Sorafenib and dacarbazine as first-line therapy for advanced melanoma: phase I and open-label phase II studies.

METHOD: The safety of oral sorafenib up to a maximum protocol-specified dose combined with dacarbazine in patients with metastatic, histologically confirmed melanoma was investigated in a phase I dose-escalation study and the activity of the combination was explored in an open-label phase II study. RESULTS: In the phase I study, three patients were treated with sorafenib 200 mg twice daily (b.i.d.) plus 1000 mg m(-2) dacarbazine on day 1 of a 21-day cycle and 15 patients had the sorafenib dose escalated to 400 mg b.i.d. without reaching the maximum tolerated dose of the combination. In the phase II study (n=83), the overall response rate was 12% (95% CI: 6, 21): one complete and nine partial, with median response duration of 46.7 weeks. Stable disease was the best response in 37%; median duration was 13.3 weeks. Median overall survival (OS) was 37.0 weeks (95% CI: 33.9, 46.0). CONCLUSION: Oral sorafenib combined with dacarbazine had acceptable toxicity and some antineoplastic activity against metastatic melanoma.

Final results of the European Advanced Renal Cell Carcinoma Sorafenib (EU-ARCCS) expanded-access study: a large open-label study in diverse community settings.

BACKGROUND: The European Advanced Renal Cell Carcinoma Sorafenib (EU-ARCCS) expanded-access study provided sorafenib to advanced renal cell carcinoma (RCC) patients in whom previous systemic therapy had failed. The study assessed the safety and use of sorafenib for the treatment of advanced RCC in a large community-based patient population across 11 countries in Europe. PATIENTS AND METHODS: EU-ARCCS was a single-arm, open-label trial of sorafenib in advanced RCC patients. End points included safety, time to progression, progression-free survival (PFS), and disease control rate (DCR). Subgroup analyses included age, Eastern Cooperative Oncology Group performance status, histology, prior therapy, and number and sites of metastases. RESULTS: About 1159 advanced RCC patients were enrolled. Most patients (94%) experienced drug-related adverse events (AEs) of any grade, with the most common grade ≥3 AEs including hand-foot skin reaction (13%), diarrhea (7%), fatigue (7%), hypertension (6%), and rash/desquamation (5%). The incidence of AEs in the subgroups was similar to that in the overall population. Median PFS was 6.6 months; DCR at ≥8 and ≥12 weeks was 85% and 78%, respectively. CONCLUSIONS: The sorafenib safety profile in European community-based practice settings was similar to that reported in clinical trials. The heterogeneous advanced RCC patient population in EU-ARCCS permitted assessment of sorafenib in important subpopulations of advanced RCC patients.

Thermodynamics of hydrophobic polyacids.

The thermodynamics of deprotonating hydrolyzed 1-1 copolymers of maleic anhydride with pentyl, hexyl and octyl vinyl ether was investigated by calorimetric and potentiometric methods. These polyacids undergo a transition from a compact to a random coil conformation upon ionization in aqueous media. The results were compared with those obtained previously for similar copolymers with smaller alkyl side-chains. The contributions of the enthalpy and entropy to the free energy were analyzed. The major effects appeared to be related to the charging of the compact form of the polyacids, the electrostriction of water by the completely ionized dicarboxylate groups and the reorganization of water around newly exposed alkyl side-chains arising from the conformational transition.

Volume effects of starch-water interactions.

Volume changes arising from the sorption of water by three starches have been determined by dilatometry. By a recently described method, parameters of the G.A.B. equation have been used to resolve the volume changes into contributions from strongly sorbed water molecules in contact with the surface and from weakly sorbed water molecules in the remaining water layers. The latter produced only small volume effects. In contrast, the contact sorption caused very large volume decreases. Changes in these decreases with changing water content indicated two types of sorption sites, possibly crystalline and amorphous. In the case of waxy maize starch, for which literature data concerning its degree of crystallinity were available, the contact sorption could be quantitatively resolved into contributions from the presumably crystalline and amorphous portions, with the former exhibiting both higher affinity and larger volume changes for water molecules than the latter.