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