A phase 1 first-in-human study evaluating safety, pharmacokinetics, and efficacy of ABBV-291, a CD79b-targeting antibody-drug conjugate, in patients with relapsed/refractory B-cell non-Hodgkin lymphoma.
Background: Chemoimmunotherapy successfully treats ~60% of patients (pts) with diffuse large B-cell lymphoma (DLBCL), the most common form of B-cell non-Hodgkin lymphoma (B-NHL). However, pts who are not cured often die from relapsed/refractory (R/R) disease, highlighting the need for new therapies. CD79b is expressed on most major subtypes of B-NHL and is a validated target in DLBCL. ABBV-291 is an antibody-drug conjugate (ADC) comprising the anti-CD79b antibody conjugated to a potent topoisomerase 1 inhibitor payload, and offers potential as a best-in-class treatment in DLBCL. Preclinical data indicate that ABBV-291 has robust antitumor activity, with superior responses compared with other anti-CD79b ADCs. There is also the possibility for lower rates of key adverse events (AEs) such as neuropathy compared with monomethyl auristatin E-payload ADCs. Herein, we describe a first-in-human study evaluating the safety, pharmacokinetics (PK), and efficacy of ABBV-291 monotherapy in pts with R/R B-NHL. Methods: This phase 1, open-label, multicenter, dose-expansion study (NCT06667687) is enrolling pts (≥18 years) who have a documented diagnosis of B-NHL (except chronic lymphocytic leukemia), measurable disease, ECOG 0–1, and are R/R to or intolerant of ≥2 prior lines of therapy, with no other available therapies of clinical benefit. Primary objectives are to assess safety/tolerability of ABBV-291 and determine its recommended phase 1 expansion dose (RP1ED). Secondary objectives are to evaluate preliminary efficacy of ABBV-291 in specified subsets of R/R B-NHL (eg DLBCL, follicular lymphoma [FL], mantle cell lymphoma [MCL]) and to characterize its PK. Exploratory objectives include investigating the association between biomarkers, safety, efficacy, and PK. The study consists of 2 parts: dose escalation (up to ~45 pts), and dose expansion and optimization (~120 pts). ABBV-291 is administered intravenously. In the BOIN-guided dose-escalation, ABBV-291 administration for the first 2 pts is staggered by ≥24 hours at the first 2 dose levels (DLs); dose-limiting toxicities (DLTs) are assessed for 35 days from the initial dose. In dose expansion, ABBV-291 is evaluated at the RP1ED in DLBCL and FL; for dose optimization, ABBV-291 is evaluated in ≥2 DLs in MCL. Pts continue treatment until disease progression, intolerable toxicity, or other study discontinuation criteria are met. Safety evaluations include AE monitoring, DLTs, vital signs, ECG, and clinical laboratory parameters. Response evaluations are performed per disease-specific response criteria and include objective response rate, duration of response, and progression-free survival. PK parameters are determined using noncompartmental methods. The study is actively enrolling globally.
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