CF102 for the Treatment of Hepatocellular Carcinoma: A Phase I/II, Open‐Label, Dose‐Escalation Study

Background. The A3 adenosine receptor (A3AR) 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 A3AR agonist, induces apoptosis of HCC cells via deregulation of the Wnt signaling path...

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Published in:The oncologist (Dayton, Ohio) Ohio), 2013-01, Vol.18 (1), p.25-26
Main Authors: Stemmer, Salomon M., Benjaminov, Ofer, Medalia, Gal, Ciuraru, Noab B., Silverman, Michael H., Bar‐Yehuda, Sara, Fishman, Sari, Harpaz, Zivit, Farbstein, Motti, Cohen, Shira, Patoka, Renana, Singer, Barak, Kerns, William D., Fishman, Pnina
Format: Article
Language:English
Subjects:
Adenosine - administration & dosage
Adenosine - analogs & derivatives
Adult
Aged
Apoptosis - drug effects
Carcinoma, Hepatocellular - drug therapy
Carcinoma, Hepatocellular - pathology
Child
Clinical Trial Results
Female
Humans
Leukocytes, Mononuclear - metabolism
Leukocytes, Mononuclear - pathology
Liver Neoplasms - drug therapy
Liver Neoplasms - pathology
Male
Middle Aged
Niacinamide - administration & dosage
Niacinamide - analogs & derivatives
Phenylurea Compounds - administration & dosage
Purinergic P1 Receptor Agonists - administration & dosage
Purinergic P1 Receptor Agonists - adverse effects
Purinergic P1 Receptor Agonists - pharmacokinetics
Receptor, Adenosine A3 - metabolism
Wnt Signaling Pathway
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Summary:Background. The A3 adenosine receptor (A3AR) 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 A3AR 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 A3AR 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. 摘要 背景. 肝细胞癌（HCC）患者的肿瘤及外周血单核细胞中，A3腺苷受体（A3AR）过度表达。口服活性候选药物CF102是A3AR激动剂，能通过Wnt信号通路失调节来诱导HCC细胞凋亡。本项I/II期开放试验评估无法切除的晚期HCC患者中CF102的安全性和临床效应。 方法. 本试验的主要目的是观察CF102口服给药（1、5和25mg，每日两次）28天周期内的安全性和药代动力学（PK）特点。次要目的是评估抗肿瘤效应和A3AR能否用作预测CF102治疗反应的生物学标记。 结果. 18例患者接受CF102治疗，每个剂量组6例。未发现严重的药物相关不良事件和剂量限制性毒性反应。CF102表现出良好的口服生物利用度以及线性PK特点。研究人群中67%之前接受过索拉菲尼，中位总生存期（ OS）为7.8个月，而Child Pugh B级患者（28%）中位OS为8.1个月。4例患者按RECIST标准评定的疾病稳定至少持续4个月。CF102能维持6个月期间的肝功能。基线时的受体过度表达水平与患者OS有相关性。其中1例患者试验前出现皮肤结节，活检证实是HCC转移，经CF102治疗3个月后转移灶完全消退。 结论. CF102安全且耐受性良好，在Child Pugh A级和B级患者中有良好的PK特点，值得进一步开展临床研发。
ISSN:1083-7159
1549-490X
DOI:10.1634/theoncologist.2012-0211