Phase I trial of fenretinide lym-x-sorb oral powder in adults with solid tumors and lymphomas

Abstract

Background: The synthetic retinoid fenretinide (N-(4-hydroxyphenyl)retinamide, 4-HPR) has shown promising anticancer activity in preclinical studies, but its limited oral bioavailability has hindered clinical assessment. A novel lipid matrix, Lym-X-Sorb (LXS), was evaluated to improve fenretinide bioavailability and attain higher plasma concentrations.

Patients and methods: Adults with refractory malignancies were administered fenretinide/LXS oral powder in 2 divided doses over 24 h for 7 consecutive days every 21 days in a standard phase I dose-escalation study with pharmacokinetic analysis.

Results: The principal toxicities observed were diarrhea, reversible night blindness, and allergic reaction. The maximum tolerated dose regimens were 1,000 mg/m(2)/day divided into 2 daily doses for 7 days, every 21 days, and 800 mg/m(2)/day divided into 3 daily doses for 7 consecutive days, every 21 days.

Conclusion: Better fenretinide formulations are needed to improve adult patient acceptability and compliance and to achieve the consistent systemic exposures associated with activity in preclinical models.

Figures

Figure 1.

4-HPR and 4-MPR plasma levels in cycle 1 for: A) patients 1–3 (Dose Level 1, 1,000 mg/m2/day, divided into two doses); and B) patients 4–6 (Dose Level 2, 1,300 mg/m2/day, divided into two doses). Sampling times are in reference to the morning dose.

Figure 2.

4-HPR plasma levels in cycle 1 for patients administered 1,000 mg/m2/day divided in two doses (BID, patients 7–9) or three doses (TID, patients10–13). Sampling times are in reference to the morning dose.

Figure 3.

4-HPR and 4-MPR plasma levels in cycle 1 for patients 14–20 (Dose Level —1, 800 mg/m2/day, divided in three doses). Sampling times are in reference to the morning dose.