A Study of JNJ-64264681 and JNJ-67856633 in Participants With Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia

A Phase 1b, Open-Label Study of the Safety, Pharmacokinetics, and Pharmacodynamics of JNJ-64264681 in Combination With JNJ-67856633 in Participants With Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia

The primary purpose of this study is to determine: the recommended Phase 2 doses (RP2Ds) of JNJ-64264681 and JNJ 67856633 when administered together in participants with B cell non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) (Part A - Dose Escalation); and the safety of the RP2Ds for this combination in different histologies/participant populations (Part B - Cohort Expansion).

Study Overview

• Status: Completed
• Conditions: Lymphoma, Non-Hodgkin; Chronic Lymphocytic Leukemia
• Intervention / Treatment: Drug: JNJ-64264681; Drug: JNJ-67856633

Detailed Description

Bruton's tyrosine kinase (BTK) is a cytoplasmic tyrosine kinase that plays a critical role in B cell activation via the B cell receptor (BCR) signaling pathway. BTK is important for normal B-cell activation and the pathophysiology of B cell malignancies. A few BTK inhibitors have demonstrated clinical activity in non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Non-Hodgkin lymphoma represents a diverse set of diseases, of which more than 60 subtypes have been identified and classified by the world health organization. JNJ-64264681 is a second-generation, orally active, selective, and irreversible covalent inhibitor of BTK and JNJ-67856633 is an orally bioavailable, potent, and selective first in class mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) inhibitor that binds to an allosteric site on MALT1 with a mixed-type mechanism. JNJ-64264681 and JNJ-67856633 inhibit BTK and MALT1, respectively, and both BTK and MALT1 are involved in transmitting the pro-survival BCR signal. The study will consist of Screening Phase (28 days); Treatment Phase (from Cycle 1 Day 1 up to end of treatment, each cycle is a 21-day cycle) and a Follow-up Phase (from end of treatment visit until lost to follow-up, withdrawal of consent, death, 6 months after start of first subsequent antineoplastic therapy, after the clinical cut off (CCO) date participants will be withdrawn from the study 30 days after the last dose of study drugs were administered). The total study duration is estimated at 2 years and 2 months. Safety assessments will include physical examinations, vital signs, electrocardiograms, clinical safety laboratory assessments, eastern cooperative oncology group performance status, echocardiogram, and adverse events monitoring.

• Study Type: Interventional
• Enrollment (Actual): 75
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • Clayton, Australia, 3168
    • Monash Medical Centre
  • Melbourne, Australia, 3000
    • Peter Maccallum Cancer Centre
  • Nedlands, Australia, 6009
    • Linear Clinical Research Ltd
  • Randwick, Australia, 2031
    • Scientia Clinical Research
• Belgium
  • Brugge, Belgium, 8000
    • AZ St.-Jan Brugge-Oostende AV
  • Gent, Belgium, 9000
    • Universitair Ziekenhuis Gent - UZ GENT
  • Yvoir, Belgium, 5530
    • CHU UCL Namur - Site Godinne
• France
  • Lille, France, 59037
    • CHRU de Lille Hopital Claude Huriez
  • Nantes Cedex 1, France, 44093
    • CHU Hotel Dieu
  • Pierre Benite, France, 69495
    • Centre Hospitalier Lyon-Sud
  • Tours Cedex 9, France, 37044
    • CHU Bretonneau
• Georgia
  • Tbilisi, Georgia, 0112
    • ARENSIA Exploratory Medicine
• Israel
  • Jerusalem, Israel, 9112001
    • Hadassah Medical Center
  • Ramat Gan, Israel, 52621
    • Sheba Medical Center
  • Tel Aviv, Israel, 6423906
    • Tel Aviv Sourasky MC
• Korea, Republic of
  • Seoul, Korea, Republic of, 3080
    • Seoul National University Hospital
  • Seoul, Korea, Republic of, 05505
    • Asan Medical Center
  • Seoul, Korea, Republic of, 06351
    • Samsung Medical Center
• Moldova, Republic of
  • Chisinau, Moldova, Republic of, Md2025
    • ARENSIA Exploratory Medicine
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Academic Medical Center
• Poland
  • Gdansk, Poland, 80 214
    • Uniwersyteckie Centrum Kliniczne
  • Katowice, Poland, 40 519
    • Pratia Onkologia Katowice
  • Krakow, Poland, 30-727
    • Pratia McM Krakow
  • Skorzewo, Poland, 60 185
    • Centrum Medyczne Pratia Poznań
• Spain
  • Barcelona, Spain, 08035
    • Hosp Univ Vall D Hebron
  • Madrid, Spain, 28040
    • Hosp Univ Fund Jimenez Diaz
• Ukraine
  • Kyiv, Ukraine, 01135
    • Medical Center of Limited Liability Company Arensia Exploratory Medicine
• United States
  • New York
    • Stony Brook, New York, United States, 11794
      • Stony Brook University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Eastern Cooperative Oncology Group (ECOG) performance status grade of 0 or 1
• Cardiac parameters within the following range: corrected QT interval (QTcF) <= 480 milliseconds
• Participants with B cell non-Hodgkin lymphoma (NHL) must have tumor tissue available at baseline as described in the protocol. This is not required for participants with chronic lymphocytic leukemia (CLL)
• Women of childbearing potential must agree to use a barrier method of contraception; use a highly effective preferably user-independent method of contraception; not to donate eggs (ova, oocytes) or freeze them for future use for the purposes of assisted reproduction during the study; not to plan to become pregnant; and not to breast-feed

Exclusion Criteria:

• Part A and select cohorts in Part B: Prior treatment with JNJ 64264681 or JNJ-67856633. Previously discontinued treatment with a Bruton's tyrosine kinase (BTK) or mucosa-associated lymphoid tissue lymphoma translocation protein (MALT) inhibitor other than JNJ 64264681 or JNJ-67856633 due to participant or doctor choice without evidence of progression or intolerable class-related toxicity will be eligible
• Known (active) central nervous system (CNS) involvement
• Received prior solid organ transplantation
• Participant has known allergies, hypersensitivity, or intolerance to JNJ-64264681 or JNJ 67856633 or excipients
• Toxicities from previous anti-cancer therapies that have not resolved to baseline levels, or to Grade less than (<) 2 (except for alopecia [>=Grade 2], vitiligo [Grade 2] and peripheral neuropathy [Grade 1])

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A: Dose escalation: JNJ-64264681 and JNJ-67856633; Participants will receive JNJ-64264681 and JNJ-67856633 will be administered together until disease progression, intolerable toxicity, withdrawal of consent, or the investigator.	Drug: JNJ-64264681; JNJ-64264681 capsules will be administered orally.; Drug: JNJ-67856633; JNJ-67856633 capsules or tablets will be administered orally.
Experimental: Part B: Cohort Expansion: JNJ-64264681 and JNJ-67856633; Participants will receive JNJ-64264681 and JNJ-67856633 at the recommended Phase 2 dose (RP2D) determined in Part 1.	Drug: JNJ-64264681; JNJ-64264681 capsules will be administered orally.; Drug: JNJ-67856633; JNJ-67856633 capsules or tablets will be administered orally.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A: Number of Participants with Dose-limiting Toxicity (DLT)	Number of participants with DLT will be assessed. The DLTs are specific adverse events and are defined as any of the following: high grade non-hematologic toxicity, or hematologic toxicity.	Up to 28 days
Part A and Part B: Number of Participants with Adverse Events (AEs) as a Measure of Safety and Tolerability	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.	Up to 3 years and 9 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma Concentrations of JNJ-64264681 and JNJ-67856633	Plasma concentrations of JNJ-64264681 and JNJ-67856633 will be assessed.	Up to 3 years and 9 months
Bruton's Tyrosine Kinase (BTK) Occupancy in Peripheral Blood Mononuclear Cell (PBMCs)	BTK occupancy will be assessed.	Up to 3 years and 9 months
Overall Response Rate (ORR)	ORR is defined according to Non-Hodgkin Lymphoma, International Workshop on Chronic Lymphocytic Leukemia (iwCLL); and Response assessment in Waldenström Macroglobulinemia (IWWM).	Up to 3 years and 9 months
Time to First Response	Time to first response defined for the responders as the time from the date of first dose of study treatment to the date of initial documentation of a first response as defined in the disease-specific response criteria.	Up to 3 years and 9 months
Duration of Response	DOR will be calculated from the date of initial documentation of a response to the date of first documented evidence of relapse, as defined in the disease-specific response criteria, or death due to any cause, whichever occurs first.	Up to 3 years and 9 months

Collaborators and Investigators

• Sponsor: Janssen Research & Development, LLC
• Investigators: Study Director: Janssen Research & Development, LLC Clinical Trials, Janssen Research & Development, LLC

Study record dates

Study Major Dates

• Study Start (Actual): February 25, 2021
• Primary Completion (Actual): January 16, 2025
• Study Completion (Actual): January 16, 2025

Study Registration Dates

• First Submitted: December 1, 2020
• First Submitted That Met QC Criteria: December 1, 2020
• First Posted (Actual): December 8, 2020

Study Record Updates

• Last Update Posted (Actual): August 21, 2025
• Last Update Submitted That Met QC Criteria: August 20, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Chronic Disease; Disease Attributes; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Leukemia, B-Cell; Leukemia; Lymphoma; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin
• Other Study ID Numbers: CR108877; 2020-003149-12 (EudraCT Number); 64264681LYM1002 (Other Identifier: Janssen Research & Development, LLC); 2024-512687-66-00 (Registry Identifier: EUCT number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The data sharing policy of the Janssen Pharmaceutical Companies of Johnson & Johnson is available at www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at yoda.yale.edu

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No