Phase I study of fenretinide (4-HPR) oral powder in patients with recurrent or resistant neuroblastoma: New Approaches to Neuroblastoma Therapy (NANT) Consortium trial

Abstract

10009 Background: Fenretinide (4-HPR), a cytotoxic retinoid, achieved limited and variable plasma levels when tested in a corn oil-based capsule. 4HPR/Lym-X-Sorb (LXS) oral powder is a new formulation intended to increase bioavailability, especially in children. Methods: This trial sought to define the toxicities, dose limiting toxicities (DLTs), maximum tolerated dose (MTD), and pharmacokinetics of 4-HPR/LXS oral powder when given mixed in Slim-Fast nutritional shakes, twice a day for 7 days, every 21 days. Eligible patients had high-risk neuroblastoma with recurrent/progressive disease, or disease refractory or persistent after frontline therapy. Dose escalation was in 30% increments using the traditional 3 + 3 design. Plasma levels were measured by HPLC. Results: Thirty-two patients accrued to 8 Dose Levels (DL) (352 –2210 mg/m2/day); 30 patients were evaluable. No MTD was identified. There was a DLT elevation of alkaline phosphatase on DL1. No other DLT's were observed. Other toxicities included dry skin, elevated triglycerides, reversible nyctalopia, and transient transaminase elevation. Course 1 day 7 peak 4HPR plasma levels (Dose (mg/m2/day) - mean, (range)) were: 352 –6 μM (3.8–9.6); 458–11.5 μM (9.7–14.9); 595–17.6 μM (6–24.3); 774–15 μM (9.1–25.3); 1006–6.7 μM (5.2–9.2); 1308–13.9 μM (2.9–23.8); 1700–19.7 μM (17.3–24.3); and 2210–10.8 μM (4–16.5). Course 2 day 7 peak plasma levels trended higher than course 1 at DL5–8. Three patients with isolated bone marrow disease and one with MIBG avid bone lesions, had complete responses (DL4, DL4, DL7, DL8) receiving 10, 17, 18 and 10 courses of therapy, respectively. Six patients had stable disease for 4–27 courses (median 5.5) (DL3, DL4, DL4, DL5, DL6, DL8). Twenty patients had progressive disease. Central review of responses is pending. Conclusions: 4-HPR/LXS oral powder was well tolerated, obtained 2 - 5 fold higher 4HPR plasma levels than fenretinide capsules on the same dose and schedule (P < 0.01), and showed anti-tumor activity (complete responses in 4/15 patients at DL4–8). Based on pharmacokinetic data, a recommended Phase II dose and schedule is 1700 mg/m2/day × 7days every 3 weeks. No significant financial relationships to disclose.