BACKGROUND: The A(3) adenosine receptor (A(3)AR) is overexpressed in the tumor and in the peripheral blood mononuclear cells of patients with hepatocellular carcinoma (HCC). The orally active drug candidate CF102, an A(3)AR agonist, induces apoptosis of HCC cells via deregulation of the Wnt signaling pathway. In this open label phase I/II trial, the safety and clinical effects of CF102 were assessed in patients with advanced unresectable HCC. METHODS: The primary objectives of this trial were to examine the safety and pharmacokinetic (PK) behavior of CF102 given orally (1, 5, and 25 mg BID) in 28-day cycles. Evaluation of anti-tumor effects and the utilization of A(3)AR as a biological predictive marker of response to CF102 were the secondary objectives. RESULTS: Eighteen patients received CF102-six at each dose level. No serious drug-related adverse events or dose-limiting toxicities were observed. CF102 demonstrated good oral bioavailability and linear PK behavior. Median overall survival in the study population, 67% of whom had received prior sorafenib, was 7.8 months, and for Child Pugh B patients (28%) it was 8.1 months. Stable disease by RECIST was observed in four patients for at least 4 months. CF102 maintained liver function over a 6-month period. A correlation between receptor overexpression levels at baseline and patients' overall survival was found. One of the patients who presented with skin nodules that were biopsy-proven to be HCC metastases prior to the trial showed complete metastasis regression during three months of treatment with CF102. CONCLUSIONS: CF102 is safe and well-tolerated, showing favorable PK characteristics in Child Pugh A and B HCC patients, justifying further clinical development.
BACKGROUND: The A(3) adenosine receptor (A(3)AR) is overexpressed in the tumor and in the peripheral blood mononuclear cells of patients with hepatocellular carcinoma (HCC). The orally active drug candidate CF102, an A(3)AR agonist, induces apoptosis of HCC cells via deregulation of the Wnt signaling pathway. In this open label phase I/II trial, the safety and clinical effects of CF102 were assessed in patients with advanced unresectable HCC. METHODS: The primary objectives of this trial were to examine the safety and pharmacokinetic (PK) behavior of CF102 given orally (1, 5, and 25 mg BID) in 28-day cycles. Evaluation of anti-tumor effects and the utilization of A(3)AR as a biological predictive marker of response to CF102 were the secondary objectives. RESULTS: Eighteen patients received CF102-six at each dose level. No serious drug-related adverse events or dose-limiting toxicities were observed. CF102 demonstrated good oral bioavailability and linear PK behavior. Median overall survival in the study population, 67% of whom had received prior sorafenib, was 7.8 months, and for Child Pugh B patients (28%) it was 8.1 months. Stable disease by RECIST was observed in four patients for at least 4 months. CF102 maintained liver function over a 6-month period. A correlation between receptor overexpression levels at baseline and patients' overall survival was found. One of the patients who presented with skin nodules that were biopsy-proven to be HCC metastases prior to the trial showed complete metastasis regression during three months of treatment with CF102. CONCLUSIONS: CF102 is safe and well-tolerated, showing favorable PK characteristics in Child Pugh A and B HCC patients, justifying further clinical development.
Authors: A Hollebecque; S Cattan; O Romano; G Sergent; A Mourad; A Louvet; S Dharancy; E Boleslawski; S Truant; F-R Pruvot; M Hebbar; O Ernst; P Mathurin Journal: Aliment Pharmacol Ther Date: 2011-09-29 Impact factor: 8.171
Authors: M Pinter; W Sieghart; F Hucke; I Graziadei; W Vogel; A Maieron; R Königsberg; A Weissmann; G Kornek; J Matejka; R Stauber; R Buder; B Grünberger; M Schöniger-Hekele; C Müller; M Peck-Radosavljevic Journal: Aliment Pharmacol Ther Date: 2011-08-24 Impact factor: 8.171
Authors: S Cohen; S M Stemmer; G Zozulya; A Ochaion; R Patoka; F Barer; S Bar-Yehuda; L Rath-Wolfson; K A Jacobson; P Fishman Journal: J Cell Physiol Date: 2011-09 Impact factor: 6.384
Authors: Matthias Pinter; Wolfgang Sieghart; Ivo Graziadei; Wolfgang Vogel; Andreas Maieron; Robert Königsberg; Adalbert Weissmann; Gabriela Kornek; Christina Plank; Markus Peck-Radosavljevic Journal: Oncologist Date: 2009-01-14
Authors: Stefania Gessi; Elena Cattabriga; Arianna Avitabile; Roberta Gafa'; Giovanni Lanza; Luigi Cavazzini; Nicoletta Bianchi; Roberto Gambari; Carlo Feo; Alberto Liboni; Sergio Gullini; Edward Leung; Stephen Mac-Lennan; Pier Andrea Borea Journal: Clin Cancer Res Date: 2004-09-01 Impact factor: 12.531
Authors: Carola Ledderose; Marco M Hefti; Yu Chen; Yi Bao; Thomas Seier; Linglin Li; Tobias Woehrle; Jingping Zhang; Wolfgang G Junger Journal: Purinergic Signal Date: 2016-08-30 Impact factor: 3.765