Abstract

Background: 4-HPR is a cytotoxic retinoid with broad anti-cancer activity in preclinical studies, but oral capsule 4-HPR had limited bioavailability and activity in clinical trials. An intravenous intralipid emulsion formulation of 4-HPR (ILE 4-HPR) was developed to increase 4-HPR systemic exposure.

Methods: ILE 4-HPR was administered as a continuous intravenous infusion for 5 of every 21 days and systemic toxicities, clinical response, and pharmacokinetics (PK) assessed. Simon design dose escalation proceeded with a 100% increase per dose level until moderate toxicity in 2 patients or 1 dose-limiting toxicity (DLT). Ten dose levels were planned starting at 80 mg/m2/day, increasing until 1810 mg/m2. Plasma 4-HPR levels were measured by high performance liquid chromatography.

Results: To date, 17 patients have been enrolled. At dose level 10 (1810 mg/m2/day), 2 patients experienced a DLT of grade 4 hypertriglyceridemia, 1 patient with transient grade 2 pancreatitis. A de-escalation to dose level 9 (1280 mg/m2/day) enrolled 5 patients: 1 had asymptomatic Grade 4 hypertriglyceridemia, 1 patient experienced pleural effusions that resolved after pleurocentesis. A de-escalation to dose level 8 (905 mg/m2/day) enrolled 5 pts: two patients experienced asymptomatic Grade 4 hypertriglyceridemias that resolved after stopping the infusion; enrollment is ongoing. PK showed a linear relationship of dose to plasma level, with steady-state 4-HPR levels of 25 μM (640 mg/m2, level 7); 54 μM (1280 mg/m2, level 9) and 62 μM (1810 mg/m2, level 10). Responses to date include a transient response in a non-Hodgkins lymphoma at 320 mg/m2, in two angioimmunoblastic T-cell lymphomas, an 8-month partial response at 1810 mg/m2/day and a 4+ month unconfirmed complete response at 905 mg/m2/day, and in a histone deacetylase inhibitor-refractory cutaneous T cell lymphoma, a 10+ month molecular complete response at 1280 mg/m2. All patients were heavily pretreated. The DLT of hypertriglyceridemia is likely related to the intralipid formulation vehicle accounting for 5/6 DLTs observed, all reversible.

Conclusions: ILE 4-HPR can be safely administered and obtained 4-HPR plasma levels 6 to 7 times higher than previously obtained by oral capsule 4-HPR. Durable clinical activity was observed in T cell lymphomas in the dose range 905–1810 mg/m2.

Supported in part by NCI U01CA62505 and the NCI RAID program.

Author notes

Disclosure:Financial Information: Dr. Reynolds and Dr. Maurer are inventors on a patent covering the 4-HPR ILE formulation that is owned by Childrens Hosp Los Angeles.