Phase I trial of fenretinide delivered orally in a novel organized lipid complex in patients with relapsed/refractory neuroblastoma: A report from the new approaches to neuroblastoma therapy (NANT) consortium

Abstract

Background A phase I study was conducted to determine the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetics of fenretinide (4-HPR) delivered in an oral powderized lipid complex (LXS) in patients with relapsed/refractory neuroblastoma. Procedure 4-HPR/LXS powder (352 - 2210 mg/m2/day) was administered on Days 0 – 6, in 21-day courses, by standard 3+3 design. Results Thirty-two patients (median age = 8 years, range 3 – 27 years) enrolled with thirty evaluable for dose escalation. Prior therapies included stem cell transplantation/support (n = 26), 13-cis-retinoic acid (n = 22), 125/131I-MIBG (n = 13), and anti-GD2 antibody (n = 6). 170+ courses were delivered. Course 1 DLTs were a Grade 3 (n = 1) alkaline phosphatase at 352 mg/m2/day. Other major toxicities were Grade 4 (n = 1) alkaline phosphatases on Courses 5 and 6 at 774 mg/m2/day, and Grade 3 (n = 1) ALT/AST elevation on Course 2 at 1700 mg/m2/day. Of twenty-nine response-evaluable patients, six had stable disease (SD)(4 – 26 courses); four with marrow- or bone disease-only had complete responses (CR)(10 - 46 courses). 4-HPR plasma levels were several fold higher (P<0.05) than previously reported using capsular fenretinide. The Day 6 mean peak 4-HPR plasma level at 1700 mg/m2/day was 21 μM. An MTD was not reached. Conclusions 4-HPR/LXS oral powder obtained higher plasma levels, with minimal toxicity and evidence of anti-tumor activity, than a previous capsule formulation. A recommended phase II schedule of 4-HPR/LXS powder is 1500 mg/m2/day, TID, on Days 0 – 6, of a 21-day course.

Preclinical Evaluation of a Novel RXR Agonist for the Treatment of Neuroblastoma

“…Because of the hypercalcemia, hypertriglyceridemia, skin and mucous membrane issues, the dosage of retinoids is sometimes limited [27]. In addition, other formulations such as fenretinide have also demonstrated difficulties in attaining adequate plasma levels and were limited due to formulations that were difficult to administer to young children [28]. The absence of known toxicities with UAB30 [7] prompted study of this agent for neuroblastoma.…”

The mechanisms of Fenretinide-mediated anti-cancer activity and prevention of obesity and type-2 diabetes

“…However, high concentrations of FEN are required to induce apoptosis [22,23]. With this in mind, high doses of FEN and formulation within novel lipid matrices to improve FEN bioavailability and to attain higher plasma concentrations have been tested in adults and in children with neuroblastoma [24,25]. Since higher plasma levels of FEN were achieved using this strategy, with minimal toxicity, a phase II trial would now be recommended to further evaluate its anti-cancer activity.…”

Retinoids and rexinoids in cancer prevention: from laboratory to clinic

“…Recently a randomized phase III study established that intermittent dosing of 13- cis -RA significantly improved survival (Table 2) [71]. A phase I trial of fenretinide delivered in an oral powderized lipid complex (LXS) was reported to have anti-tumor activity in patients with refractory neuroblastoma, reaching higher plasma levels yet reduced toxicity as compared to conventional pills [72]. …”