Clinical activity and correlative DCE-MRI imaging of G-202, a thapsigargin-based prostate-specific membrane antigen-activated prodrug, in progressive hepatocellular cancer

Autor: Putao Cen, Luis T. Campos, Benjamin Tubb, Michael R. Kurman, Victoria Allgood, John Sarantopoulos, Devalingam Mahalingam, John Nemunaitis, Julie Rowe
Rok vydání: 2015
Předmět:
Zdroj: Journal of Clinical Oncology. 33:301-301
ISSN: 1527-7755
0732-183X
DOI: 10.1200/jco.2015.33.3_suppl.301
Popis: 301 Background: G-202 is a thapsigargin-based prodrug whose cytotoxic activity is blocked by a masking peptide that is cleaved by prostate-specific membrane antigen (PSMA), a membrane-bound protease expressed in prostate cancer and the endothelium of tumor vasculature but not in most other tissues or normal tissue vasculature. In a Phase I study of G-202, prolonged disease stabilization was observed in the subset of patients with hepatocellular carcinoma (HCC) and prompted development of a Phase II study to further evaluate activity of G-202 in patients with HCC who have progressed on sorafenib. Methods: G-202 is administered by iv infusion on Days 1, 2 and 3 of a 28-day cycle; prophylactic hydration is administered with infusion to ameliorate incidence of creatinine elevations. HCC is typically highly-vascularized, and DCE-MRI is performed in consenting patients at baseline and after treatment on approximately Day 6 of Cycle 2 to evaluate possible effects of G-202 on blood flow metrics in hepatic lesions. DCE-MRI is a non-invasive method of investigating vascular structure and function and is sensitive to alterations in vascular permeability and blood flow. DCE-MRI measurements were made on 1.5 Tesla MRI and the volume transfer coefficients, Ktrans, of HCC tumor lesions were calculated using arterial input function derived from signal in abdominal aorta. Results: Among the 22 patients treated to date, G-202 related SAEs in this patient population have been creatinine increase/acute renal failure/acute kidney injury (3 pts) and congestive heart failure (1 pt). While objective responses (CR, PR) have not been observed in these patients with advanced disease, the rate of disease stabilization has been remarkable, with >70% of patients exhibiting SD. In patients undergoing DCE-MRI, an average 56% decrease in Ktranshas been observed after administration of G-202. Conclusions: G-202 is generally well-tolerated and promotes disease stabilization in patients with advanced HCC who have progressed on sorafenib. DCE-MRI findings of decreased tumor Ktrans values suggests that G-202 reduces early arterial blood flow in hepatic lesions. Clinical trial information: NCT01777594.
Databáze: OpenAIRE
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