A phase II, multicenter, single-arm study of mipsagargin (G-202) as a second-line therapy following sorafenib for adult patients with progressive advanced hepatocellular carcinoma

Devalingam Mahalingam, Julio Peguero, Putao Cen, Sukeshi P. Arora, John Sarantopoulos, Julie Rowe, Victoria Allgood, Benjamin Tubb, Luis Campos

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Background: Mipsagargin (G-202) is a thapsigargin-based prodrug with cytotoxic activity masked by a peptide that is cleaved by prostate-specific membrane antigen (PSMA), a protease expressed in prostate cancer cells and the endothelium of tumor vasculature. It was hypothesized that PSMA-mediated activation of mipsagargin would result in disruption of the tumor vasculature, leading to a decrease in blood flow, and in direct cytotoxic effects on tumor cells, resulting in anti-tumor activity. Method: In this open-label, Phase II study, mipsagargin was administered intravenously on Days 1, 2, and 3 of a 28-day cycle to patients with hepatocellular carcinoma (HCC) who progressed on or after treatment with sorafenib or intolerant of sorafenib. Assessments included time to disease progression (TTP), response rate, progression-free survival (PFS), overall survival (OS), and safety. Blood flow metrics in hepatic lesions were evaluated using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Results: Of 25 treated patients, 19 were evaluable for efficacy. None had an objective response, 12 (63.2%) had a best response of stable disease, and 12 (63.2%) showed radiologic progression; seven patients (36.8%) were censored. The median TTP was 134.0 days, median PFS was 129.0 days, and median OS was 205.0 days. Of five patients with DCE-MRI data for 11 HCC lesions, all demonstrated a reduced Ktrans (mean, 52%). The most common treatment-emergent AEs were Grade 1–2 and consisted of increased blood creatinine (68.0%), fatigue (56.0%), and nausea (44.0%). Conclusions: Mipsagargin is relatively well tolerated and promotes prolonged disease stabilization in patients with advanced HCC that had progressed on prior treatment with sorafenib. A significant decrease in Ktrans upon treatment suggests mipsagargin reduces blood flow in hepatic lesions.

Original languageEnglish (US)
Article number833
JournalCancers
Volume11
Issue number6
DOIs
StatePublished - Jun 1 2019

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Hepatocellular Carcinoma
Disease-Free Survival
Disease Progression
Neoplasms
Magnetic Resonance Imaging
Therapeutics
Thapsigargin
Survival
Liver
Prodrugs
Nausea
Endothelium
Fatigue
Creatinine
Prostatic Neoplasms
Peptide Hydrolases
sorafenib
Safety
Peptides
human glutamate carboxypeptidase II

Keywords

  • G-202
  • Hepatocellular carcinoma
  • Mipsagargin
  • Prodrug

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

A phase II, multicenter, single-arm study of mipsagargin (G-202) as a second-line therapy following sorafenib for adult patients with progressive advanced hepatocellular carcinoma. / Mahalingam, Devalingam; Peguero, Julio; Cen, Putao; Arora, Sukeshi P.; Sarantopoulos, John; Rowe, Julie; Allgood, Victoria; Tubb, Benjamin; Campos, Luis.

In: Cancers, Vol. 11, No. 6, 833, 01.06.2019.

Research output: Contribution to journalArticle

Mahalingam, Devalingam ; Peguero, Julio ; Cen, Putao ; Arora, Sukeshi P. ; Sarantopoulos, John ; Rowe, Julie ; Allgood, Victoria ; Tubb, Benjamin ; Campos, Luis. / A phase II, multicenter, single-arm study of mipsagargin (G-202) as a second-line therapy following sorafenib for adult patients with progressive advanced hepatocellular carcinoma. In: Cancers. 2019 ; Vol. 11, No. 6.
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abstract = "Background: Mipsagargin (G-202) is a thapsigargin-based prodrug with cytotoxic activity masked by a peptide that is cleaved by prostate-specific membrane antigen (PSMA), a protease expressed in prostate cancer cells and the endothelium of tumor vasculature. It was hypothesized that PSMA-mediated activation of mipsagargin would result in disruption of the tumor vasculature, leading to a decrease in blood flow, and in direct cytotoxic effects on tumor cells, resulting in anti-tumor activity. Method: In this open-label, Phase II study, mipsagargin was administered intravenously on Days 1, 2, and 3 of a 28-day cycle to patients with hepatocellular carcinoma (HCC) who progressed on or after treatment with sorafenib or intolerant of sorafenib. Assessments included time to disease progression (TTP), response rate, progression-free survival (PFS), overall survival (OS), and safety. Blood flow metrics in hepatic lesions were evaluated using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Results: Of 25 treated patients, 19 were evaluable for efficacy. None had an objective response, 12 (63.2{\%}) had a best response of stable disease, and 12 (63.2{\%}) showed radiologic progression; seven patients (36.8{\%}) were censored. The median TTP was 134.0 days, median PFS was 129.0 days, and median OS was 205.0 days. Of five patients with DCE-MRI data for 11 HCC lesions, all demonstrated a reduced Ktrans (mean, 52{\%}). The most common treatment-emergent AEs were Grade 1–2 and consisted of increased blood creatinine (68.0{\%}), fatigue (56.0{\%}), and nausea (44.0{\%}). Conclusions: Mipsagargin is relatively well tolerated and promotes prolonged disease stabilization in patients with advanced HCC that had progressed on prior treatment with sorafenib. A significant decrease in Ktrans upon treatment suggests mipsagargin reduces blood flow in hepatic lesions.",
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T1 - A phase II, multicenter, single-arm study of mipsagargin (G-202) as a second-line therapy following sorafenib for adult patients with progressive advanced hepatocellular carcinoma

AU - Mahalingam, Devalingam

AU - Peguero, Julio

AU - Cen, Putao

AU - Arora, Sukeshi P.

AU - Sarantopoulos, John

AU - Rowe, Julie

AU - Allgood, Victoria

AU - Tubb, Benjamin

AU - Campos, Luis

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AB - Background: Mipsagargin (G-202) is a thapsigargin-based prodrug with cytotoxic activity masked by a peptide that is cleaved by prostate-specific membrane antigen (PSMA), a protease expressed in prostate cancer cells and the endothelium of tumor vasculature. It was hypothesized that PSMA-mediated activation of mipsagargin would result in disruption of the tumor vasculature, leading to a decrease in blood flow, and in direct cytotoxic effects on tumor cells, resulting in anti-tumor activity. Method: In this open-label, Phase II study, mipsagargin was administered intravenously on Days 1, 2, and 3 of a 28-day cycle to patients with hepatocellular carcinoma (HCC) who progressed on or after treatment with sorafenib or intolerant of sorafenib. Assessments included time to disease progression (TTP), response rate, progression-free survival (PFS), overall survival (OS), and safety. Blood flow metrics in hepatic lesions were evaluated using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Results: Of 25 treated patients, 19 were evaluable for efficacy. None had an objective response, 12 (63.2%) had a best response of stable disease, and 12 (63.2%) showed radiologic progression; seven patients (36.8%) were censored. The median TTP was 134.0 days, median PFS was 129.0 days, and median OS was 205.0 days. Of five patients with DCE-MRI data for 11 HCC lesions, all demonstrated a reduced Ktrans (mean, 52%). The most common treatment-emergent AEs were Grade 1–2 and consisted of increased blood creatinine (68.0%), fatigue (56.0%), and nausea (44.0%). Conclusions: Mipsagargin is relatively well tolerated and promotes prolonged disease stabilization in patients with advanced HCC that had progressed on prior treatment with sorafenib. A significant decrease in Ktrans upon treatment suggests mipsagargin reduces blood flow in hepatic lesions.

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