Phase I/II trial of dexverapamil, epirubicin and granulocyte/macrophage-colony-stimulating factor in patients with advanced pancreatic adenocarcinoma.

A group of 28 previously untreated patients with locally advanced or metastatic adenocarcinoma of the pancreas were entered in this phase I/II study. Treatment consisted of oral dexverapamil 1000 - 1200 mg/day for 3 days, epirubicin given as an intravenous bolus injection on day 2 with a starting dose of 90 mg/m 2 , and 400 μg granulocyte/macrophage-colony-stimulating factor (GM-CSF) administered subcutaneously from day 5 through 14. Epirubicin dose escalation levels were 90, 105, 120 and 135 mg/m 2 . Consecutive cohorts of 4 - 8 patients were planned at each dose level. Treatment cycles were repeated every 3 weeks. Haematological toxicity, specifically granulocytopenia constituted the dose-limiting toxicity with a maximum tolerated dose of 120 mg/m 2 for epirubicin. Despite routine supportive therapy with GM-CSF, 4, 2, and 5 patients experienced grade 4 granulocytopenia during their first two treatment courses at levels of 105, 120, and 135 mg/m 2 respectively. Non-haematological toxicity was uncommon, generally modest, and did not demonstrate a clear relationship with the anthracycline dose. Dexverapamil-related cardiovascular symptoms occurred frequently, but they never resulted in serious toxicity requiring active medical intervention or permanent discontinuation of therapy. Of the 28 patients, 9 achieved partial reponses to this therapy. The recommended dose of epirubicin for this regimen with dexverapamil and GM-CSF is 120 mg/m 2 every 3 weeks. Therapeutic results suggest this regimen to be an effective and tolerable treatment strategy in pancreatic cancer, which should be evaluated further.