KB-Lanra 1001: A Phase 1b/2 Study of Safety, PK, PD, and Preliminary Efficacy of the Selective SYK Inhibitor Lanraplenib in Combination with the FLT3 Inhibitor Gilteritinib in FLT3-Mutated R/R AML
Bibliographic record
Abstract
Background and Significance: FMS-like tyrosine kinase (FLT3)-mutation (FLT3 mut) in patients with newly diagnosed and relapsed/refractory (R/R) acute myeloid leukemia (AML) is associated with shorter overall survival (OS) and relapse-free survival. Gilteritinib is an approved therapy for R/R FLT3 mut AML, but reduction in FLT3 mut burden and sustained efficacy are rarely achieved, thus necessitating investigation of rational therapeutic combinations to improve outcomes. Spleen Tyrosine Kinase (SYK) is a non-receptor tyrosine kinase known to regulate intracellular signaling in response to extracellular stimuli via its immunoreceptor tyrosine-based activation motif (ITAM). SYK serves as a relay to an oncogenic transcriptional regulatory network (TRN) linked to HOXA9 and MEIS1-facilitated suppression of myeloid progenitor maturation and proliferation. SYK cooperates with internal tandem duplication (ITD)-mutated FLT3 to drive leukemogenesis. Lanraplenib (LANRA) is an oral, potent, selective, next-generation SYK inhibitor with a 24-hour half-life, and once-daily (QD) dosing. In preclinical studies, the combination of LANRA and the FLT3 inhibitor gilteritinib demonstrated strong antileukemic effects ex vivo, resulting in deeper responses, and extended overall survival in FLT3 ITD-driven AML patient-derived xenograft mouse models. LANRA in combination with gilteritinib is currently being evaluated in patients with R/R FLT3 mut AML in the KB-LANRA 1001 trial (NCT05028751). Study Design and Methods: KB-LANRA 1001 is a global, multicenter, open-label phase 1b/2 trial designed to determine the safety and maximally tolerated and/or recommended phase 2 dose (MTD/RP2D) of LANRA in combination with standard dose gilteritinib (120 mg QD) in patients with R/R FLT3 mut AML. Secondary endpoints include evaluating pharmacokinetics (PK), pharmacodynamics (PD), and response evaluation (complete response (CR), CR with partial hematologic recovery (CRh), duration of response (DoR), event-free survival (EFS) and OS of the combination. Key exploratory endpoints include reduction of FLT3 mutvariant allele frequency among patients who achieve CR/CRh, correlation with selected baseline biomarkers that may predict efficacy outcomes, and assessment of LANRA PD properties (including target engagement). Eligibility requirements include documented FLT3 mut (ITD, tyrosine kinase domain [TKD] or both), age ≥18, and receipt of at least 1 prior therapy. Oral LANRA + gilteritinib will be administered daily until progression/relapse, intolerance, or failure to achieve at least a partial response (PR) after 6 cycles. The phase 1b component will follow a 3+3 dose escalation design. A dose-escalation committee (DEC) will decide LANRA dose escalation based on prospectively defined definitions of dose-limiting toxicity and safety metrics. Enrollment of additional patients to dose cohort(s) previously cleared for safety and tolerability by the DEC will be allowed under specific conditions. The phase 2 component will further evaluate safety, PK, PD, and anti-leukemic activity of the combination at the LANRA RP2D
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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 | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.002 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.004 |
| Insufficient payload (model declined to judge) | 0.005 | 0.002 |
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".