Professor Chan Cheah

Janssen Research & Development

Ib

• Diffuse Large B-Cell Lymphoma
• High-Grade B-Cell Lymphoma
• Follicular Lymphoma
• Transformed Follicular Lymphoma
• Mantle Cell Lymphoma
• Waldenstrom Macroglobulinaemia
• Marginal Zone Lymphoma
• MALT Lymphoma
• Chronic Lymphocytic Leukaemia
• Small Lymphocytic Leukaemia

This trial is open for recruitment for patients with b-cell lymphoma or chronic lymphocytic leukaemia that has returned, worsened or not responded to previous treatment. It looks at combining two tablets called JNJ-67856633 and JNJ-6426481 which act together to block important proteins called BTK and MALT1 inside lymphoma cells, causing them to die. Both drugs will be taken continuously unless the side effects are unacceptable or they no longer work.

Inclusion Criteria:

1. ≥18 years of age.
2. Eastern Cooperative Oncology Group (ECOG) performance status grade of 0 or 1.
3. Participants must have histological documentation of disease: B-cell NHL or CLL/SLL requiring therapy:
   1. Part A:
      1. B-Cell NHL – the following histologies of B-cell NHL that require systemic treatmentwill be enrolled, with the following disease-specific criteria:
         1. DLBCL/HBCL  – Received first-line chemotherapy and 1 subsequent line of systemic therapy that may or may not include autologous stem cell transplantation.
         2. FL (including tFL) – Previously treated with at least 2 prior lines of systemic therapy, including a standard anti-CD20 antibody.
         3. MCL or WM – Relapsed or progressing/nonresponsive to at least 2 prior lines of systemic therapy (prior BTK inhibitor treatment acceptable, provided discontinuation not due to disease progression)
         4. MZL (including MALT lymphoma) – Previously treated with at least 2 prior lines of therapy appropriate for the individual patient’s disease.
      2. CLL/SLL – that meets criteria for systemic treatment per the iwCLL guidelines and is relapsed or progressing/nonresponsive after at least 2 prior systemic therapies. If the participant had prior treatments that included BTK inhibitors they must not have progressed on that line of treatment.
   2. Part B:
      1. All above requirements for Part A apply. In addition, participants must have measurable disease as defined by the appropriate disease response criteria.
         1. B-cell NHL: In addition to the above requirements, participants must have measurable disease as defined by the appropriate disease response criteria. Specific cohorts will have malignancies with mutational status of interest, as determined by the sponsor, based on the results of the archived (or fresh) tumor biopsy obtained at screening and as reported by the study site.
         2. CLL or SLL: Participants must have measurable disease.
4. Hematology laboratory parameters within protocol ranges.
5. Chemistry laboratory parameters within protocol ranges.
6. Cardiac parameters within the following range: corrected QT interval (QTcF) ≤480 milliseconds based on the average of triplicate assessments performed as close as possible in succession (the full set of triplicates should be completed in less than 10 minutes).
7. Ejection fraction, as measured by the preferred local modality, and within normal range per local parameters.
8. Participants with B cell NHL must have tumor tissue available at baseline. This is not required for participants with CLL.
   1. For Part A, a fresh tumor biopsy is preferred. If a fresh biopsy is not obtained, archived tissue must
      be available.
   2. For Part B, participants must have a fresh tumor biopsy, unless archived tissue obtained after the
      last treatment is available.
9. Women of childbearing potential must agree to all of the  contraception as defined in the the study and for 30 days after the last dose of study drug.
10. A male must agree to all of the  contraception during the study and for 90 days after the last dose of study drug.
11. Participants must sign an ICF indicating that he or she understands the purpose of, and the procedures required for the study, and is willing to participate in the study.
12. Willing and able to adhere to the lifestyle restrictions specified.

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.
3. Received prior solid organ transplantation.
4. Either of the following:
   1. Received an autologous stem cell transplant ≤3 months before the first dose of study drug.
   2. Prior treatment with allogenic stem cell transplant ≤6 months before the first dose of study drug, has evidence of graft versus host disease, or requires immunosuppressant therapy for graft versus host disease within the last 2 weeks.
5. Prior chemotherapy, targeted therapy, immunotherapy, radiotherapy (with the exclusion of palliative radiation to limited sites that do not interfere with response assessment based on a sufficient number of other sites), or treatment with an investigational anti-cancer agent or an investigational drug (including investigational vaccines) within 2 weeks before the first administration of JNJ-64264681 and JNJ-67856633. For investigational agents where the half-life is known, there should be a treatment-free window of at least 2 weeks or 5 half-lives.
6. Participant has known allergies, hypersensitivity, or intolerance to JNJ-64264681 or JNJ-6785566 or excipients.
7. Participant is taking long-term corticosteroids (>10 mg daily prednisone equivalents).
8. 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]).
9. History of clinically significant cardiovascular disease within the 6 months prior to the first dose of study drug.
10. Clinically significant pulmonary compromise requiring supplemental oxygen use to maintain adequate oxygenation.
11. Prolonged coagulation values (prothrombin time, international normalized ratio, activated partial thromboplastin time) in the absence of direct oral anti-coagulants treatment, at screening that are clinically significant per investigator discretion, or has a history of subdural hematoma, abnormal bleeding tendency, or congenital bleeding diathesis.
12. Active liver cirrhosis of Child Pugh Class B or Class C.
13. Unable to swallow capsules or tablets or has malabsorption syndrome, disease that significantly affects gastrointestinal function, resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction.
14. Evidence of active viral, bacterial, or fungal infection requiring systemic anti-infective treatment within 7 days before the first dose of study drug.
15. Participant has a known positive test result for human immunodeficiency virus or acquired immune deficiency syndrome , unless viral load is undetectable and CD4 count is above 200 on stable highly active anti-retroviral therapy.
16. Participant has active or chronic hepatitis B or hepatitis C infection.
17. Trauma or had major surgery (eg, entailing entry into a major body cavity, or significant blood loss or fluid shifts) within 28 days prior to the first dose of study drug.
18. Any serious underlying medical or psychiatric condition (eg, alcohol or drug abuse, dementia or altered mental status); or any issue that would impair the ability of the participant to receive or tolerate the planned treatment at the investigational site, to understand informed consent, or due to which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, could compromise the participant’s well-being) or that could prevent, limit, or confound the protocol-specified assessments.
19. Requires a prohibited medication that cannot be discontinued or substituted, or temporally interrupted during the study.
20. Received a live attenuated vaccine within 1 month before the planned first dose of study drug.
21. Active autoimmune disease within the past 2 years that requires systemic immunosuppressive medications (ie, chronic corticosteroid, methotrexate, or tacrolimus).
22. Malignancy diagnosis other than the disease under study within 1 year prior to the first dose of the study drug; exceptions are squamous and basal cell carcinoma of the skin, carcinoma in situ of the cervix and any malignancy that is considered cured or has minimal risk of recurrence within 1 year of first dose of study drug.

Cancer Trials Haem1

cancertrialshaem1@linear.org.au

08 6382 5127

64264681LYM1002

NCT04657224