disease Cohort

  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.

  Up to 6 years 11 months

• Percentage of Participants With Treatment-emergent Adverse Event (TEAEs): Study Cohort

  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.

  Up to 6 years 10 months

Secondary Outcomes (5)

• Duration of Response (DoR): Study Cohort

  Up to 6 years 11 months

• Duration of Stable Disease or Better: Study Cohort

  Up to 6 years and 11 months

• Progression-free Survival (PFS): Study Cohort

  Up to 6 years 11 months

• Overall Survival (OS): Study Cohort

  Up to 6 years 11 months

• Percentage of Participants With Lymphoma-related Symptoms: Study Cohort

  Up to 6 years 11 months

Study Arms (6)

Cohort A1

EXPERIMENTAL

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; Drug: Nivolumab

Cohort A2

EXPERIMENTAL

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; Drug: Nivolumab

Cohort B1

EXPERIMENTAL

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; Drug: Nivolumab

Cohort B2

EXPERIMENTAL

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; Drug: Nivolumab

Cohort B3

EXPERIMENTAL

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; Drug: Nivolumab

Cohort B4

EXPERIMENTAL

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; Drug: Nivolumab

Interventions

Ibrutinib DRUG

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.

Also known as: JNJ54179060

Cohort A1; Cohort A2; Cohort B1; Cohort B2; Cohort B3; Cohort B4

Nivolumab DRUG

Participants will receive nivolumab intravenously as 3 mg/kg on Day 1 every cycle of 14 days.

Also known as: BMS-936558

Cohort A1; Cohort A2; Cohort B1; Cohort B2; Cohort B3; Cohort B4

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Janssen Research & Development, LLC: lead
• Bristol-Myers Squibb: collaborator

Study Sites (18)

Unknown Facility

New York, New York, United States

Location

Unknown Facility

Bedford Park, Australia

Location

Unknown Facility

Darlinghurst, Australia

Location

Unknown Facility

Woolloongabba, Australia

Location

Unknown Facility

Haifa, Israel

Location

Unknown Facility

Jeursalem, Israel

Location

Unknown Facility

Ramat Gan, Israel

Location

Unknown Facility

Tel Aviv, Israel

Location

Unknown Facility

Chorzów, Poland

Location

Unknown Facility

Gdansk, Poland

Location

Unknown Facility

Krakow, Poland

Location

Unknown Facility

Wroclaw, Poland

Location

Unknown Facility

Barcelona, Spain

Location

Unknown Facility

Madrid, Spain

Location

Unknown Facility

Salamanca, Spain

Location

Unknown Facility

Ankara, Turkey (Türkiye)

Location

Unknown Facility

Istanbul, Turkey (Türkiye)

Location

Unknown Facility

Izmir, Turkey (Türkiye)

Location

Related Publications (2)

• 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.

  PMID: 34500472 DERIVED

• 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.

  PMID: 30642819 DERIVED

MeSH Terms

Conditions

Hematologic Neoplasms

Interventions

ibrutinib; Nivolumab

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Limitations and Caveats

Though it was planned to administer Ibrutinib 280 milligrams (mg) to participants in case the toxicity increased, no participants received ibrutinib 280 mg in the study.

Results Point of Contact

• Title: Executive Medical Director
• Organization: Janssen Research & Development, LLC

ClinicalTrialDisclosure@its.jnj.com

844-434-4210

Study Officials

• Janssen Research & Development, LLC Clinical Trial

  Janssen Research & Development, LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 30, 2014
• First Posted: January 1, 2015
• Study Start: March 11, 2015
• Primary Completion: February 9, 2022
• Study Completion: February 9, 2022
• Last Updated: May 25, 2025
• Results First Posted: June 15, 2023

Record last verified: 2025-05

Locations

US (1); AU (3); PL (4); TU (3); ES (3); IL (4)