Study to Evaluate Adverse Events and Change in Disease Activity in Adult Participants With B-Cell Malignancies Receiving Oral ABBV-525 Tablets

Study Overview
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Brief Summary
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B-cell malignancies are a group of cancers of B lymphocytes, a type of white blood cell responsible for fighting infections. The purpose of this study is to assess safety, tolerability, pharmacokinetics and preliminary efficacy of ABBV-525 as a monotherapy. ABBV-525 is an investigational drug being developed for the treatment of B-Cell Malignancies. Study doctors put the participants in groups called treatment arms. Participants will receive ABBV-525 at different doses. Approximately 100 adult participants will be enrolled in the study across sites worldwide. In part 1 (dose escalation), participants will receive escalating oral doses of ABBV-525. In part 2 (dose optimization), participants will receive one of two oral doses of ABBV-525, until the recommended phase 2 dose (RP2D) is determined. In part 3 (dose expansion), participants will receive the RP2D oral dose of ABBV-525. The estimated duration of the study is up to 64 months. There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the study at a hospital or clinic and may require frequent medical assessments, blood tests, and scans.

Official Title
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A First-in-Human Study of ABBV-525 (MALT1 Inhibitor) in B-Cell Malignancies

Conditions
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B Cell Malignancies, Diffuse Large B-Cell Lymphoma, Chronic Lymphocytic Leukemia, Non-Hodgkin's Lymphoma

Intervention / Treatment
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* Drug: ABBV-525


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Dose Escalation (Part 1) Only: Participants with a documented diagnosis of one of the following third line or later of treatment (3L)+ mature B-cell malignancies, from the World Health Organization (WHO)-defined histologies as defined in the protocol. Dose Optimization (Part 2) Only: Participants with documented diagnosis of chronic lymphocytic leukemia (CLL) who are 3L+, +/- cysteine-to-serine point mutation at residue 481 of BTK-domain active site (C481S with histology based on WHO criteria, with measurable disease requiring treatment as defined by the International Workshop on Chronic Lymphocytic Leukemia (iwCLL). Dose Expansion (Part 3) Only: Participants with documented diagnosis of non-germinal center B cell (GCB) Diffuse large B-cell lymphoma (DLBCL) who are 3L+ chimeric antigen receptor T-cells (CAR-T)/Hematopoietic cell transplant (HCT) relapsed/refractory (R/R) and/or ineligible with histology based on WHO criteria, with measurable disease requiring treatment. Participant has an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1. Participant has a life expectancy >= 12 weeks. Adequate hematological and hepatic function as defined in the protocol. Must have archival or freshly collected tumor tissue for correlative studies before study enrollment. Participants with prior central nervous system (CNS) disease that has been effectively treated may be eligible. Participants with resolved coronavirus disease 2019 (COVID-19) infection are eligible. Exclusion Criteria: Known active CNS disease, or primary CNS lymphoma. Known bleeding disorders. Known history of stroke or intracranial hemorrhage within 12 months prior to first dose of study treatment. Uncontrolled active systemic infection, or active cytomegalovirus infection. Active hepatitis B or C infection. Known history of human immunodeficiency virus (HIV). Known active COVID-19 infection. Participant must not have signs/symptoms associated with COVID-19 infection or known exposure to a confirmed case of COVID-19 infection during screening. If participant has signs/symptoms suggestive of COVID-19 infection, the participant must have a negative molecular (eg, polymerase chain reaction) test or 3 negative antigen test results at least 24 hours apart.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ABBV-525 Dose Escalation<br>Participants will receive escalating doses of ABBV-525 until doses for optimization are determined, as part of an approximately 64 month study period. | Drug: ABBV-525<br>* Oral; Tablet<br>|
| Experimental: ABBV-525 Dose Optimization<br>Participants will receive one of two doses of ABBV-525 until the recommended phase 2 dose (RP2D) is determined, as part of an approximately 64 month study period. | Drug: ABBV-525<br>* Oral; Tablet<br>|
| Experimental: ABBV-525 Dose Expansion<br>Participants will receive the RP2D dose of ABBV-525, as part of an approximately 64 month study period. | Drug: ABBV-525<br>* Oral; Tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AE) | An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) is defined as any untoward medical occurrence, whether associated with study drug or not, that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is an important medical event requiring medical or surgical intervention to prevent serious outcome. | Up to Approximately 64 Months | 
| Number of Participants With Dose-Limiting Toxicities (DLT) | A DLT is defined as any AE for which a clear alternative cause cannot be established (eg, attributed to the disease under study, another disease, or to a concomitant medication by the study investigators or medical monitor). | Up to Approximately 28 Days | 
| Number of Tumor Lysis Syndrome (TLS) | TLS is confirmed by evaluation of electrolyte and fluid status and renal status including urine output. | Up to Approximately 64 Months | 
| Number of Participants With Clinically Significant Changes From Baseline in Clinical Laboratory Parameters | Clinical laboratory parameters included tests of hematology, chemistry, urinalysis and prolactin. The investigator will assess the results for clinical significance. | Up to Approximately 64 Months | 
| Number of Participants With Clinically Significant Changes From Baseline in Vital Sign Parameters | Vital sign parameters included body temperature, systolic and diastolic blood pressure, pulse rate, and respiratory rate. The investigator will assess the results for clinical significance. | Up to Approximately 64 Months | 
| Number of Participants With Clinically Significant Changes From Baseline in Electrocardiograms (ECG) | A standard 12-lead ECG will be performed. The investigator will assess the results for clinical significance. | Up to Approximately 64 Months | 
| Maximum Observed Plasma Concentration (Cmax) of ABBV-525 | Maximum observed plasma concentration of ABBV-525. | Up to 12 Months | 
| Time to Cmax (Tmax) of ABBV-525 | Time to Cmax of ABBV-525. | Up to 12 Months | 
| Area Under the Plasma Concentration-Time Curve (AUC) of ABBV-525 | Area under the plasma concentration-time curve of ABBV-525. | Up to 12 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | ORR is defined as the percentage of participants with a best overall response (BOR) of complete response (CR)/very good partial response (VGPR)/partial response (PR) in participants receiving at least 1 dose of study drug. | Up to Approximately 64 Months | 
| Duration of Response (DOR) | DOR is defined for participants achieving CR/VGPR/PR as the time from the initial response per Investigator review to disease progression or death of any cause, whichever occurs earlier. | Up to Approximately 64 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diffuse Large B-Cell Lymphoma, B-cell Malignancies, Chronic Lymphocytic Leukemia, Non-Hodgkin's Lymphoma, ABBV-525, Cancer