lanraplenib (GS-9876)

P1/2, N=24, Terminated, Kronos Bio | Trial completion date: Oct 2024 --> Apr 2024 | Active, not recruiting --> Terminated; Sponsor decision

This transporter-mediated restriction of brain penetration for both drugs could be almost fully inhibited by coadministration of the dual ABCB1/ABCG2 inhibitor elacridar, without signs of acute toxicity. This interaction was, however, unlikely to be mediated through any of the studied transporters or CYP3A. The obtained insights may perhaps help to further improve the safety and efficacy of entospletinib and lanraplenib.

NSC689534 might be a candidate drug for cSCC targeting TPX2 and KIF11, which are hub genes in cSCC.

P1/2, N=24, Active, not recruiting, Kronos Bio | Recruiting --> Active, not recruiting | Phase classification: P1b/2 --> P1/2 | N=100 --> 24 | Trial primary completion date: Nov 2023 --> May 2024

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

Entospletinib (ENTO) and lanraplenib (LANRA) are inhibitors of spleen tyrosine kinase (SYK); the latter is a next-generation SYK inhibitor and is currently being evaluated in combination with gilteritinib (GILT) in patients with relapsed or refractory FLT3-mutated AML (NCT05028751)...Two different AML patient cohorts were assessed by ex vivo treatment with ENTO, LANRA and combinations of LANRA (trametinib, gilteritinib (GILT), aPD-1) over a range of time points (2h, 4h, 3d and 9d) and readouts for cellular phenotype (e.g., differentiation state, immune cell populations) and functional readouts (pSYK, viability) for each cohort were analyzed by HP-FC and sc-MI and associated with available mutation information (bulk gene and single cell RNA sequencing)...These support studies investigating the use of pSYK inhibitors in combination with other therapies to reduce tumor burden, and as an improved line of treatment for AML. Acknowledgements: We are appreciative of the patients and families for their time and participation.

P1b/2, N=100, Recruiting, Kronos Bio | N=55 --> 100

Eligible pts must have documented FLT3 mutation from a reference lab, and can have received prior therapy with a FLT3 inhibitor (including midostaurin, gilteritinib, quizartinib, or ceronlanib). Accrual is ongoing.

Conclusions ABC transporters play an important role in the brain disposition of entospletinib and lanraplenib, although they have only a slight impact on the plasma exposure of entospletinib. The role for the OATP uptake transporters seems to be less prominent for both drugs, but they might be involved in the tissue disposition of lanraplenib, but not of entospletinib.

Introduction: Spleen tyrosine kinase (SYK) acts as a key integrator of cellular signaling from surface contact and receptor tyrosine kinase receptors containing an immunoreceptor tyrosine-based activation motif (ITAM). SYK is a promising therapeutic target for genetically defined subsets of AML. Two highly selective SYK inhibitors are currently undergoing clinical testing in different but complementary clinical settings. Given its central role as a modulator of leukemogenic signaling, SYK inhibition has the potential to synergize with other targeted therapies in AML.