A phase I clinical trial of FOLFIRI in combination with the pancyclin–dependentkinase (CDK) inhibitor flavopiridol

Abstract

e14511 Background: Preclinical data indicate that sequential treatment with flavopiridol (F) increases irinotecan- and 5-FU-induced apoptosis. Clinically, F showed promising activity when combined with irinotecan (Shah et al CCR 2005). Methods: We conducted a phase I trial of FOLFIRI + F every 2 weeks in patients (pts) with advanced solid tumors. Based on sequence- dependent inhibition, F was given 3 h after irinotecan but before 5-FU. Two maximum tolerated doses (MTD) were determined: MTD1 (F over 1 h) and MTD2 (F 30-min bolus + 4 h infusion). F pharmacokinetics (PK) were determined. Results: Of 74 pts treated, 63 were evaluable for toxicity and 56 for response. Pt characteristics: median age 60 (range 19–83), KPS 90 (70–90), prior regimens 3 (1–10). 39 pts received prior irinotecan. Tumor types: colorectal, gastric, HCC, GE junction, small bowel, pancreas, bile duct, breast, bladder, ovarian, sarcoma, melanoma, anal, urethral, thymic, head & neck, unknown primary. MTD1: F 80mg/ m2 with irinotecan 180mg/m2, LV 400mg/m2, 5FU: 400mg/m2 bolus + 2400mg/m2 over 48 h. Dose-limiting toxicities (DLT) were diarrhea, fatigue, neutropenia, neuropathy. MTD2: F 35mg/m2 bolus + 35mg/m2 over 4 h with the same FOLFIRI dose. DLTs were diarrhea, neutropenia, and fatigue. Clinical activity included 2 partial responses (small bowel cancer, 10.3 m; bladder cancer, 10 m) and 1 complete response (mucosal melanoma 10.3 m). 22 pts had stable disease (median 5.9 m; range 1.5–25.7 m). Clinical benefit rate (CR + PR + SD for > 3 m) was 39% (22/56). Of 25 pts with colorectal cancer, 11 had as best response SD for > 3m (median 6 m, range 4.2–15.4 m), despite failing ≥ 1 irinotecan-containing regimen. 6 of those had significant decreases (36–78%) in CEA. F PK showed interpatient variability with no significant interaction between FOLFIRI dose and F Cmax. F Cmax increased with increasing F dose. At MTDs, there was higher Cmax in pts who experienced DLT (3.48μM) vs those who did not (2.21μM). Conclusions: F can be safely given as a bolus (80mg/m2) or split dose (35mg/m2 bolus + 35mg/ m2 over 4 h) in combination with irinotecan 180mg/m2, LV 400mg/m2, 5FU: 400mg/m2 bolus + 2400mg/m2 over 48 h. Promising clinical activity is seen in mucosal melanoma and irinotecan-refractory colon cancer. (Supported by NCI R01CA67819) [Table: see text]