A phase II study of sunitinib in patients with recurrent and/or metastatic non-nasopharyngeal head and neck cancer.

PURPOSE: Patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (RM-SCCHN) bear a grave prognosis. There are unmet needs for the development of novel agents for this incurable disease. Angiogenesis is an important biological process in SCCHN. We, therefore, evaluated the activity and safety of sunitinib, an oral tyrosine kinase inhibitor that targets multiple receptors, in patients with RM-SCCHN. PATIENTS AND METHODS: Seventeen patients were treated with sunitinib 50 mg per day administrated in 4-week cycles followed by a rest period of 2 weeks. Sunitinib and SU012662 plasma levels were determined based on a validated liquid chromatography-tandem mass spectrometry method and pharmacokinetic data were fitted in a non-compartmental analysis. RESULTS: Totally, 28 6-week cycles of treatment with sunitinib were administered (median, 2 cycles). Only three patients demonstrated stabilization of the disease; therefore, the study had to be terminated prematurely due to futility. Grade 3 toxicities, apart from fatigue, were infrequent. Other frequently reported side effects were skin discoloration, neutropenia, and thrombocytopenia. Ten various bleeding complications were reported in seven patients. Mean maximum concentrations (C(max)) were reached during the first day of treatment for sunitinib at 38.98 (+ or - 22.66) ng/ml and for SU012662 at 11.12 (+ or - 24.57) ng/ml. Our results showed that SU012662 has a longer half-life and a larger volume of distribution than the parent drug sunitinib. None of the biological markers tested was of any prognostic value. CONCLUSIONS: According to our findings, sunitinib monotherapy was not proven active in RM-SCCHN, and no further development of the drug in this indication is warranted.

A dose escalation and pharmacokinetic study of the biweekly administration of paclitaxel, gemcitabine and oxaliplatin in patients with advanced solid tumors.

PURPOSE: To determine the dose-limiting toxicities (DLTs) and the maximum tolerated doses (MTDs) of the paclitaxel, gemcitabine, oxaliplatin combination administered biweekly in patients with advanced solid tumors. PATIENTS AND METHODS: Patients received escalated doses of paclitaxel (starting dose: 100 mg/m(2)), gemcitabine (starting dose: 800 mg/m(2)) and oxaliplatin (starting dose: 50 mg/m(2)) on days 1 and 15 in cycles of every 4 weeks. DLTs were evaluated during the first cycle. RESULTS: Twenty-seven patients (median age 65 years) with performance status 0-1 were treated on six dose escalation levels. Eleven patients (40.7%) were chemotherapy naïve, six (22.2%) had received 1 prior chemotherapy regimen and ten (37.1%) 2 or more. The DLT level was reached at the doses of paclitaxel 110 mg/m(2), gemcitabine 1,150 mg/m(2) and LOHP 70 mg/m(2). The dose-limiting events were grade 4 neutropenia and grade 3 febrile neutropenia. Neutropenia was the most common adverse event. A median of 3 cycles per patient was administered. One complete and five partial responses were observed in patients with ovarian carcinoma, NSCLC, urothelial cancer, mesothelioma and cancer of unknown primary. No pharmacokinetic drug interactions were detected. CONCLUSIONS: The recommended doses for future phase II studies of this combination are paclitaxel 110 mg/m(2), gemcitabine 1,000 mg/m(2) and oxaliplatin 70 mg/m(2) every 2 weeks. The regimen is generally well tolerated and merits further evaluation.

Phase 1 trial of lipoplatin and gemcitabine as a second-line chemotherapy in patients with nonsmall cell lung carcinoma.

BACKGROUND: : Lipoplatin is a new liposomal cisplatin that already has been tested in solid tumors, with encouraging results. The purpose of the current study was to determine the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT) of a 21-day regimen of lipoplatin plus a fixed dose of gemcitabine in patients with refractory or resistant nonsmall cell lung carcinoma (NSCLC) with an Eastern Cooperative Oncology Group (ECOG) performance status of

A dose escalation and pharmacokinetic study of biweekly pegylated liposomal doxorubicin, paclitaxel and oxaliplatin in patients with advanced solid tumors.

PURPOSE: To evaluate the maximum tolerated doses (MTD) and the dose-limiting toxicities (DLT) of the combination of pegylated liposomal doxorubicin (PEG-LD), paclitaxel and oxaliplatin (L-OHP) administered every 2 weeks in patients with advanced solid tumors. METHODS: Thirty-nine pretreated patients with advanced solid tumors received escalated doses of PEG-LD (10-16 mg/m(2)), paclitaxel (100-120 mg/m(2)) and L-OHP (50-70 mg/m(2)) every 2 weeks. As one cycle of treatment was considered the administration of both drugs on days 1 and 15 of a 4-week cycle. RESULTS: The MTDs were PEG-LD 14 mg/m(2), paclitaxel 120 mg/m(2) and L-OHP 70 mg/m(2). Neutropenia was the DLT in all but one case with only one episode of febrile neutropenia and no toxic deaths. Four (4%) and 13 (12%) cycles were complicated by grades 4 and 3 neutropenia, respectively. Grades 2-3 fatigue and neurotoxicity occurred in 13 and 12% of cycles, respectively. Responses were observed in patients with breast, endometrial and ovarian carcinomas. CONCLUSIONS: This is a quite well-tolerated regimen which merits further evaluation in phase II studies.

Coadministration of oxaliplatin does not influence the pharmacokinetics of gemcitabine.

We investigated the possible pharmacokinetic interactions of gemcitabine and oxaliplatin in patients with advanced solid tumors. Ten patients with advanced stage solid tumors were treated with gemcitabine (1500 mg/m) as a 30-min intravenous infusion on days 1 and 8, followed by oxaliplatin (130 mg/m) as a 4-h intravenous infusion, on day 8 every 21 days. Pharmacokinetic data for 24 h after dosing were obtained for both day 1 (gemcitabine without oxaliplatin coadministration) and day 8 (gemcitabine with oxaliplatin) during the first cycle of treatment. Gemcitabine levels in plasma were quantified using a reverse-phase high-performance liquid chromatography assay with ultraviolet detection, and total and ultrafiltrated platinum levels by flameless atomic absorption spectrophotometry with deuterium correction. All pharmacokinetic parameters of gemcitabine seemed to be unchanged when coadministered with oxaliplatin (day 8) compared with pharmacokinetic data of gemcitabine given as a single agent (day 1). The mean (maximum) concentration of gemcitabine on days 1 and 8 was 13.57 (+/-7.42) and 10.23 (+/-5.21) mg/l, respectively (P=0.28), and the mean half-life was 0.32 and 0.44 h, respectively (P=0.40). Similarly, the P-values for AUC0-24 and the observed clearance were 0.61 and 0.30, respectively. Plasma total and free platinum levels were in agreement with other published data. Gemcitabine disposition appeared to be unaffected by oxaliplatin coadministration because no significant changes in pharmacokinetics between day 1 (gemcitabine without oxaliplatin coadministration) and day 8 (gemcitabine with oxaliplatin) were observed.