Avelumab in Combination with Axitinib as First-Line Treatment in Patients with Advanced Hepatocellular Carcinoma: Results from the Phase 1b VEGF Liver 100 Trial.

INTRODUCTION: Combining an immune checkpoint inhibitor with a targeted antiangiogenic agent may leverage complementary mechanisms of action for the treatment of advanced/metastatic hepatocellular carcinoma (aHCC). Avelumab is a human anti-PD-L1 IgG1 antibody with clinical activity in various tumor types; axitinib is a selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3. We report the final analysis from VEGF Liver 100 (NCT03289533), a phase 1b study evaluating safety and efficacy of avelumab plus axitinib in treatment-naive patients with aHCC. METHODS: Eligible patients had confirmed aHCC, no prior systemic therapy, ≥1 measurable lesion, Eastern Cooperative Oncology Group performance status ≤1, and Child-Pugh class A disease. Patients received avelumab 10 mg/kg intravenously every 2 weeks plus axitinib 5 mg orally twice daily until progression, unacceptable toxicity, or withdrawal. Endpoints included safety and investigator-assessed objective response per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and modified RECIST (mRECIST) for HCC. RESULTS: Twenty-two Japanese patients were enrolled and treated with avelumab plus axitinib. The minimum follow-up was 18 months as of October 25, 2019 (data cutoff). Grade 3 treatment-related adverse events (TRAEs) occurred in 16 patients (72.7%); the most common (≥3 patients) were hypertension (n = 11 [50.0%]), palmar-plantar erythrodysesthesia syndrome (n = 5 [22.7%]), and decreased appetite (n = 3 [13.6%]). No grade 4 TRAEs or treatment-related deaths occurred. Ten patients (45.5%) had an immune-related AE (irAE) of any grade; 3 patients (13.6%) had an infusion-related reaction (IRR) of any grade, and no grade ≥3 irAE and IRR were observed. The objective response rate was 13.6% (95% CI: 2.9-34.9%) per RECIST 1.1 and 31.8% (95% CI: 13.9-54.9%) per mRECIST for HCC. CONCLUSION: Treatment with avelumab plus axitinib was associated with a manageable toxicity profile and showed antitumor activity in patients with aHCC.

Self-dissolving microneedles for the percutaneous absorption of EPO in mice.

Erythropoietin (EPO) loaded microneedles were prepared using thread-forming polymer as a base for the percutaneous administration of EPO. The used polymers were dextrin, chondroitin sulfate and albumin. Under room temperature, EPO solution was added to high concentration of polymer solution and microneedles were prepared by forming thread with polypropylene tips. The mean weight of microneedle was 0.59 +/- 0.01 mg and length and basal diameter were 3.24 +/- 0.16 and 0.55 +/- 0.03 mm, respectively. Four microneedles were percutaneously (pc) administered to mice at the EPO dose levels of 100 IU/kg. After administration, blood samples were collected for 24 h and serum EPO levels were measured. Dextrin EPO microneedles were administered both pc and subcutaneously (sc) to mice. Serum EPO levels vs. time profiles showed Cmax of 138.6 +/- 16.1 and 146.5 +/- 8.0 mIU/ml, respectively. Tmax were 7.5 h. The values of bioavailability (BA) of EPO were 82.1 and 99.4%, respectively. By decreasing the dose from 100 to 50 and 25 IU/kg, dose-dependent serum EPO levels vs. time profiles were not clearly obtained. When chondroitin sulfate and albumin were used as the microneedle base, the serum EPO levels vs. time profiles showed almost the same pattern. Cmax of chondroitin sulfate and albumin microneedles were 96.3 +/- 8.8 and 132.2 +/- 18.9 mIU/ml, respectively. AUCs were 835.1 and 1098.7 mIU h/ml. Tmax were 8 and 6.8 h. These results suggest the usefulness of microneedles for the percutaneous administration of EPO.

Liquid filled nanoparticles as a drug delivery tool for protein therapeutics.

In the present study, an attempt was made to study the feasibility of nanoparticulate adsorbents in the presence of an absorption enhancer, as a drug delivery tool for the administration of erythropoietin (EPO) to the small intestine. Liquid filled nano- and micro-particles (LFNPS/LFMPS) were prepared using solid adsorbents such as porous silicon dioxide (Sylysia 550), carbon nanotubes (CNTs), carbon nanohorns, fullerene, charcoal and bamboo charcoal. Surfactants such as a saturated polyglycolysed C8-C18 glyceride (Gelucire 44/14), PEG-8 capryl/caprylic acid glycerides (Labrasol) and polyoxyethylene hydrogenated castor oil derivative (HCO-60) were used as an absorption enhancer at 50mg/kg along with casein/lactoferrin as enzyme inhibitors. The absorption of EPO was studied by measuring serum EPO levels by an ELISA method after small intestinal administration of EPO-LFNPS preparation to rats at the EPO dose level of 100 IU/kg. Among the adsorbents studied, CNTs showed the highest serum EPO level of 62.7 +/- 11.6 mIU/ml. In addition, with the use of casein, EPO absorption was improved, C(max) 143.1 +/- 15.2 mIU/ml. Labrasol showed the highest absorption enhancing effect after intra-jejunum administration than Gelucire 44/14 and HCO-60, 25.6 +/- 3.2 and 22.2 +/- 3.6 mIU/ml, respectively. Jejunum was found to be the best absorption site for the absorption of EPO from LFNPS. The use of CNTs as LFNPS, improved the bioavailability of EPO to 11.5% following intra-small intestinal administration.