The purposes of this trial are:• To find out the side effects (unexpected or unwanted reactions from taking a drug) when JNJ-64264681 and JNJ-67856633 are given in combination. • To find out how and at what dose(s) the combination of JNJ-64264681…
ID
Source
Brief title
Condition
- Other condition
- Lymphomas non-Hodgkin's B-cell
Synonym
Health condition
Chronic Lymphocytic Leukemia
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Part A (Dose Escalation) Determine the recommended Phase 2 doses (RP2Ds) of
JNJ-64264681 and JNJ-67856633 when administered together in participants with B
cell NHL and CLL
Part B (Cohort Expansion) Determine the safety of the RP2D(s) for this
combination in different histologies/ participant populations
Secondary outcome
Assess the PK of JNJ-64264681 and JNJ-67856633 when administered together
Assess the PD of JNJ-64264681 and JNJ-67856633 when administered together
Assess the preliminary clinical activity of JNJ-64264681 and JNJ-67856633 when
administered together
Background summary
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
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). JNJ-64264681 is a second-generation, orally active,
irreversible covalent BTK inhibitor. Given its BTK inhibitory potency,
along with nonclinical data to date, JNJ-64264681 is likely to have similar
anti-lymphoma activity to already approved BTK inhibitors. Mucosa-associated
lymphoid tissue lymphoma translocation protein 1 (MALT1) is a key mediator of
the BCR signal transduction pathway positioned downstream of BTK. MALT1 plays a
key role in activating the classical nuclear factor kappa-light-chain-enhancer
of activated B cells (NF-*B) signaling pathway. As such MALT1 has been shown to
play a critical role in supporting tumor growth in different types of lymphoma,
including activated B-cell-like subtype of diffuse large B cell lymphoma
(DLBCL). JNJ-67856633 is an orally bioavailable, potent, and allosteric
inhibitor of MALT1 that has demonstrated promising clinical signals and
favorable toxicity profile in a Phase 1 study sponsored by Janssen
Pharmaceutical Companies (sponsor). Furthermore, the sponsor has investigated
the rationale and synergistic activity of JNJ-64264681 and JNJ-67856633 in
preclinical cellular as well as mouse models. This study will evaluate
JNJ-64264681 in combination with JNJ-67856633 in a first-in-human study of NHL
and CLL
Study objective
The purposes of this trial are:
• To find out the side effects (unexpected or unwanted reactions from taking a
drug) when JNJ-64264681 and JNJ-67856633 are given in combination.
• To find out how and at what dose(s) the combination of JNJ-64264681 and
JNJ-67856633 should be given for treating patients with B-cell Non-Hodgkin*s
Lymphoma (B-cell NHL) and Chronic Lymphocytic Leukemia (CLL).
• To find out how long JNJ-64264681 and JNJ-67856633 stay in and act on the
body, and how the body responds to them, when given in combination. This is
shown by laboratory blood tests.
Study design
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).
Intervention
Participants receive the combination JNJ-64264681 (capsule) and JNJ-67856633
(capsule or tablet) daily or twice daily. The dosage will be determined based
on the available data.
Study burden and risks
The viability of 4 different ABC-DLBCL lines and 4 different MCL lines was
evaluated in vitro following treatment with different doses of JNJ-64264681 and
JNJ-67856633 administered together. Strong synergistic effects of the
JNJ-64264681 and JNJ-67856633 combination were observed in 3 DLBCL cell lines
carrying CD79b mutations and 1 of 4 MCL cell lines. Treatment with JNJ-64264681
and JNJ-67856633 administered together demonstrated statistically significant
TGI compared with vehicle control in 2 CD79b mutant mouse lymphoma models, 1
based on a DLBCL cell line (OCI-LY10) and 1 on a patient-derived DLBCL model
LY2298. In both models, the combination of the 2 study drugs showed increased
growth inhibition compared
with single agents, and tumor regression in the combination arm. Furthermore,
JNJ-64264681 and JNJ-67856633 administered together showed a significant
downregulation of IL-10 secretion in the serum of LY2298 tumor-bearing mice to
a greater extent than when the drugs were administered alone, demonstrating a
biological effect of the combination. There was no significant effect on
general health and body weight in any of the arms in both these studies
including the combination arms. Taken together, these studies provide support
for clinical investigation of the combination therapy
of the BTK inhibitor, JNJ-64264681, and the MALT1 inhibitor, JNJ-67856633, as a
valid strategy. in combatting ABC-DLBCL and other B cell malignancies with the
potential to delay resistance generation due to stronger anti-tumor effects.
The potential risks for JNJ-64264681 and JNJ-67856633 administered as
monotherapy are outlined in section 2.3. JNJ-64264681 and JNJ-67856633 when
administered together has not been studied in humans.
Graaf Engelbertlaan 75
DS Breda 4837
NL
Graaf Engelbertlaan 75
DS Breda 4837
NL
Listed location countries
Age
Inclusion criteria
1. >=18 years of age
2. Eastern Cooperative Oncology Group (ECOG) performance status grade of 0 or 1
3. Cardiac parameters within the following range: corrected QT interval (QTcF)
<= 480 milliseconds
4. 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)
5. 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 breastfeed
Exclusion criteria
1. Part A and select cohorts in Part B: Prior treatment with JNJ-64264681 or
JNJ-67856633. Previously discontinued treatment with a BTK or 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.
2. Known (active) CNS involvement for dose escalation and specific expansion
cohorts as determined by the SET.
3. Received prior solid organ transplantation.
4. Participant has known allergies, hypersensitivity, or intolerance to
JNJ-64264681 or JNJ-6785566 or excipients (refer to the respective IBs).
5. Toxicities from previous anti-cancer therapies that have not resolved to
baseline levels, or to Grade <2 (except for alopecia [>=Grade 2], vitiligo
[Grade 2] and peripheral neuropathy [Grade 1]).
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| Other | 04657224 |
| EudraCT | EUCTR2020-003149-12-NL |
| CCMO | NL76498.018.21 |