Pilot study of the combination of sorafenib and fractionated irinotecan in pediatric relapse/refractory hepatic cancer (FINEX pilot study).

BACKGROUND: Preclinical observations suggested a synergistic effect of sorafenib (SFN) and irinotecan (CPT-11) in hepatoblastoma (HB). Thus, we conducted a feasibility study of fractionated CPT-11 combined with SFN to develop a new therapy against relapsed/refractory pediatric hepatic cancer (HC). PROCEDURE: The study was originally designed as a phase I, standard 3+3 dose-finding study to evaluate dose-limiting toxicities (DLTs) for the regimen and the optimal CPT-11 dose in combination with SFN against relapsed/refractory pediatric HC, including HB and hepatocellular carcinoma (HCC). The enrolled patients received SFN at 200 mg/m2 every 12 hours or 400 mg/m2 every 24 hours daily combined with CPT-11 at 20 mg/m2 /day on days 1 to 5 as an initial level 1 dose. RESULTS: Six patients with HB (n = 4) or HCC (n = 2) were enrolled and treated with CPT-11 dose level 1. The median age at enrollment was 8.7 (6.2-16.3) years. All patients received platinum-containing chemotherapy, and five or two patients received CPT-11 or SFN before enrollment, respectively. Regimen toxicities were evaluable in all patients. One of six patients experienced a grade 4 transaminase levels increase, which was defined as a DLT per protocol. Grade 3/4 neutropenia and a grade 3 transaminase level increase occurred in three patients and one patient, respectively. All patients reported grade 1/2 toxicities such as anemia, skin toxicity, gastrointestinal symptoms, and hypoalbuminemia. CONCLUSIONS: Although the study was terminated before determining the maximum-tolerated CPT-11 dose, SFN and CPT-11 at the level 1 dose were concluded to be tolerable in pediatric patients with HC.

The Collagen Gel Droplet-embedded Culture Drug Sensitivity Test in Relapsed Hepatoblastoma.

There are few treatment options for patients with unresectable or refractory hepatoblastoma which has failed to respond to the standard treatment. The rarity of the disease and lack of experimental materials have hampered the development of new treatments. In this study, the collagen gel droplet-embedded culture drug sensitivity test was used to evaluate the effectiveness of the multikinase inhibitors sorafenib and sunitinib, and other drugs, in relapsed hepatoblastoma tumor tissues. Tumor samples from 6 patients with relapsed hepatoblastoma were tested for drug sensitivity by the collagen gel droplet-embedded culture drug sensitivity test; evaluable results were obtained from 5 of them. All samples were judged to be sensitive to sorafenib with a 50% growth inhibitory concentration (IC50) of 0.5 to 3.1 µg/mL. Sunitinib did not achieve IC50 in 2 of 3 samples within the tested concentration range based on clinically observed serum concentrations. In the drug combination assay using a hepatoblastoma cell line, sorafenib showed synergistic effects with SN-38, an active metabolite of irinotecan. Our results provide the basic science background warranting future clinical trials of a combination of sorafenib and irinotecan for relapsed or refractory hepatoblastoma.