A phase I study of FOLFOX administered with flavopiridol (F) in patients with refractory solid tumors

Abstract

3569 Background: F, a cyclin-dependent kinase inhibitor, shows promising solid tumor activity when combined with CPT-11 (Shah et al, CCR 2005) and docetaxel (Fornier et al, CCR 2007). Preclinical data indicate that F enhances oxaliplatin (OX)-and 5FU-induced apoptosis. Methods: We conducted a phase I trial of FOLFOX + F every two weeks in patients with refractory solid tumors. F was administered with OX but before 5FU based on sequence dependent growth inhibition. Dose escalation of 5FU and OX was initially performed with F fixed at 40 mg/m2. 5FU was then de-escalated to allow dose escalation of F. F pharmacokinetics were determined. Results: 40 patients were enrolled. Patient characteristics: median age 54 (range 20–77), KPS 90 (80–90), prior regimens 3 (0–10). 11 pts received prior OX. Tumor types included colon, pancreas, gastric, germ cell, ampullary, rectal, breast, anal, head & neck, and renal. With F 40 mg/m2 over 1 hr and dose escalation of 5FU and OX, the maximum tolerated dose (MTD) was F 40mg/m2 with OX 85mg/m2, LV 400mg/m2, 5FU: 400mg/m2 bolus and 2400mg/m2 over 48h. Dose-limiting toxicities (DLT) were nausea, vomiting, hyponatremia and neutropenia. With 5FU de-escalation and F dose escalation, the MTD was F 80mg/m2 with OX 85mg/m2, LV 400mg/m2, 5FU: 400mg/m2 bolus and 1,800mg/m2 over 48h. DLTs were diarrhea, nausea and vomiting. Clinical activity was noted in patients with platinum-refractory metastatic germ cell tumors. This included 1 PR (4.7 months) and 1 MR (9.1m). A third patient who had prior OX had a decline in AFP but discontinued therapy due to OX hypersensitivity. PRs were also observed in pancreas (7.9m), gastric (6.4m) and ampullary carcinoma (7.7m). F PK was noted to have significant interpatient variability. However, F Cmax increased with dose (1.95μM ± 0.56 at 70–80mg/m2 vs 1.23μM ± 0.56 at 40mg/m2, p=0.002). At the MTD, DLT was associated with higher F Cmax (2.26μM ± 0.03 vs 1.45μM ± 0.44 for other patients in the cohort, p=0.07). Conclusions: The recommended phase II dose (one level below MTD) is F 70mg/m2 with OX 85mg/m2, LV 400mg/m2, 5FU 400mg/m2 bolus and 1,800mg/m2 over 48h. This regimen shows promising clinical activity especially in platinum- refractory germ cell tumors. (Supported by NCI R01CA67819) No significant financial relationships to disclose.