Phase I and pharmacokinetic study of recombinant human granulocyte-macrophage colony-stimulating factor given in combination with fluorouracil plus calcium leucovorin in metastatic gastrointestinal adenocarcinoma

Purpose: To determine the toxicities and potential for dose escalation of intravenous (IV) bolus fluorouracil (5-FU) given with 500 mg/m²/d leucovorin (LCV) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Patients and Methods: Thirty-seven patients received escalating doses of 5-FU/LCV on days 1 to 5 with subcutaneous GM-CSF either 5 or 10 μg/kg/d starting on day 6 or 3 μg/kg/d starting on day 1. 5-FU was escalated from 370 mg/m²/d by 15% increments between patient cohorts and within patients according to tolerance. Results: With GM-CSF starting on day 6, dose-limiting toxicity occurred during cycle no. 1 in all three patients entered at 5-FU 490 mg/m²/d. However, individual patients tolerated 5-FU doses up to 644 mg/m²/d. When all cycles were analyzed, grade 3 to 4 mucositis and grade 4 granulocytopenia complicated ≤ 15% and ≤ 6% of cycles with 5-FU doses s 560 mg/m²/d (115 cycles). With GM-CSF starting on day 1, dose-limiting granulocytopenia occurred during cycle no. 1 in five of 10 patients entered at 5-FU 490 mg/m²/d. Although the granulocyte nadirs were significantly lower at each 5-FU dose level with the concurrent GM-CSF schedule (eg, 490 mg/m²/d: median, 879/μL v3,286/μL; two-tailed P[P₂] < .001), dose-limiting granulocytopenia complicated s 16% of cycles with 5-FU =s 560 mg/m²/d (99 cycles); a grade 3 mucositis occurred in ≤ 20% of cycles. Grade 3 to 4 diarrhea was unusual with either GM-CSF schedule. Most patients treated with GM-CSF a 5 μg/kg/d required dose reductions for constitutional toxicity; 3.0 to 3.8 μg/kg/d was better tolerated. Venous thrombosis occurred in 17% of patients (concurrent v sequential GM-CSF, 29% v 5%; P₂ = .08). The median delivered 5-FU dose-intensity for GM-CSF starting either on day 6 or on day 1 was 615 and 647 mg/m²/wk (P₂ = .41), respectively. Pharmacologic exposure to 5-FU increased with higher doses of 5-FU, and concurrent GM-CSF administration did not affect 5-FU clearance. Conclusion: A starting dose of 425 mg/m²/d of 5-FU with LCV on days 1 to 5 could be safely combined with GM-CSF starting either on day 1 or day 6, with further 5-FU dose escalation according to individual tolerance.