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

doi:10.3390/cancers11060833

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.

Highlights

Worldwide, liver cancer is the second most common cause of cancer death in men and the sixth most common cause in women due to its poor prognosis, and hepatocellular carcinoma (HCC)accounts for 70% to 90% of primary liver cancers [1]
Prolonged time to disease progression (TTP) in a population of patients who had progressed on prior treatment with sorafenib
These observations importantly suggest that mipsagargin may have clinical activity in HCC, including in the population of patients with advanced, refractory HCC

Summary

Introduction

Liver cancer is the second most common cause of cancer death in men and the sixth most common cause in women due to its poor prognosis, and hepatocellular carcinoma (HCC)accounts for 70% to 90% of primary liver cancers [1]. The median survival time is 16 to 20 months for those presenting with an intermediate stage of disease, and only six months from diagnosis for patients presenting with unresectable, advanced-stage disease [2]. Despite the evolution of systemic therapy options, many patients with advanced HCC still succumb to this disease [5]. HCC is a highly vascularized tumor [3], and ongoing angiogenesis may be essential to its growth, invasion, and metastasis [6,7,8]. The enhanced vascularity of HCC allows for radiological diagnosis of HCC This high degree of vascularization may make HCC sensitive to therapies targeting the tumor neovasculature. 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. None had an objective response, 12 (63.2%) had a best response of stable disease, and 12

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Discussion

Conclusion