The overall goals of this project are to test a high-dose parenteral infusion of hydroxyurea (HU) incorporated into a weekly regimen with high-dose fluorouracil (5FU), interferon-alpha (IFN) and filgrastim (G) in patients with refractory GI malignancies, and to determine the effects of this biochemically modulated combination of nucleotide pools in vivo. In vitro the combination of 5FU + HU + IFN-alpha was synergistic against 2 human colon cancer cell lines, at clinically achievable concentrations. Detailed biochemical studies of the effects of these agents on mRNA, protein levels and activity for the target enzymes, ribonucleotide reductase (RR) and thymidylate synthase (TS), were performed in vitro which demonstrated a positive interaction between 5FU + HU + IFN. Furthermore, a highly sensitive DNA polymerase assay was employed to measure the effects on deoxyribonucleotide triphosphates (dNTPs) both in vitro and in vivo in patient peripheral blood mononuclear cells (PBMC), and have demonstrated inhibition of purine and pyrimidine pools. Based on this promising in vitro data, the applicant has recently completed a Phase I trial of high-dose 5FU, HU and IFN plus or minus filgrastim (FHI-G) which demonstrated the tolerability of this regimen.
The Specific Aims of this application are to conduct a Phase II trial of FHI-G in patients with malignancies of the pancreas, hepatobiliary system and stomach and to measure the effects of this treatment on pools of dNTPs from PBMC. The applicant's Phase I trial employed 5FU, 2.6 g/m2 as a 24h infusion weekly +HU, 4.3 g/m2 as a 48 h weekly infusion + IFN-alpha, 9 MU subcutaneously three times per week. This regimen was tolerable with administration of filgrastim. The major toxicities were hematologic, with acceptable levels of fatigue, diarrhea and stomatitis. Responses were observed in biliary tract (1/2), gastric (5/8) and pancreatic (1/6) carcinoma. The applicant intends to extend his previous observations by conducting a Phase I trial of FHI-G using the 48-hr HU infusion + filgrastim and delineate the effects of combined inhibition of RR and TS on pools of dNTPs to attempt to predict who will respond to such treatment.
| Wadler, S; Damle, S; Haynes, H et al. (1999) Phase II/pharmacodynamic trial of dose-intensive, weekly parenteral hydroxyurea and fluorouracil administered with interferon alfa-2a in patients with refractory malignancies of the gastrointestinal tract. J Clin Oncol 17:1771-8 |
