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TAKEAIM LEUKEMIA- A PHASE 1/2A STUDY OF THE IRAK4 INHIBITOR EMAVUSERTIB (CA-4948) AS MONOTHERAPY OR IN COMBINATION WITH AZACITIDINE OR VENETOCLAX IN RELAPSED/REFRACTORY AML OR MDS
Author(s): ,
Gullermo Garcia-Manero
Affiliations:
Luekemia,MD Anderson Cancer Center,Houston,États-unis;Luekemia,MD Anderson Cancer Center,Houston,Vereinigte Staaten;Luekemia,MD Anderson Cancer Center,Houston,Stati Uniti;Luekemia,MD Anderson Cancer Center,Houston,United States;Luekemia,MD Anderson Cancer Center,Houston,Estados Unidos;Luekemia,MD Anderson Cancer Center,Houston,Verenigde Staten;Luekemia,MD Anderson Cancer Center,Houston,Estados Uni
,
Eric S. Winer
Affiliations:
Dana-Faber Cancer Institute,Boston,États-unis;Dana-Faber Cancer Institute,Boston,Vereinigte Staaten;Dana-Faber Cancer Institute,Boston,Stati Uniti;Dana-Faber Cancer Institute,Boston,United States;Dana-Faber Cancer Institute,Boston,Estados Unidos;Dana-Faber Cancer Institute,Boston,Verenigde Staten;Dana-Faber Cancer Institute,Boston,Estados Unidos;Dana-Faber Cancer Institute,Boston,United States;Dan
,
Daniel J. DeAngelo
Affiliations:
Dana-Faber Cancer Institute,Boston,États-unis;Dana-Faber Cancer Institute,Boston,Vereinigte Staaten;Dana-Faber Cancer Institute,Boston,Stati Uniti;Dana-Faber Cancer Institute,Boston,United States;Dana-Faber Cancer Institute,Boston,Estados Unidos;Dana-Faber Cancer Institute,Boston,Verenigde Staten;Dana-Faber Cancer Institute,Boston,Estados Unidos;Dana-Faber Cancer Institute,Boston,United States;Dan
,
Stefano Tarantolo
Affiliations:
Nebraska Cancer Specialist,Omaha,États-unis;Nebraska Cancer Specialist,Omaha,Vereinigte Staaten;Nebraska Cancer Specialist,Omaha,Stati Uniti;Nebraska Cancer Specialist,Omaha,United States;Nebraska Cancer Specialist,Omaha,Estados Unidos;Nebraska Cancer Specialist,Omaha,Verenigde Staten;Nebraska Cancer Specialist,Omaha,Estados Unidos;Nebraska Cancer Specialist,Omaha,United States;Nebraska Cancer Spe
,
David A. Sallman
Affiliations:
Moffitt Cancer Center,Tampa,États-unis;Moffitt Cancer Center,Tampa,Vereinigte Staaten;Moffitt Cancer Center,Tampa,Stati Uniti;Moffitt Cancer Center,Tampa,United States;Moffitt Cancer Center,Tampa,Estados Unidos;Moffitt Cancer Center,Tampa,Verenigde Staten;Moffitt Cancer Center,Tampa,Estados Unidos;Moffitt Cancer Center,Tampa,United States;Moffitt Cancer Center,Tampa,USA
,
James Dugan
Affiliations:
Novant Health Cancer Institute, Forsyth Medical Center,Winston-Salem,États-unis;Novant Health Cancer Institute, Forsyth Medical Center,Winston-Salem,Vereinigte Staaten;Novant Health Cancer Institute, Forsyth Medical Center,Winston-Salem,Stati Uniti;Novant Health Cancer Institute, Forsyth Medical Center,Winston-Salem,United States;Novant Health Cancer Institute, Forsyth Medical Center,Winston-Salem
,
Stefanie Groepper
Affiliations:
Marien Hospital/ Univ. of Dusseldorf Germany,Dusseldorf,Allemagne;Marien Hospital/ Univ. of Dusseldorf Germany,Dusseldorf,Deutschland;Marien Hospital/ Univ. of Dusseldorf Germany,Dusseldorf,Germania;Marien Hospital/ Univ. of Dusseldorf Germany,Dusseldorf,Germany;Marien Hospital/ Univ. of Dusseldorf Germany,Dusseldorf,Alemania;Marien Hospital/ Univ. of Dusseldorf Germany,Dusseldorf,Duitsland;Marien
,
Aristoteles Giagounidis
Affiliations:
Marien Hospital/ Univ. of Dusseldorf Germany,Dusseldorf,Allemagne;Marien Hospital/ Univ. of Dusseldorf Germany,Dusseldorf,Deutschland;Marien Hospital/ Univ. of Dusseldorf Germany,Dusseldorf,Germania;Marien Hospital/ Univ. of Dusseldorf Germany,Dusseldorf,Germany;Marien Hospital/ Univ. of Dusseldorf Germany,Dusseldorf,Alemania;Marien Hospital/ Univ. of Dusseldorf Germany,Dusseldorf,Duitsland;Marien
,
Katharina Götze
Affiliations:
Faculty of Medicine Technical University of Munic,Munich,Allemagne;Faculty of Medicine Technical University of Munic,Munich,Deutschland;Faculty of Medicine Technical University of Munic,Munich,Germania;Faculty of Medicine Technical University of Munic,Munich,Germany;Faculty of Medicine Technical University of Munic,Munich,Alemania;Faculty of Medicine Technical University of Munic,Munich,Duitsland;
,
Klaus H. Metzeler
Affiliations:
Hematology, Cellular Therapy and Hemostaseology,University Hospital Leipzig,Leipzig,Allemagne;Hematology, Cellular Therapy and Hemostaseology,University Hospital Leipzig,Leipzig,Deutschland;Hematology, Cellular Therapy and Hemostaseology,University Hospital Leipzig,Leipzig,Germania;Hematology, Cellular Therapy and Hemostaseology,University Hospital Leipzig,Leipzig,Germany;Hematology, Cellular Ther
,
Chia-Cheng Li
Affiliations:
Curis,Lexington,États-unis;Curis,Lexington,Vereinigte Staaten;Curis,Lexington,Stati Uniti;Curis,Lexington,United States;Curis,Lexington,Estados Unidos;Curis,Lexington,Verenigde Staten;Curis,Lexington,Estados Unidos;Curis,Lexington,United States;Curis,Lexington,USA
,
Li Zhou
Affiliations:
Curis,Lexington,États-unis;Curis,Lexington,Vereinigte Staaten;Curis,Lexington,Stati Uniti;Curis,Lexington,United States;Curis,Lexington,Estados Unidos;Curis,Lexington,Verenigde Staten;Curis,Lexington,Estados Unidos;Curis,Lexington,United States;Curis,Lexington,USA
,
Elizabeth Martinez
Affiliations:
Curis,Lexington,États-unis;Curis,Lexington,Vereinigte Staaten;Curis,Lexington,Stati Uniti;Curis,Lexington,United States;Curis,Lexington,Estados Unidos;Curis,Lexington,Verenigde Staten;Curis,Lexington,Estados Unidos;Curis,Lexington,United States;Curis,Lexington,USA
,
Maureen Lane
Affiliations:
Curis,Lexington,États-unis;Curis,Lexington,Vereinigte Staaten;Curis,Lexington,Stati Uniti;Curis,Lexington,United States;Curis,Lexington,Estados Unidos;Curis,Lexington,Verenigde Staten;Curis,Lexington,Estados Unidos;Curis,Lexington,United States;Curis,Lexington,USA
,
Reinhard von Roemeling
Affiliations:
Curis,Lexington,États-unis;Curis,Lexington,Vereinigte Staaten;Curis,Lexington,Stati Uniti;Curis,Lexington,United States;Curis,Lexington,Estados Unidos;Curis,Lexington,Verenigde Staten;Curis,Lexington,Estados Unidos;Curis,Lexington,United States;Curis,Lexington,USA
,
Matthias Bohme
Affiliations:
Curis,Lexington,États-unis;Curis,Lexington,Vereinigte Staaten;Curis,Lexington,Stati Uniti;Curis,Lexington,United States;Curis,Lexington,Estados Unidos;Curis,Lexington,Verenigde Staten;Curis,Lexington,Estados Unidos;Curis,Lexington,United States;Curis,Lexington,USA
,
Anne Sophie Kubasch
Affiliations:
University Hospital Leipzig,Leipzig,Allemagne;University Hospital Leipzig,Leipzig,Deutschland;University Hospital Leipzig,Leipzig,Germania;University Hospital Leipzig,Leipzig,Germany;University Hospital Leipzig,Leipzig,Alemania;University Hospital Leipzig,Leipzig,Duitsland;University Hospital Leipzig,Leipzig,Alemanha;University Hospital Leipzig,Leipzig,Германия;University Hospital Leipzig,Leipzig,
,
Amit Verma
Affiliations:
Albert Einstein College of Medicine, Montefiore Medical Center,Bronx,États-unis;Albert Einstein College of Medicine, Montefiore Medical Center,Bronx,Vereinigte Staaten;Albert Einstein College of Medicine, Montefiore Medical Center,Bronx,Stati Uniti;Albert Einstein College of Medicine, Montefiore Medical Center,Bronx,United States;Albert Einstein College of Medicine, Montefiore Medical Center,Bronx
Uwe Platzbecker
Affiliations:
University Hospital Leipzig,Leipzig,Allemagne;University Hospital Leipzig,Leipzig,Deutschland;University Hospital Leipzig,Leipzig,Germania;University Hospital Leipzig,Leipzig,Germany;University Hospital Leipzig,Leipzig,Alemania;University Hospital Leipzig,Leipzig,Duitsland;University Hospital Leipzig,Leipzig,Alemanha;University Hospital Leipzig,Leipzig,Германия;University Hospital Leipzig,Leipzig,
(Abstract release date: 05/12/22) EHA Library. Garcia-Manero G. 06/11/22; 356993; S129
Dr. Guillermo Garcia-Manero
Dr. Guillermo Garcia-Manero
Contributions
Abstract
Presentation during EHA2022: All Oral presentations will be presented between Friday, June 10 and Sunday, June 12 and will be accessible for on-demand viewing from Monday, June 20 until Monday, August 15, 2022 on the Congress platform.

Abstract: S129

Type: Oral Presentation

Session title: Novel insights into AML treatment

Background
Emavusertib (CA-4948) is a novel oral inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4) and FLT3. IRAK4 is critical in triggering inflammation, oncogenesis, and survival of cancer cells. Genetic mutations in the splicing factors SF3B1 and U2AF1 drive overexpression of a highly active long isoform of IRAK4 and have been associated with disease progression and poor prognosis of high-risk myelodysplastic syndrome (HR-MDS) and acute myeloid leukemia (AML). 

Aims
Assessment of safety, clinical activity, and Recommended Phase 2 Dose (RP2D) of emavusertib as monotherapy or in combination with azacitidine (AZA) or venetoclax (VEN).

Methods
This is an open-label, phase 1/2a dose escalation and cohort expansion trial (NCT04278768). In phase 1 Dose Escalation, patients with R/R AML or HR-MDS are treated with emavusertib monotherapy. Phase 1b includes 2 arms of combination therapy: emavusertib + AZA and emavusertib + VEN. The primary objectives of this study are to assess the safety, clinical activity, and identify the RP2D of emavusertib as monotherapy or in combination with AZA or VEN in R/R AML or HR-MDS. The Phase 2a Dose Expansion includes patients for emavusertib monotherapy: R/R AML with FLT3 mutation, or AML and HR-MDS R/R to HMA with U2AF1 or SF3B1 mutations.

Results
As of December 16th, 2021, 49 patients have been treated in the phase 1 portion, of whom 43 started by September 30th, allowing 2 on-study disease assessments. The median number of prior therapies was 2 (range 1-5). Four monotherapy dose levels of emavusertib were tested (200 to 500 mg orally BID). No dose-limiting toxicities were observed at 200 mg and 300 mg BID. No Grade 4 or 5 treatment-related AEs (TRAEs) were reported, and all the TRAEs were manageable. Reversible, manageable Grade 3 rhabdomyolysis occurred in 1/26 (4%) patients at 300 mg BID, 2/17 (12%) at 400 mg BID, and 1/3 (33%) at 500 mg BID. RP2D was determined as 300 mg BID. Of 43 patients starting before Sept 30th, 2021, 14 had SF3B1, U2AF1 or FLT3 mutations and demonstrated more promising efficacy. In the 5 evaluable AML patients with spliceosome mutations, 40% reached CR/CRh (1 CR, 1 CRh), both with study duration >6 months. In the 7 spliceosome-mutated HR-MDS patients, 57% reached marrow CR, including 1 with RBC transfusion independence and 1 proceeding to HSCT. One of the three FLT3-mutated AML reached CR, and 2 became FLT3-negative. Among the 29 patients without SF3B1/U2AF1/FLT3 mutations, 1 reached CR and 2 PR. Phase 1b and Phase 2a are ongoing. RNA-seq on selected samples showed decrease in relative expression of IRAK4-long isoforms with response to emavusertib.

Conclusion
Emavusertib is well tolerated and effective in heavily pretreated AML and HR-MDS patients, especially in those with U2AF1/SF3B1/FLT3 mutations. No dose-limiting myelosuppression was reported, suggesting emavusertib may be a candidate for combination therapy. Accrual of Phases 1b and 2a is ongoing.

Keyword(s): Acute myeloid leukemia, FLT3, Mutation, Myelodysplastic syndrome

Presentation during EHA2022: All Oral presentations will be presented between Friday, June 10 and Sunday, June 12 and will be accessible for on-demand viewing from Monday, June 20 until Monday, August 15, 2022 on the Congress platform.

Abstract: S129

Type: Oral Presentation

Session title: Novel insights into AML treatment

Background
Emavusertib (CA-4948) is a novel oral inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4) and FLT3. IRAK4 is critical in triggering inflammation, oncogenesis, and survival of cancer cells. Genetic mutations in the splicing factors SF3B1 and U2AF1 drive overexpression of a highly active long isoform of IRAK4 and have been associated with disease progression and poor prognosis of high-risk myelodysplastic syndrome (HR-MDS) and acute myeloid leukemia (AML). 

Aims
Assessment of safety, clinical activity, and Recommended Phase 2 Dose (RP2D) of emavusertib as monotherapy or in combination with azacitidine (AZA) or venetoclax (VEN).

Methods
This is an open-label, phase 1/2a dose escalation and cohort expansion trial (NCT04278768). In phase 1 Dose Escalation, patients with R/R AML or HR-MDS are treated with emavusertib monotherapy. Phase 1b includes 2 arms of combination therapy: emavusertib + AZA and emavusertib + VEN. The primary objectives of this study are to assess the safety, clinical activity, and identify the RP2D of emavusertib as monotherapy or in combination with AZA or VEN in R/R AML or HR-MDS. The Phase 2a Dose Expansion includes patients for emavusertib monotherapy: R/R AML with FLT3 mutation, or AML and HR-MDS R/R to HMA with U2AF1 or SF3B1 mutations.

Results
As of December 16th, 2021, 49 patients have been treated in the phase 1 portion, of whom 43 started by September 30th, allowing 2 on-study disease assessments. The median number of prior therapies was 2 (range 1-5). Four monotherapy dose levels of emavusertib were tested (200 to 500 mg orally BID). No dose-limiting toxicities were observed at 200 mg and 300 mg BID. No Grade 4 or 5 treatment-related AEs (TRAEs) were reported, and all the TRAEs were manageable. Reversible, manageable Grade 3 rhabdomyolysis occurred in 1/26 (4%) patients at 300 mg BID, 2/17 (12%) at 400 mg BID, and 1/3 (33%) at 500 mg BID. RP2D was determined as 300 mg BID. Of 43 patients starting before Sept 30th, 2021, 14 had SF3B1, U2AF1 or FLT3 mutations and demonstrated more promising efficacy. In the 5 evaluable AML patients with spliceosome mutations, 40% reached CR/CRh (1 CR, 1 CRh), both with study duration >6 months. In the 7 spliceosome-mutated HR-MDS patients, 57% reached marrow CR, including 1 with RBC transfusion independence and 1 proceeding to HSCT. One of the three FLT3-mutated AML reached CR, and 2 became FLT3-negative. Among the 29 patients without SF3B1/U2AF1/FLT3 mutations, 1 reached CR and 2 PR. Phase 1b and Phase 2a are ongoing. RNA-seq on selected samples showed decrease in relative expression of IRAK4-long isoforms with response to emavusertib.

Conclusion
Emavusertib is well tolerated and effective in heavily pretreated AML and HR-MDS patients, especially in those with U2AF1/SF3B1/FLT3 mutations. No dose-limiting myelosuppression was reported, suggesting emavusertib may be a candidate for combination therapy. Accrual of Phases 1b and 2a is ongoing.

Keyword(s): Acute myeloid leukemia, FLT3, Mutation, Myelodysplastic syndrome

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