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Sorafenib (BAY 43-9006), a novel, oral multi-kinase inhibitor, blocks serine/threonine and receptor tyrosine kinases in the tumor and vasculature. Sorafenib demonstrated single-agent activity in Phase I studies, and was tolerated and inhibited tumor growth in combination with doxorubicin in preclinical studies. This Phase I dose-escalation study determined the safety, pharmacokinetics and efficacy of sorafenib plus doxorubicin.Thirty-four patients with refractory, solid tumors received doxorubicin 60 mg/m(2) on Day 1 of 3-week cycles, and oral sorafenib from Day 4 of Cycle 1 at 100, 200 or 400 mg bid.Common drug-related adverse events were neutropenia (56%), hand-foot skin reaction (44%), stomatitis (32%), and diarrhea (32%). The maximum tolerated dose was not reached. One patient with pleural mesothelioma achieved a partial response (modified WHO criteria) and remained on therapy for 39.7 weeks. Fifteen patients (48%) achieved stable disease for/=12 weeks. Doxorubicin exposure increased moderately with sorafenib 400 mg bid. The pharmacokinetics of sorafenib and doxorubicinol were not affected.Sorafenib 400 mg bid plus doxorubicin 60 mg/m(2) was well tolerated. The increased doxorubicin exposure with sorafenib 400 mg bid did not result in significantly increased toxicity; low patient numbers make the clinical significance of this unclear. These promising efficacy results justify further clinical investigation.

Background: The aim of this study was to define the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and pharmacokinetics of the camptothecin glycoconjugate BAY 38-3441, administered as an infusion for 30 min on two separate schedules every 3 weeks. Patients and methods: A total of 81 patients with advanced solid tumors were treated with BAY 38-3441 either at doses of 20, 40, 67, 100, 140, 210, 315, 470 and 600 mg/m2/day for 1 day every 3 weeks (single-dose schedule), or at doses of 126, 189, 246, 320 and 416 mg/m2/day once daily for three consecutive days every 3 weeks (3-day schedule). Plasma sampling was performed to characterize the pharmacokinetics of BAY 38-3441 and camptothecin with these schedules. Results: DLTs included renal toxicity, granulocytopenia and thrombocytopenia on the single-day schedule at doses ≥470 mg/m2/day, and diarrhea and thrombocytopenia on the 3-day schedule at doses ≥320 mg/m2/day. Other non-DLTs were gastrointestinal, dermatological and hematological. Pharmacokinetics of BAY 38-3441 and camptothecin appear to be dose-dependent, but not linear. Conclusions: Renal toxicity was dose-limiting for BAY 38-3441 using 30-min infusions on the single-dose schedule. Dose escalation to 470 mg/m2/day is feasible using a 2-h infusion. However, because of the superior safety profile, we recommend the 3-day schedule for BAY 38-3441 at a dose of 320 mg/m2/day as 30-min infusions for further phase II studies.

Background Because of the increasing number of long-term survivors of metastatic testicular germ-cell cancer, a general concern has been secondary morbidities, especially cardiovascular risk factors. Patients and methods Thirty-two patients treated with cisplatin- and doxorubicin-containing chemotherapy ≥13 years before the time of analyses were evaluated for neuro-, oto-, pulmonary-, vascular- and gonadal toxicity including evaluation of myocardial damage and cardiovascular risk factors and analysis of microcirculation. Results Thirty percent of the patients showed abnormal left ventricle function. Elevated follicle stimulating hormone (FSH) and luteinising hormone (LH) levels in 75% of patients were often associated with low testosterone levels. Elevated total cholesterol levels were found in 82% and higher triglyceride levels in 44% of patients, most of them were overweight. About 25% of the patients developed diastolic arterial hypertension after chemotherapy. Reduced hearing was confirmed in 23% of patients, especially at frequencies higher than 3000 Hz. Moreover, 53% of patients presented transient evoked otoacoustic emissions. In 38% of patients non-symptomatic neuropathy was detected, in 28% symptomatic neuropathy, and in 6% disabling polyneuropathy. In 80% of patients with neuropathic symptoms additional morphological and functional abnormalities were found by nailfold capillary videomicroscopy, compared to only 57% of the patients without neuropathic symptoms. Conclusions Patients cured by cisplatin-based chemotherapy for metastatic testicular cancer have to be cognizant of their unfavorable cardiovascular risk profile, that might be a greater risk than developing a relapse or second malignancy.

Aim: TACE with Irinotecan loaded drug-eluting beads has shown activity in colorectal liver metastases. A neoangiogenic reaction due to ischemia may be among the factors interfering with its effectiveness. In this study we evaluated the changes in VEGF-A serum level as a potential surrogate for this neoangiogenic reaction in patients treated with TACE. Methods: Patients with predominant and life threatening liver metastases from CRC which were refractory to all drugs approved for metastasized CRC and documented tumor progression during or shortly after the last chemotherapy, were prospectively treated with DEBIRI with a size of 100-300 µm. Therapy was applied by a temporary catheter placed in the liver arteries. Usually each lobe of the liver was treated two times with an interval of 4 weeks. Each treatment of one liver lobe was performed with 1 vial of the DC-Beads loaded with 100 mg Irinotecan. Blood samples to measure the VEGF-A-serum levels were taken before TACE and at days 8, 15 and 22 after first treatment. Results: Complete blood samples to evaluate the VEGF-A-level were taken from 37 patients (24 m/13 f; median age 64 y) from 2/11 to 5/13. 51% of patients had an increase of the VEGF-A-level compared to baseline of median 75 % after 21 days, whereas 49% of patients had a decrease of the VEGF-A-Level of median 34% after 21 days, respectively. The changes of the VEGF-A-level at day 8 were predictive for the following course of the levels. Baseline levels were significantly higher in patients pretreated with Bevacizumab within the last 9 weeks prior to first DEBIRI (p Conclusions: These findings show different behavior of the serum VEGF-A-levels after DEBIRI-TACE, suggesting that the occlusion of blood vessels and subsequent ischemia induces neo-angiogenesis due to VEGF-A in a subset of 51% of these patients. VEGF-A -level decrease in patients with a Bevacizumab therapy within the last 9 weeks prior to first TACE may be due to a neoangiogenesis-pathway other than VEGF-mediated. These results could implicate that drugs targeting the VEGF-pathway might be effective as an additive therapy to chemoembolization in a subset of patients e.g. those with a low baseline VEGF-A-level. Disclosure: S. Pluntke: Consultancy Terumo Germany. All other authors have declared no conflicts of interest.