A phase I study of the safety and pharmacokinetics of the combination of pertuzumab (rhuMab 2C4) and capecitabine in patients with advanced solid tumors.

PURPOSE: To study the safety, pharmacokinetics, and recommended dose of the combination of pertuzumab, a humanized monoclonal antibody HER2-dimerization inhibitor, and capecitabine in patients with advanced malignancies. EXPERIMENTAL DESIGN: Patients that had progressed to standard treatment were treated with pertuzumab at a fixed dose of 1,050 mg given i.v. on day 1 plus capecitabine at doses of 825-1,000-1,250 mg/m(2), twice daily orally on days 1 to 14 of each 21-day treatment cycle, in three sequential cohorts. The pharmacokinetics of capecitabine and pertuzumab were studied. Patients received a single dose of capecitabine in a pretreatment phase (day -7) followed by serum sampling for capecitabine and its metabolites. RESULTS: Nineteen patients were accrued and 18 were assessable. The combination of capecitabine and pertuzumab was well tolerated at all dose levels and no dose-limiting toxicities were observed. The most frequent adverse event was asthenia, which was grade 3 in two patients. One asymptomatic pulmonary embolism occurred. No other grade 3 or 4 adverse events or cardiac or left ventricular ejection fraction events were reported. There was no apparent change in the pharmacokinetics of capecitabine and its metabolites when combined with pertuzumab. The pharmacokinetics of pertuzumab was apparently not modified when administered with capecitabine. Disease stabilization was observed in 11 patients. CONCLUSIONS: Pertuzumab and capecitabine were well tolerated at all dose levels. Escalation beyond the highest dose level tested was not planned, as this included the recommended doses of monotherapy for both drugs. In conclusion, this combination is ready for phase II testing.

A phase II study of weekly cisplatin and gemcitabine in patients with advanced pancreatic cancer: is this a strategy still worth pursuing?

OBJECTIVES: A phase 2 study to assess the activity of the cisplatin-gemcitabine combination in patients with advanced pancreatic cancer. METHODS: Chemotherapy-naive patients with locally advanced/metastatic/relapsed adenocarcinoma of the pancreas received cisplatin 25 mg/m2 followed by gemcitabine 1000 mg/m2 intravenously on days 1, 8, and 15 of a 28-day cycle. Radiologic response was assessed after 3 cycles, and treatment continued for up to 6 cycles in the absence of disease progression. RESULTS: Thirty-six patients were enrolled, 35 patients were evaluable for toxicity. Hematological toxicity was significant but mostly asymptomatic with grade 3 to 4 (% of patients): leucopenia, 40%; neutropenia, 60%; thrombocytopenia, 60%. There were only 3 episodes of neutropenic sepsis and 2 significant bleeding episodes. Grade 3 to 4 nonhematological toxicities were uncommon but included constipation, infection without neutropenia, lethargy, and thromboembolic events. Of 32 evaluable patients, 62.8% achieved stable disease (SD) or better (SD, 53.4%; partial response, 9.4%). Twenty-nine patients were evaluable for clinical benefit response: 11 (31%) were clinical benefit responders, whereas 13 (36%) remained stable. With complete follow-up, the median time to disease progression was 5.75 months; median survival was 9.5 months, 6-month survival was 72.2%, and 1-year survival was 41.7%. CONCLUSIONS: The combination of gemcitabine and cisplatin is clearly an active regimen and may improve survival based on our 1-year and median survival findings and results from other institutions. However, only an adequately powered randomized controlled trial will assess any real survival benefit over single agent gemcitabine.