Phase I trial of fenretinide (4-HPR) intravenous emulsion in hematologic malignancies: A California Cancer Consortium study (PhI-42).

Abstract

8073 Background: Fenretinide (4-HPR) is a cytotoxic retinoid with broad anticancer activity in preclinical studies. Due to limited bioavailability of a capsule formulation an intravenous intralipid-like emulsion formulation (4-HPR ILE) was developed to increase systemic exposures. Methods: 4-HPR was administered as a continuous intravenous infusion for 120 hrs every 21 days. Systemic toxicities, responses, and pharmacokinetics were assessed. Accelerated Simon design proceeded until moderate or dose-limiting toxicities (DLT) were scored on Course 1. Doses were 80 mg/m2/day to 1810 mg/m2/day. Patients with asymptomatic hypertriglyceridemia were scored separately. All patients were heavily pretreated. Results: Toxicity-evaluable patients = 25. At 1810 mg/m2/day, two patients experienced DLT hypertriglyceridemia, one with transient Grade 2 pancreatitis; at 1280 mg/m2/day (8 pts), two had asymptomatic Grade 4 hypertriglyceridemia, one experienced DLT pleural effusions; at 905 mg/m2/day (6 pts) 2 experienced asymptomatic Grade 4 hypertriglyceridemia; All 5 pts at 640 mg/m2/day tolerated treatment. Pharmacokinetics showed a dose-to-plasma level relationship with mean steady-state 4-HPR levels of ~mid-20’s μM (640 mg/m2); ~mid-30’s μM (905 mg/m2/day); and ~mid-50’s μM (1280 mg/m2). Responses to date include a 64% CR+PR+SD response rate (36% CR+PR response rate) in 11 relapsed T-cell lymphomas which included histone deacetylase inhibitor-refractory patients, and a PRu response in a NHL B-cell lymphoma. Reversible hypertriglyceridemia related to the intralipid vehicle accounted for 6/7 DLTs. Conclusions: MTD = 1280 mg/m2/day x 5 days, every three weeks. 4-HPR ILE was safely administered and obtained 4-HPR plasma levels 6 -7 times higher than previously obtained using oral capsules. Durable complete responses were observed in T-cell lymphomas from 905 – 1810 mg/m2/day. An expanded cohort is accruing to a dosing schedule modified to decrease asymptomatic hypertriglyceridemia of 600 mg/m2 on Day 1 (to allow for induction of serum lipases) followed by 1200 mg/m2 Days 2-5. Supported by NCI U01 CA062505 and CPRIT RP10072.