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

For Dose Escalation (Part 1) only (including backfill): Participants have received at least two prior systemic therapies, have no available therapies known to provide clinical benefit (e.g., standard chemotherapy or HCT), have measurable disease requiring treatment, and have a documented diagnosis for one of the following third line or later B-cell malignancies, from one of the following world health organization (WHO)-defined histologies (Swerdlow et al 2016):

• Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL)

  1. For Dose Escalation (Part 1) backfill only - Bruton's tyrosine kinase inhibitor (BTKi)/Bruton's tyrosine kinase degrader (BTKd)-naïve CLL/SLL. Participants with a documented diagnosis of CLL/SLL who have received at least one prior systemic therapy that cannot be a BTK inhibitor or degrader, and, with the exception of BTK pathway agents, have no available therapies known to provide clinical benefit (e.g., standard chemotherapy or HCT), and have measurable disease requiring treatment.
  2. For Dose Escalation (Part 1) backfill only - BTKi/BCL-2i combination regimen-exposed 2L CLL/SLL. Participants with a documented diagnosis of CLL/SLL who have received one prior systemic therapy with a BTKi and BCL-2i combination regimen, have no available therapies known to provide clinical benefit (e.g., standard chemotherapy or HCT), and have measurable disease requiring treatment.

• 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 2a) CLL/SLL only: Participants with a documented diagnosis of CLL/SLL in their first-line or later treatment.

For Dose Expansion (Part 2a) DLBCL only: Participants have received at least two prior systemic therapies, have no available therapies known to provide clinical benefit (e.g., standard chemotherapy or HCT), have measurable disease requiring treatment, and have documented diagnosis of CAR-T/HCT R/R or ineligible non-GCB DLBCL who are in their third line or later treatment with histology based on criteria established by the WHO.

For Dose Exploration of ABBV-101 combination with venetoclax (Part 2b) CLL/SLL only: Participants with a documented diagnosis of CLL/SLL in their first-line or later treatment: In safety lead-in for each dose level, participants must have received at least one prior systemic therapy.

Has an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0, 1, or 2. For EU only: Participant has an ECOG PS of 0 or 1.

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.