Phase II study of the ALK5 inhibitor galunisertib in very low-, low-, and intermediate-risk myelodysplastic syndromes

Valeria Santini, David Valcarcel, Uwe Platzbecker, Rami S. Komrokji, Ann L. Cleverly, Michael M. Lahn, Jan Janssen, Yumin Zhao, Alan Chiang, Aristoteles Giagounidis, Susan C. Guba, Ivelina Gueorguieva, Allicia C. Girvan, Mariana Da Silva Ferreira, Tushar D. Bhagat, Kith Pradhan, Ulrich Steidl, Ashwin Sridharan, Britta Will, Amit Verma

Research output: Contribution to journalArticle

Abstract

Purpose: Overactivation of TGF-b signaling is observed in myelodysplastic syndromes (MDS) and is associated with dysplastic hematopoietic differentiation. Galunisertib, a first-in-class oral inhibitor of the TGF-b receptor type 1 kinase (ALK5) has shown effectiveness in preclinical models of MDS and acceptable toxicity in phase I studies of solid malignancies. Patients and Methods: A phase II multicenter study of galunisertib was conducted in patients with very low-, low-, or intermediate-risk MDS by the Revised International Prognostic Scoring System criteria with hemoglobin 10.0 g/dL. Patients received oral galunisertib 150 mg twice daily for 14 days on/14 days off. Results: Ten of 41 evaluable patients (24.4%; 95% confidence interval, 12.4–40.3) achieved hematologic improvement erythroid response by International Working Group (IWG) 2006 criteria. A total of 18 of 41 patients (43.9%) achieved erythroid response as per IWG 2000 criteria. Nine of 28 (32.1%) of transfusion-dependent patients had hematologic improvement. A total of 18 of 41 (44%) patients had a significant reduction in fatigue. Overall median duration of response was 90 days in all patients. Rigorous stem and progenitor flow cytometry showed that patients with an early stem cell differentiation block were more likely to respond to galunisertib. The most common treatment-emergent adverse events were grade 1 or 2 in 20 (49%) of 41 patients, including any-grade fatigue (8/41, 20%), diarrhea (7/41, 17%), pyrexia (5/41, 12%), and vomiting (5/41, 12%). Conclusions: In summary, galunisertib treatment has an acceptable safety profile and was associated with hematologic improvements in lower- and intermediate-risk MDS, with responses in heavily transfusion-dependent patients and in those with signs of an early stem cell differentiation block.

Original languageEnglish (US)
Pages (from-to)6976-6985
Number of pages10
JournalClinical Cancer Research
Volume25
Issue number23
DOIs
StatePublished - Dec 1 2019

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LY-2157299
Myelodysplastic Syndromes
Fatigue
Cell Differentiation
Stem Cells

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Phase II study of the ALK5 inhibitor galunisertib in very low-, low-, and intermediate-risk myelodysplastic syndromes. / Santini, Valeria; Valcarcel, David; Platzbecker, Uwe; Komrokji, Rami S.; Cleverly, Ann L.; Lahn, Michael M.; Janssen, Jan; Zhao, Yumin; Chiang, Alan; Giagounidis, Aristoteles; Guba, Susan C.; Gueorguieva, Ivelina; Girvan, Allicia C.; Da Silva Ferreira, Mariana; Bhagat, Tushar D.; Pradhan, Kith; Steidl, Ulrich; Sridharan, Ashwin; Will, Britta; Verma, Amit.

In: Clinical Cancer Research, Vol. 25, No. 23, 01.12.2019, p. 6976-6985.

Research output: Contribution to journalArticle

Santini, V, Valcarcel, D, Platzbecker, U, Komrokji, RS, Cleverly, AL, Lahn, MM, Janssen, J, Zhao, Y, Chiang, A, Giagounidis, A, Guba, SC, Gueorguieva, I, Girvan, AC, Da Silva Ferreira, M, Bhagat, TD, Pradhan, K, Steidl, U, Sridharan, A, Will, B & Verma, A 2019, 'Phase II study of the ALK5 inhibitor galunisertib in very low-, low-, and intermediate-risk myelodysplastic syndromes', Clinical Cancer Research, vol. 25, no. 23, pp. 6976-6985. https://doi.org/10.1158/1078-0432.CCR-19-1338
Santini, Valeria ; Valcarcel, David ; Platzbecker, Uwe ; Komrokji, Rami S. ; Cleverly, Ann L. ; Lahn, Michael M. ; Janssen, Jan ; Zhao, Yumin ; Chiang, Alan ; Giagounidis, Aristoteles ; Guba, Susan C. ; Gueorguieva, Ivelina ; Girvan, Allicia C. ; Da Silva Ferreira, Mariana ; Bhagat, Tushar D. ; Pradhan, Kith ; Steidl, Ulrich ; Sridharan, Ashwin ; Will, Britta ; Verma, Amit. / Phase II study of the ALK5 inhibitor galunisertib in very low-, low-, and intermediate-risk myelodysplastic syndromes. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 23. pp. 6976-6985.
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abstract = "Purpose: Overactivation of TGF-b signaling is observed in myelodysplastic syndromes (MDS) and is associated with dysplastic hematopoietic differentiation. Galunisertib, a first-in-class oral inhibitor of the TGF-b receptor type 1 kinase (ALK5) has shown effectiveness in preclinical models of MDS and acceptable toxicity in phase I studies of solid malignancies. Patients and Methods: A phase II multicenter study of galunisertib was conducted in patients with very low-, low-, or intermediate-risk MDS by the Revised International Prognostic Scoring System criteria with hemoglobin 10.0 g/dL. Patients received oral galunisertib 150 mg twice daily for 14 days on/14 days off. Results: Ten of 41 evaluable patients (24.4{\%}; 95{\%} confidence interval, 12.4–40.3) achieved hematologic improvement erythroid response by International Working Group (IWG) 2006 criteria. A total of 18 of 41 patients (43.9{\%}) achieved erythroid response as per IWG 2000 criteria. Nine of 28 (32.1{\%}) of transfusion-dependent patients had hematologic improvement. A total of 18 of 41 (44{\%}) patients had a significant reduction in fatigue. Overall median duration of response was 90 days in all patients. Rigorous stem and progenitor flow cytometry showed that patients with an early stem cell differentiation block were more likely to respond to galunisertib. The most common treatment-emergent adverse events were grade 1 or 2 in 20 (49{\%}) of 41 patients, including any-grade fatigue (8/41, 20{\%}), diarrhea (7/41, 17{\%}), pyrexia (5/41, 12{\%}), and vomiting (5/41, 12{\%}). Conclusions: In summary, galunisertib treatment has an acceptable safety profile and was associated with hematologic improvements in lower- and intermediate-risk MDS, with responses in heavily transfusion-dependent patients and in those with signs of an early stem cell differentiation block.",
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T1 - Phase II study of the ALK5 inhibitor galunisertib in very low-, low-, and intermediate-risk myelodysplastic syndromes

AU - Santini, Valeria

AU - Valcarcel, David

AU - Platzbecker, Uwe

AU - Komrokji, Rami S.

AU - Cleverly, Ann L.

AU - Lahn, Michael M.

AU - Janssen, Jan

AU - Zhao, Yumin

AU - Chiang, Alan

AU - Giagounidis, Aristoteles

AU - Guba, Susan C.

AU - Gueorguieva, Ivelina

AU - Girvan, Allicia C.

AU - Da Silva Ferreira, Mariana

AU - Bhagat, Tushar D.

AU - Pradhan, Kith

AU - Steidl, Ulrich

AU - Sridharan, Ashwin

AU - Will, Britta

AU - Verma, Amit

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Purpose: Overactivation of TGF-b signaling is observed in myelodysplastic syndromes (MDS) and is associated with dysplastic hematopoietic differentiation. Galunisertib, a first-in-class oral inhibitor of the TGF-b receptor type 1 kinase (ALK5) has shown effectiveness in preclinical models of MDS and acceptable toxicity in phase I studies of solid malignancies. Patients and Methods: A phase II multicenter study of galunisertib was conducted in patients with very low-, low-, or intermediate-risk MDS by the Revised International Prognostic Scoring System criteria with hemoglobin 10.0 g/dL. Patients received oral galunisertib 150 mg twice daily for 14 days on/14 days off. Results: Ten of 41 evaluable patients (24.4%; 95% confidence interval, 12.4–40.3) achieved hematologic improvement erythroid response by International Working Group (IWG) 2006 criteria. A total of 18 of 41 patients (43.9%) achieved erythroid response as per IWG 2000 criteria. Nine of 28 (32.1%) of transfusion-dependent patients had hematologic improvement. A total of 18 of 41 (44%) patients had a significant reduction in fatigue. Overall median duration of response was 90 days in all patients. Rigorous stem and progenitor flow cytometry showed that patients with an early stem cell differentiation block were more likely to respond to galunisertib. The most common treatment-emergent adverse events were grade 1 or 2 in 20 (49%) of 41 patients, including any-grade fatigue (8/41, 20%), diarrhea (7/41, 17%), pyrexia (5/41, 12%), and vomiting (5/41, 12%). Conclusions: In summary, galunisertib treatment has an acceptable safety profile and was associated with hematologic improvements in lower- and intermediate-risk MDS, with responses in heavily transfusion-dependent patients and in those with signs of an early stem cell differentiation block.

AB - Purpose: Overactivation of TGF-b signaling is observed in myelodysplastic syndromes (MDS) and is associated with dysplastic hematopoietic differentiation. Galunisertib, a first-in-class oral inhibitor of the TGF-b receptor type 1 kinase (ALK5) has shown effectiveness in preclinical models of MDS and acceptable toxicity in phase I studies of solid malignancies. Patients and Methods: A phase II multicenter study of galunisertib was conducted in patients with very low-, low-, or intermediate-risk MDS by the Revised International Prognostic Scoring System criteria with hemoglobin 10.0 g/dL. Patients received oral galunisertib 150 mg twice daily for 14 days on/14 days off. Results: Ten of 41 evaluable patients (24.4%; 95% confidence interval, 12.4–40.3) achieved hematologic improvement erythroid response by International Working Group (IWG) 2006 criteria. A total of 18 of 41 patients (43.9%) achieved erythroid response as per IWG 2000 criteria. Nine of 28 (32.1%) of transfusion-dependent patients had hematologic improvement. A total of 18 of 41 (44%) patients had a significant reduction in fatigue. Overall median duration of response was 90 days in all patients. Rigorous stem and progenitor flow cytometry showed that patients with an early stem cell differentiation block were more likely to respond to galunisertib. The most common treatment-emergent adverse events were grade 1 or 2 in 20 (49%) of 41 patients, including any-grade fatigue (8/41, 20%), diarrhea (7/41, 17%), pyrexia (5/41, 12%), and vomiting (5/41, 12%). Conclusions: In summary, galunisertib treatment has an acceptable safety profile and was associated with hematologic improvements in lower- and intermediate-risk MDS, with responses in heavily transfusion-dependent patients and in those with signs of an early stem cell differentiation block.

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