A phase 1 study of oral navelbine in patients with advanced solid tumors

Abstract

13095 Background: Anti-tubulin agents have potent anti-angiogenic effects (Blood 94: 4143–4155, 1999). Recent evidence suggests that “metronomic” drug schedules employing doses sufficient to inhibit angiogenesis yet low enough to allow more frequent administration may enhance the effectiveness of antiangiogenic therapy (J Clin Invest 105: 1045–7, 2000). We therefore performed a phase I trial to determine feasibility and safety of administering and oral navelbine (ON) preparation that is 40% bioavailable thrice weekly (TIW). Methods: ON was given TIW (eg, Monday-Wednesday-Friday) using the dosing escalation schema outlined below with 3–6 patients/cohort. Dose limiting toxicity (DLT) during cycle 1 was defined as a) neutrophil nadir < 500/uL, b) platelet nadir < 50,000/uL, c) febrile neutropenia, or d) grade 3–4 non-hematologic toxicity. One patient was not evaluable (NE) due to urosepsis unrelated to treatment. No patient had a DLT. The most common toxicities were grade 2 nausea (n = 1), dyspepsia (n = 1) and abdominal cramping (n = 2), and grade 3 neutropenia (N = 1). One patient with renal cell carcinoma had stable disease for 19 months; a second with prostate cancer had a greater than 50% PSA response that lasted 18 weeks. Results and Conclusions: The recommended phase II dose of ON is at least 50 mg TIW. Further dose escalation was not possible due to cessation of the drug supply by the manufacturer. Correlative studies of surrogate angiogenesis markers (urine VEGF and serum VCAM-1 and Tie2in serum by ELISA) are currently being analyzed and will be presented. [Table: see text] No significant financial relationships to disclose.