A First-in-Human Phase 1 Study of Abbv-319, an Antibody-Drug Conjugate Composed of a CD19 Antibody Linked to a Potent Proprietary Glucocorticoid Receptor Modulator, in Patients with Relapsed or Refractory B-Cell Malignancies

Background Systemic glucocorticosteroids (ie, glucocorticoid receptor modulators [GRMs]) show robust monotherapy activity against B-cell malignancies at high doses; however, they may be accompanied by steroid-associated toxicities that limit dosing. CD19 is a marker essential for B-cell proliferation and has high expression across B-cell malignancies including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia (CLL). ABBV-319 is a CD19-GRM antibody-drug conjugate (ADC) composed of an optimized high-affinity immunoglobulin G1 antibody conjugated to a potent proprietary glucocorticosteroid payload. ABBV-319 takes advantage of both enhanced antibody-dependent cellular cytotoxicity (via afucosylation) and targeted GRM payload delivery to maximize anticancer activity while lowering the risk of systemic steroid toxicities. Preclinically, ABBV-319 demonstrates sustained antitumor efficacy in models of human B-cell malignancies that compares favorably with approved therapeutics. This phase 1 study evaluates safety and clinical activity of ABBV-319 monotherapy in patients with relapsed or refractory (R/R) B-cell malignancies. Methods This is a phase 1, first-in-human, open-label, dose-escalation, dose-expansion, biomarker/pharmacodynamic (PD) study in patients aged ≥18 years with R/R B-cell malignancies. Key eligibility criteria include measurable disease and Eastern Cooperative Oncology Group performance status of 0 or 1. In addition, patients must meet predefined criteria for adrenal, bone marrow, kidney, and liver function, coagulation parameter levels, and hemoglobin A1c levels (dose escalation only) during screening. The primary objectives are to evaluate safety, tolerability, pharmacokinetics (PK), and immunogenicity of ABBV-319 and identify a recommended phase 2 dose (RP2D). The secondary objective is to evaluate the efficacy of ABBV-319 in patients with R/R DLBCL, FL, and CLL. Exploratory objectives include evaluating the effect of ABBV-319 on QT prolongation and evaluating PD and predictive biomarkers. This study will be conducted in 2 parts - dose escalation (Part 1) and dose expansion (Part 2). Part 1 aims to determine the RP2D for ABBV-319 following a Bayesian optimal interval design, with a maximum of 2-fold increments that reduce as the dose increases. RP2D will be determined on the basis of all the data collected in Part 1 including safety, tolerability, PK, PD, and efficacy, if available. Part 2 will further evaluate ABBV-319 at the RP2D in 3 separate subtypes of B-cell malignancies - DLBCL, FL, and CLL. A total of 114 patients are planned to be enrolled - 54 patients with various R/R B-cell malignancies in Part 1, and 60 patients in Part 2 (20 patients included for each R/R B-cell malignancy subtype: DLBCL, FL, and CLL). ABBV-319 will be administered intravenously until disease progression, intolerable toxicity, or other study discontinuation criteria are met, for a maximum of ~24 months from the last patient enrolled. Safety assessments include adverse event monitoring (per National Cancer Institute Common Terminology Criteria for Adverse Events v5.0), physical examinations, vital sign measurements, and clinical laboratory testing. Dose-limiting toxicities will be assessed. PK parameters including maximum observed serum/plasma concentration (Cmax), time to Cmax, terminal plasma elimination half-life, and area under the serum/plasma concentration-time curve will be analyzed using noncompartmental methods for ABBV-319 total antibody, ADC, and unconjugated GRM payload. Antidrug antibodies (ADAs) and neutralizing ADAs may also be determined, as appropriate. Efficacy will be evaluated in terms of response per disease-specific criteria (including International Workshop on Chronic Lymphocytic Leukemia, International Workshop on Waldenstrom's Macroglobulinemia, and Lugano classification). Duration of response, time to response, progression-free survival, and overall survival will be evaluated per Kaplan-Meier analysis. QT prolongation, PD, and biomarker data will be assessed as changes from baseline and may be summarized for each scheduled postbaseline visit.