Study to Evaluate Adverse Events, Change in Disease Activity, and How Oral ABBV-101 Moves Through the Body in Adult Participants With B-Cell Malignancies

Study Overview
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Brief Summary
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Non-Hodgkin's lymphoma (NHL) is a cancer that arises from the transformation of normal B and T lymphocytes (white blood cells). The purpose of this study is to assess the safety, pharmacokinetics, and preliminary efficacy of ABBV-101 in adult participants in relapsed or refractory (R/R) non-Hodgkin's lymphomas: third line or later of treatment (3L) + chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), diffuse large b-cell lymphoma (DLBCL), non-germinal center B cell (GCB) DLBCL, mantle cell lymphoma (MCL), follicular lymphoma (FL), marginal zone lymphoma (MZL), Waldenström macroglobulinemia (WM), or transformed indolent NHL. Adverse events will be assessed. ABBV-101 is an investigational drug being developed for the treatment of NHL. This study will include a dose escalation phase to determine the maximum administered dose (MAD)/Maximum tolerated dose (MTD) of ABBV-101 and a dose expansion phase to determine the change in disease activity in participants with CLL or non-GCB DLBCL. Approximately 188 adult participants with multiple NHL subtypes will be enrolled in the study in sites world wide. In the Dose Escalation phase of the study participants will receive escalating oral doses of ABBV-101, until the MAD/MTD is determined, as part of the approximately 60 month study duration. In the dose expansion phase of the study participants receive oral ABBV-101, as part of the approximately 60 month study duration. 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 an approved institution (hospital or clinic). The effect of the treatment will be frequently checked by medical assessments, blood tests, and side effects.

Official Title
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First-in-Human Study to Evaluate the Safety, Pharmacokinetics, and Preliminary Efficacy of the BTK Degrader, ABBV-101, in Participants With B-cell Malignancies

Conditions
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Hematologic Cancer

Intervention / Treatment
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* Drug: ABBV-101


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For Dose Escalation (Part 1) only: Participants with documented diagnosis for one of the following 3L+ B-cell malignancies, from one of the following WHO-defined histologies (Swerdlow et al 2016): Chronic lymphocytic leukemia (CLL) Small lymphocytic lymphoma (SLL) Chimeric antigen receptor T-cells (CAR-T)/hematopoietic cell transplant (HCT) relapsed/refractory (R/R) or ineligible diffuse large b-cell lymphoma (DLBCL) from the following histologies: DLBCL not otherwise specified (NOS) (germinal center B cell [GCB] and non-GCB DLBCL), T-cell/histiocyte-rich large B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, anaplastic lymphoma kinase positive (ALK+) large B-cell lymphoma, high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, and high-grade B-cell lymphoma NOS. Mantle cell lymphoma (MCL) Follicular lymphoma [FL] (grades 1-3b) Marginal zone lymphoma [MZL] (splenic, extranodal, and nodal) Waldenström macroglobulinemia (WM) Transformed indolent non-Hodgkin's lymphoma (iNHL) For Dose Expansion (Part 2) only: Participants with documented diagnosis of CLL who are 3L+ including those with Bruton's tyrosine kinase (BTK) mutations or CAR-T/HCT R/R or ineligible non-GCB DLBCL who are 3L+ with histology based on criteria established by the World Health Organization (WHO). Has an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0, 1, or 2. Participant has a life expectancy >= 12 weeks. Prior Bruton's tyrosine kinase inhibitor (BTKi) is allowed. Adequate hematologic, renal, and hepatic function per the protocol. Participants with prior central nervous system (CNS) disease that have been effectively treated may be eligible. Exclusion Criteria: Previously treated with a Bruton's tyrosine kinase (BTK) degrader. Known active CNS disease, or primary CNS lymphoma. Uncontrolled active systemic infection, or active cytomegalovirus infection, known history of human immunodeficiency virus (HIV), active hepatitis B or C infection.

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: Dose Escalation ABBV-101<br>Participants with relapsed or refractory (R/R) Non-Hodgkin's lymphoma (NHL) will receive escalating doses of ABBV-101, until the maximum administered dose (MAD)/Maximum tolerated dose (MTD) is determined, as part of the approximately 60 month study duration. | Drug: ABBV-101<br>* Oral:Tablet<br>|
| Experimental: Dose Expansion ABBV-101 R/R Chronic Lymphocytic Lymphoma (CLL)<br>Participants with R/R CLL will receive ABBV-101 at the dose determined in the dose escalation arm, as part of the approximately 60 month study duration. | Drug: ABBV-101<br>* Oral:Tablet<br>|
| Experimental: Dose Expansion ABBV-101 R/R non-GCB DLBCL<br>Participants with R/R non-germinal center B cell (GCB) diffuse large B-cell lymphoma (DLBCL) will receive ABBV-101 at the dose determined in the dose escalation arm, as part of the approximately 60 month study duration. | Drug: ABBV-101<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) | AE is defined as 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. | Up to Approximately Two Years | 
| Change in Laboratory Parameters | Number of participants with clinically significant change from baseline in clinical laboratory test results like hematology will be reported. | Up to Approximately Two Years | 
| Change in Vital Signs | Number of participants with clinically significant change from baseline in vital signs like systolic and diastolic blood pressure will be reported. | Up to Approximately Two Years | 
| Change in Electrocardiogram (ECG) | 12-lead resting ECGs will be recorded. Parameters include RR interval, PR interval, QT interval, and QRS duration. | Up to Approximately Two Years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Serum Concentration (Cmax) of ABBV-101 | Maximum observed serum concentration of ABBV-101. | Up to Approximately One Year | 
| Time to Cmax (Tmax) of ABBV-101 | Time to Cmax of ABBV-101. | Up to Approximately One Year | 
| Area Under the Serum Concentration Versus Time Curve (AUC) of ABBV-101 | Area under the serum concentration versus time curve (AUC) of ABBV-101. | Up to Approximately One Year | 
| Number of Participants with Response of Partial Response (PR) or Better per Disease-Specific Criteria | Number of participants with response of PR or better per disease-specific criteria. | Up to Approximately Two Years | 
| Duration of Response (DOR) | DOR is defined for participants achieving a complete response (CR)/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 Two Years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic lymphocytic leukemia (CLL), Small lymphocytic lymphoma (SLL), Chimeric antigen receptor T-cells (CAR-T), Hematopoietic cell transplant (HCT), Relapsed/refractory (R/R) or ineligible Diffuse large b-cell lymphoma (DLBCL), Mantle cell lymphoma (MCL), Follicular lymphoma (FL), Marginal zone lymphoma (MZL), Waldenström macroglobulinemia (WM), Transformed Indolent non-Hodgkin's lymphoma (INHL), Hematologic Cancer, ABBV-101