TITANium: An open-label, global multicenter phase 1/2 study of AZD5492, a first-in-class subcutaneous CD8-guided tri-specific T-cell engager (TCE), in patients (pts) with relapsed or refractory (r/r) B-cell malignancies.
Bibliographic record
Abstract
TPS7091 Background: Bispecific CD20 x CD3 TCEs are changing the treatment landscape for pts with r/r non-Hodgkin lymphomas (NHL); however, they are associated with immune-related toxicities, namely cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), which limit their use. AZD5492 is a first-in-class, humanized, asymmetric, subcutaneously-administered, trispecific monoclonal IgG1 antibody that harbors two Fab binding domains to CD20, one VHH binding domain to T-cell receptor and one VHH binding domain to a CD8 co-receptor. Preclinical data have shown that AZD5492 drives B-cell killing through preferential engagement of CD8+ T cells, with reduced CD4+ T-cell activation and associated cytokine production. Thus, AZD5492 may have a wider therapeutic index and safety advantage compared with first generation CD20 x CD3 TCEs which equally engage and activate CD4+ and CD8+ T cells. In an in vivo NHL model, AZD5492 showed potent antitumor activity with reduced cytokine release compared with a CD20 x CD3 comparator. TITANium is a global Phase 1/2 multicenter dose escalation (Part A) and expansion (Part B) study (NCT06542250) of AZD5492 in pts with r/r B-cell malignancies. Methods: We present the study design of Part A. Eligible pts are aged ≥18 years with histologically documented CD20+ mature B-cell neoplasm, specifically large B-cell lymphoma (LBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), and small lymphocytic lymphoma (SLL), with ≥1 measurable lesion (except for CLL) and r/r disease after ≥2 prior lines of therapy. Pts with history of Grade ≥3 CRS or ICANS, post-transplant lymphoproliferative disease, Ritcher’s transformation, Burkitt’s lymphoma or Burkitt-like lymphoma are excluded. Part A will consist of two independent dose escalation groups: Part A1 will enroll pts with MCL or CLL/SLL; Part A2 will enroll pts with LBCL or FL. Dose escalation will start with pts receiving AZD5492 subcutaneously at a fixed dose per dose-level. An immune-related toxicity during Part A will trigger a double step-up strategy. Thereafter, treatment will continue for a limited duration. Each part will continue dose escalation independently, using fixed or step-up dosing. Part A will initially follow an accelerated titration design and will switch to a modified toxicity probability interval-2 design when triggered by emerging data. The primary objective is to assess safety and tolerability of AZD5492. Key secondary objectives are to evaluate preliminary efficacy, pharmacokinetics and immunogenicity of AZD5492. Enrollment began in September 2024 and is currently ongoing. Clinical trial information: NCT06542250 .
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.002 | 0.003 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".