Novel transforming growth factor beta receptor I kinase inhibitor galunisertib (LY2157299) in advanced hepatocellular carcinoma

Sandrine Faivre, Armando Santoro, Robin K Kelley, Ed Gane, Charlotte E Costentin, Ivelina Gueorguieva, Claire Smith, Ann Cleverly, Michael M Lahn, Eric Raymond, Karim A Benhadji, Gianluigi Giannelli

Research output: Contribution to journalArticle

Abstract

BACKGROUND AND AIMS: We assessed the activity of galunisertib, a small molecule inhibitor of the transforming growth factor beta (TGF-β1) receptor I, in second-line patients with hepatocellular carcinoma (HCC) in two cohorts of baseline serum alpha fetoprotein (AFP).

METHODS: Patients with advanced HCC who progressed on or were ineligible to receive sorafenib, Child-Pugh A/B7 and ECOG PS ≤1 were enrolled into Part A (AFP ≥ 1.5× ULN) or Part B (AFP < 1.5× ULN). Patients were treated with 80 or 150 mg galunisertib BID for 14 days per 28-day cycle. Endpoints were time-to-progression (TTP) and changes in circulating AFP and TGF-β1 levels, as well as safety, pharmacokinetics, progression-free survival and overall survival (OS).

RESULTS: Patients (n = 149) were enrolled with median age 65 years. Median TTP was 2.7 months (95% CI: 1.5-2.9) in Part A (n = 109) and 4.2 months (95% CI: 1.7-5.5) in Part B (n = 40). Median OS was 7.3 months (95% CI: 4.9-10.5) in Part A and 16.8 months (95% CI: 10.5-24.4) in Part B. OS was longer in AFP responders (>20% decrease from baseline, Part A) compared to non-responders (21.5 months vs 6.8 months). OS was longer in TGF-β1 responders (>20% decrease from baseline, all patients) compared to non-responders. The most common Grade 3/4 treatment-related adverse events were neutropenia (n = 4) and fatigue, anaemia, increased bilirubin, hypoalbuminemia and embolism (each, n = 2).

CONCLUSIONS: Galunisertib treatment had a manageable safety profile in patients with HCC. Lower baseline AFP and a response in AFP or TGF-β1 levels (vs no response) correlated with longer survival.

TRIAL REGISTRATION NUMBER: NCT01246986 at ClinicalTrials.gov.

Original languageEnglish
Pages (from-to)1468-1477
Number of pages10
JournalLiver International
Volume39
Issue number8
DOIs
Publication statusPublished - Aug 2019

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LY-2157299
alpha-Fetoproteins
Hepatocellular Carcinoma
Phosphotransferases
Transforming Growth Factor beta Receptors
Hypoalbuminemia
Neutropenia
Embolism
Bilirubin
Transforming Growth Factor beta
Fatigue
Anemia
TGF-beta type I receptor
Safety
Survival

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Novel transforming growth factor beta receptor I kinase inhibitor galunisertib (LY2157299) in advanced hepatocellular carcinoma. / Faivre, Sandrine; Santoro, Armando; Kelley, Robin K; Gane, Ed; Costentin, Charlotte E; Gueorguieva, Ivelina; Smith, Claire; Cleverly, Ann; Lahn, Michael M; Raymond, Eric; Benhadji, Karim A; Giannelli, Gianluigi.

In: Liver International, Vol. 39, No. 8, 08.2019, p. 1468-1477.

Research output: Contribution to journalArticle

Faivre, S, Santoro, A, Kelley, RK, Gane, E, Costentin, CE, Gueorguieva, I, Smith, C, Cleverly, A, Lahn, MM, Raymond, E, Benhadji, KA & Giannelli, G 2019, 'Novel transforming growth factor beta receptor I kinase inhibitor galunisertib (LY2157299) in advanced hepatocellular carcinoma', Liver International, vol. 39, no. 8, pp. 1468-1477. https://doi.org/10.1111/liv.14113
Faivre, Sandrine ; Santoro, Armando ; Kelley, Robin K ; Gane, Ed ; Costentin, Charlotte E ; Gueorguieva, Ivelina ; Smith, Claire ; Cleverly, Ann ; Lahn, Michael M ; Raymond, Eric ; Benhadji, Karim A ; Giannelli, Gianluigi. / Novel transforming growth factor beta receptor I kinase inhibitor galunisertib (LY2157299) in advanced hepatocellular carcinoma. In: Liver International. 2019 ; Vol. 39, No. 8. pp. 1468-1477.
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abstract = "BACKGROUND AND AIMS: We assessed the activity of galunisertib, a small molecule inhibitor of the transforming growth factor beta (TGF-β1) receptor I, in second-line patients with hepatocellular carcinoma (HCC) in two cohorts of baseline serum alpha fetoprotein (AFP).METHODS: Patients with advanced HCC who progressed on or were ineligible to receive sorafenib, Child-Pugh A/B7 and ECOG PS ≤1 were enrolled into Part A (AFP ≥ 1.5× ULN) or Part B (AFP < 1.5× ULN). Patients were treated with 80 or 150 mg galunisertib BID for 14 days per 28-day cycle. Endpoints were time-to-progression (TTP) and changes in circulating AFP and TGF-β1 levels, as well as safety, pharmacokinetics, progression-free survival and overall survival (OS).RESULTS: Patients (n = 149) were enrolled with median age 65 years. Median TTP was 2.7 months (95{\%} CI: 1.5-2.9) in Part A (n = 109) and 4.2 months (95{\%} CI: 1.7-5.5) in Part B (n = 40). Median OS was 7.3 months (95{\%} CI: 4.9-10.5) in Part A and 16.8 months (95{\%} CI: 10.5-24.4) in Part B. OS was longer in AFP responders (>20{\%} decrease from baseline, Part A) compared to non-responders (21.5 months vs 6.8 months). OS was longer in TGF-β1 responders (>20{\%} decrease from baseline, all patients) compared to non-responders. The most common Grade 3/4 treatment-related adverse events were neutropenia (n = 4) and fatigue, anaemia, increased bilirubin, hypoalbuminemia and embolism (each, n = 2).CONCLUSIONS: Galunisertib treatment had a manageable safety profile in patients with HCC. Lower baseline AFP and a response in AFP or TGF-β1 levels (vs no response) correlated with longer survival.TRIAL REGISTRATION NUMBER: NCT01246986 at ClinicalTrials.gov.",
author = "Sandrine Faivre and Armando Santoro and Kelley, {Robin K} and Ed Gane and Costentin, {Charlotte E} and Ivelina Gueorguieva and Claire Smith and Ann Cleverly and Lahn, {Michael M} and Eric Raymond and Benhadji, {Karim A} and Gianluigi Giannelli",
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T1 - Novel transforming growth factor beta receptor I kinase inhibitor galunisertib (LY2157299) in advanced hepatocellular carcinoma

AU - Faivre, Sandrine

AU - Santoro, Armando

AU - Kelley, Robin K

AU - Gane, Ed

AU - Costentin, Charlotte E

AU - Gueorguieva, Ivelina

AU - Smith, Claire

AU - Cleverly, Ann

AU - Lahn, Michael M

AU - Raymond, Eric

AU - Benhadji, Karim A

AU - Giannelli, Gianluigi

N1 - © 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

PY - 2019/8

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N2 - BACKGROUND AND AIMS: We assessed the activity of galunisertib, a small molecule inhibitor of the transforming growth factor beta (TGF-β1) receptor I, in second-line patients with hepatocellular carcinoma (HCC) in two cohorts of baseline serum alpha fetoprotein (AFP).METHODS: Patients with advanced HCC who progressed on or were ineligible to receive sorafenib, Child-Pugh A/B7 and ECOG PS ≤1 were enrolled into Part A (AFP ≥ 1.5× ULN) or Part B (AFP < 1.5× ULN). Patients were treated with 80 or 150 mg galunisertib BID for 14 days per 28-day cycle. Endpoints were time-to-progression (TTP) and changes in circulating AFP and TGF-β1 levels, as well as safety, pharmacokinetics, progression-free survival and overall survival (OS).RESULTS: Patients (n = 149) were enrolled with median age 65 years. Median TTP was 2.7 months (95% CI: 1.5-2.9) in Part A (n = 109) and 4.2 months (95% CI: 1.7-5.5) in Part B (n = 40). Median OS was 7.3 months (95% CI: 4.9-10.5) in Part A and 16.8 months (95% CI: 10.5-24.4) in Part B. OS was longer in AFP responders (>20% decrease from baseline, Part A) compared to non-responders (21.5 months vs 6.8 months). OS was longer in TGF-β1 responders (>20% decrease from baseline, all patients) compared to non-responders. The most common Grade 3/4 treatment-related adverse events were neutropenia (n = 4) and fatigue, anaemia, increased bilirubin, hypoalbuminemia and embolism (each, n = 2).CONCLUSIONS: Galunisertib treatment had a manageable safety profile in patients with HCC. Lower baseline AFP and a response in AFP or TGF-β1 levels (vs no response) correlated with longer survival.TRIAL REGISTRATION NUMBER: NCT01246986 at ClinicalTrials.gov.

AB - BACKGROUND AND AIMS: We assessed the activity of galunisertib, a small molecule inhibitor of the transforming growth factor beta (TGF-β1) receptor I, in second-line patients with hepatocellular carcinoma (HCC) in two cohorts of baseline serum alpha fetoprotein (AFP).METHODS: Patients with advanced HCC who progressed on or were ineligible to receive sorafenib, Child-Pugh A/B7 and ECOG PS ≤1 were enrolled into Part A (AFP ≥ 1.5× ULN) or Part B (AFP < 1.5× ULN). Patients were treated with 80 or 150 mg galunisertib BID for 14 days per 28-day cycle. Endpoints were time-to-progression (TTP) and changes in circulating AFP and TGF-β1 levels, as well as safety, pharmacokinetics, progression-free survival and overall survival (OS).RESULTS: Patients (n = 149) were enrolled with median age 65 years. Median TTP was 2.7 months (95% CI: 1.5-2.9) in Part A (n = 109) and 4.2 months (95% CI: 1.7-5.5) in Part B (n = 40). Median OS was 7.3 months (95% CI: 4.9-10.5) in Part A and 16.8 months (95% CI: 10.5-24.4) in Part B. OS was longer in AFP responders (>20% decrease from baseline, Part A) compared to non-responders (21.5 months vs 6.8 months). OS was longer in TGF-β1 responders (>20% decrease from baseline, all patients) compared to non-responders. The most common Grade 3/4 treatment-related adverse events were neutropenia (n = 4) and fatigue, anaemia, increased bilirubin, hypoalbuminemia and embolism (each, n = 2).CONCLUSIONS: Galunisertib treatment had a manageable safety profile in patients with HCC. Lower baseline AFP and a response in AFP or TGF-β1 levels (vs no response) correlated with longer survival.TRIAL REGISTRATION NUMBER: NCT01246986 at ClinicalTrials.gov.

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DO - 10.1111/liv.14113

M3 - Article

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JO - Liver International

JF - Liver International

SN - 1478-3223

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