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DRUG:

lanraplenib (GS-9876)

i
Other names: GS-9876, GS 9876
Company:
Galapagos, Gilead, Kronos Bio
Drug class:
SYK inhibitor
7ms
KB-LANRA- 1001: A Study to Evaluate Lanraplenib (LANRA) in Combination With Gilteritinib in Participants With FLT3-mutated Relapsed or Refractory Acute Myeloid Leukemia (AML) (clinicaltrials.gov)
P1/2, N=24, Terminated, Kronos Bio | Trial completion date: Oct 2024 --> Apr 2024 | Active, not recruiting --> Terminated; Sponsor decision
Trial completion date • Trial termination • Combination therapy
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FLT3 (Fms-related tyrosine kinase 3)
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FLT3 mutation
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Xospata (gilteritinib) • lanraplenib (GS-9876)
8ms
The ABCB1 and ABCG2 efflux transporters limit brain disposition of the SYK inhibitors entospletinib and lanraplenib. (PubMed, Toxicol Appl Pharmacol)
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.
Journal
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ABCB1 (ATP Binding Cassette Subfamily B Member 1) • ABCG2 (ATP Binding Cassette Subfamily G Member 2) • SYK (Spleen tyrosine kinase) • CYP3A4 (Cytochrome P450, family 3, subfamily A, polypeptide 4)
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entospletinib (GS-9973) • elacridar (GF120918) • lanraplenib (GS-9876)
10ms
Novel Signaling Pathway and NSC689534 as a Potential Drug Candidate for Cutaneous Squamous Cell Carcinoma. (PubMed, Front Biosci (Landmark Ed))
NSC689534 might be a candidate drug for cSCC targeting TPX2 and KIF11, which are hub genes in cSCC.
Journal
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CDK1 (Cyclin-dependent kinase 1) • KIF11 (Kinesin Family Member 11)
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lanraplenib (GS-9876)
11ms
KB-LANRA- 1001: A Study to Evaluate Lanraplenib (LANRA) in Combination With Gilteritinib in Participants With FLT3-mutated Relapsed or Refractory Acute Myeloid Leukemia (AML) (clinicaltrials.gov)
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 closed • Phase classification • Enrollment change • Trial primary completion date • Combination therapy
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FLT3 (Fms-related tyrosine kinase 3)
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FLT3 mutation
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Xospata (gilteritinib) • lanraplenib (GS-9876)
12ms
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 (ASH 2023)
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
Clinical • P1/2 data • Combination therapy
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FLT3 (Fms-related tyrosine kinase 3) • HOXA9 (Homeobox A9) • SYK (Spleen tyrosine kinase) • MEIS1 (Meis Homeobox 1)
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FLT3 mutation
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Xospata (gilteritinib) • lanraplenib (GS-9876)
1year
Combined Single Cell Flow Cytometry and Imaging Analyses Reveal Immunomodulatory Effects Exerted By Targeted Phospho-SYK Inhibitors with Elevated Sensitivity in NPM1 Mutated AML (ASH 2023)
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.
Immunomodulating
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FLT3 (Fms-related tyrosine kinase 3) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • mTOR (Mechanistic target of rapamycin kinase) • SYK (Spleen tyrosine kinase)
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IDH1 mutation • IDH2 mutation • FLT3 mutation • NPM1 mutation • FLT3 mutation + NPM1 mutation • MLL mutation • SYK mutation
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Mekinist (trametinib) • Xospata (gilteritinib) • entospletinib (GS-9973) • lanraplenib (GS-9876)
over1year
Enrollment change • Combination therapy
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FLT3 (Fms-related tyrosine kinase 3)
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FLT3 mutation
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Xospata (gilteritinib) • lanraplenib (GS-9876)
over1year
KB-LANRA 1001: A PHASE 1B/2 STUDY ON 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 (EHA 2023)
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.
Clinical • P1/2 data • Combination therapy
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FLT3 (Fms-related tyrosine kinase 3) • HOXA9 (Homeobox A9) • SYK (Spleen tyrosine kinase) • MEIS1 (Meis Homeobox 1)
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FLT3 mutation
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Xospata (gilteritinib) • Rydapt (midostaurin) • Vanflyta (quizartinib) • lanraplenib (GS-9876)
almost2years
Influence of efflux and uptake transporters on the pharmacokinetics of the SYK inhibitors entospletinib and lanraplenib (ESMO-TAT 2023)
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.
PK/PD data
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ABCB1 (ATP Binding Cassette Subfamily B Member 1) • ABCG2 (ATP Binding Cassette Subfamily G Member 2) • SYK (Spleen tyrosine kinase)
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entospletinib (GS-9973) • lanraplenib (GS-9876)
2years
SYK Inhibitors, Entospletinib and Lanraplenib, Show Potent Anti-Leukemic Activity in Combination with Targeted Agents (ASH 2022)
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.
Combination therapy • IO biomarker
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FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A) • HOXA9 (Homeobox A9) • SYK (Spleen tyrosine kinase) • CD14 (CD14 Molecule) • ITGAM (Integrin, alpha M) • MEIS1 (Meis Homeobox 1)
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FLT3 mutation • NPM1 mutation • MLL rearrangement • MLL rearrangement
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Venclexta (venetoclax) • Xospata (gilteritinib) • entospletinib (GS-9973) • revumenib (SNDX-5613) • lanraplenib (GS-9876)
2years
Identification and validation of four photodynamic therapy related genes inhibiting MAPK and inducing cell cycle alteration in squamous cell carcinoma. (PubMed, Front Oncol)
Expressing mRNA profile data sets GSE98767, GSE45216, and GSE84758 were acquired from the GEO database...The PDT treatment suppressed the G1 to G2/M phase in JNK overexpressed A431 cells. CCNL1, DNAJB1, DUSP6, and EFNB2 were identified as potential PDT target genes in cSCC treatment, whose potential therapeutic mechanism was inhibiting the MAPK pathway and inducing cell cycle alternation.
Journal
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EFNB2 (Ephrin B2) • DNAJB1 (DnaJ Heat Shock Protein Family (Hsp40) Member B1) • DUSP6 (Dual specificity phosphatase 6) • CCNL1 (Cyclin L1) • MCM2 (Minichromosome maintenance complex component 2)
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lanraplenib (GS-9876)
over2years
PHARMACOLOGICAL INHIBITION OF SYK CONFERS ANTI-PROLIFERATIVE AND NOVEL ANTI-TUMOR IMMUNE RESPONSES IN AML (EHA 2022)
The selective, orally bioavailable SYK inhibitor entospletinib (ENTO) has demonstrated clinical activity and tolerability in HOXA9/MEIS1- driven AML...Lanraplenib (LANRA) is a next-generation SYK inhibitor with similar potency and selectivity to ENTO but with more favorable pharmacologic properties that is currently being evaluated in combination with gilteritinib in pts with relapsed or refractory FLT3 -mutated AML (NCT05028751)...Our studies illustrate that ENTO and LANRA may restore T-cell proliferation in a subset of AML pts with dysfunctional T-cell responses, suggesting a novel mechanism of action. Additional studies are required to fully understand the mechanism of SYK-mediated antitumor immune responses in AML.
PD(L)-1 Biomarker • IO biomarker
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FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • HOXA9 (Homeobox A9) • SYK (Spleen tyrosine kinase) • MEIS1 (Meis Homeobox 1)
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FLT3 mutation • NPM1 mutation
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Xospata (gilteritinib) • entospletinib (GS-9973) • lanraplenib (GS-9876)
over2years
SYK INHIBITION DRIVES DEEP RESPONSES IN A BIOMARKER GUIDED SUBSET OF AML ALONE AND IN RATIONAL COMBINATIONS (EHA 2022)
The selective, orally bioavailable SYK inhibitor entospletinib (ENTO) has demonstrated clinical activity and tolerability in HOXA9/MEIS1- driven AML...Lanraplenib (LANRA) is a next-generation SYK inhibitor with similar potency and selectivity to ENTO but with more favorable pharmacologic properties that is currently being evaluated in combination with gilteritinib in patients with relapsed or refractory (R/R) FLT3 -mutated AML (NCT05028751)...Results Kinase selectivity profiling found >10-fold higher selectivity of ENTO and LANRA for SYK vs other kinases with improved potency and selectivity compared with the approved first-generation agent, fostamatinib...Combinations with AML standard-of-care and investigational agents, including azacytidine, showed at least additive effects. Strong synergy with the JAK inhibitor ruxolitinib was consistent mechanistically with a reporter model that demonstrated the ability of LANRA to block activation of STAT5 in response to proleukemic paracrine signaling. Finally, robust synergy across a range of LANRA concentrations was found when paired with venetoclax and gilteritinib...The highly predictive response for SYK inhibition with concurrent NPM1 m/ FLT3 -ITD mutations and synergy with gilteritinib observed in patient derived models is supportive of its clinical evaluation in combination with a FLT3 inhibitor. Our work supports the rationale for an ongoing Phase 1b/2 study of LANRA in combination with gilteritinib in patients with R/R FLT3 -mutated AML.
FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • HOXA9 (Homeobox A9) • SYK (Spleen tyrosine kinase) • MEIS1 (Meis Homeobox 1) • STAT5A (Signal Transducer And Activator Of Transcription 5A)
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FLT3 mutation • NPM1 mutation
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Venclexta (venetoclax) • Xospata (gilteritinib) • azacitidine • Jakafi (ruxolitinib) • entospletinib (GS-9973) • Tavalisse (fostamatinib) • lanraplenib (GS-9876)
over2years
PHASE 1B/2 STUDY ON 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 (KB-LANRA 1001) (EHA 2022)
Those who have been treated with midostaurin or other multikinase inhibitors are eligible, though pts who failed to achieve at least a partial response or who relapsed following prior exposure to gilteritinib or other next-generation FLT3 inhibitor monotherapy are excluded. Results Trial in progress. Conclusion Accrual is ongoing.
Clinical • P1/2 data • Combination therapy
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FLT3 (Fms-related tyrosine kinase 3) • HOXA9 (Homeobox A9) • SYK (Spleen tyrosine kinase) • MEIS1 (Meis Homeobox 1)
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FLT3-ITD mutation • FLT3 mutation
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Xospata (gilteritinib) • Rydapt (midostaurin) • lanraplenib (GS-9876)
over2years
Trial initiation date • Combination therapy
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FLT3 (Fms-related tyrosine kinase 3)
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FLT3 mutation
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Xospata (gilteritinib) • lanraplenib (GS-9876)
almost3years
Identification of CDK1 as a candidate marker in cutaneous squamous cell carcinoma by integrated bioinformatics analysis. (PubMed, Transl Cancer Res)
The GSE117247, GSE32979, and GSE98767 datasets comprising a total of 32 cSCC samples and 31 normal skin tissue samples were obtained from the National Center for Biotechnology Information Gene Expression Omnibus database...CDK1 is a gene closely related to the occurrence and development of cSCC, which may play an important role. Bioinformatics analysis shows that it is involved in the important pathway of the pathogenesis of cSCC, and may be recognized and applied as a new biomarker in the future diagnosis and treatment of cSCC.
Journal
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AURKA (Aurora kinase A) • HDAC1 (Histone Deacetylase 1) • CDC20 (Cell Division Cycle 20) • CDK1 (Cyclin-dependent kinase 1) • BUB1 (BUB1 Mitotic Checkpoint Serine/Threonine Kinase) • BUB1B (BUB1 Mitotic Checkpoint Serine/Threonine Kinase B) • FEN1 (Flap Structure-Specific Endonuclease 1) • MAPK14 (Mitogen-Activated Protein Kinase 14)
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lanraplenib (GS-9876)
almost3years
Enrollment open • Combination therapy
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FLT3 (Fms-related tyrosine kinase 3)
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FLT3 mutation
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Xospata (gilteritinib) • lanraplenib (GS-9876)
3years
Preclinical Activity of Selective SYK Inhibitors, Entospletinib and Lanraplenib, Alone or Combined with Targeted Agents in Ex Vivo AML Models with Diverse Mutational Backgrounds (ASH 2021)
Matrix combination assays were performed by combining ENTO or LANRA with either cytarabine ( NPM1 mut), gilteritinib ( FLT3 mut), or trametinib ( RAS mut) with cell viability and death assessed after a 3-day incubation period. These results support the clinical evaluation of LANRA in genetically defined subsets of AML. A phase 1b/2 study of LANRA in combination with the selective FLT3 inhibitor gilteritinib, in patients with relapsed or refractory FLT3 mut AML is planned for the end of this year.
Preclinical
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FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • NPM1 (Nucleophosmin 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • HOXA9 (Homeobox A9) • SYK (Spleen tyrosine kinase) • MEIS1 (Meis Homeobox 1)
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NRAS mutation • FLT3 mutation • NPM1 mutation • MLL rearrangement • MLL rearrangement • MLL mutation
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Mekinist (trametinib) • cytarabine • Xospata (gilteritinib) • entospletinib (GS-9973) • lanraplenib (GS-9876)