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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: 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.4-HPR/LXS powder (352-2,210?mg/m(2) /day) was administered on Days 0-6, in 21-day courses, by standard 3?+?3 design.Thirty-two patients (median age?=?8 years, range 3-27 years) enrolled with 30 evaluable for dose escalation. Prior therapies included stem cell transplantation/support (n?=?26), 13-cis-retinoic acid (n?=?22), (125/131) I-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/m(2) /day. Other major toxicities were Grade 4 (n?=?1) alkaline phosphatases on Courses 5 and 6 at 774?mg/m(2) /day, and Grade 3 (n?=?1) ALT/AST elevation on Course 2 at 1,700?mg/m(2) /day. Of 29 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 folds higher (P?

SUBMITTER: Maurer BJ

PROVIDER: S-EPMC4066886 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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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.

Maurer Barry J BJ Kang Min H MH Villablanca Judith G JG Janeba Jitka J Groshen Susan S Matthay Katherine K KK Sondel Paul M PM Maris John M JM Jackson Hollie A HA Goodarzian Fariba F Shimada Hiroyuki H Czarnecki Scarlett S Hasenauer Beth B Reynolds C Patrick CP Marachelian Araz A

Pediatric blood & cancer 20130629 11

<h4>Background</h4>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.<h4>Procedure</h4>4-HPR/LXS powder (352-2,210 mg/m(2) /day) was administered on Days 0-6, in 21-day courses, by standard 3 + 3 design.<h4>Results</h4>Thirty-two patients (median age = 8 years, range 3-27 years) enrolled with 30 ev ...[more]

PMID: 23813912

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Project description:PURPOSE:The New Approaches to Neuroblastoma Therapy Response Criteria (NANTRC) were developed to optimize response assessment in patients with recurrent/refractory neuroblastoma. Response predictors and associations of the NANTRC version 1.0 (NANTRCv1.0) and prognostic factors with outcome were analyzed. METHODS:A retrospective analysis was performed of patients with recurrent/refractory neuroblastoma enrolled from 2000 to 2009 on 13 NANT Phase 1/2 trials. NANTRC overall response integrated CT/MRI (Response Evaluation Criteria in Solid Tumors [RECIST]), metaiodobenzylguanidine (MIBG; Curie scoring), and percent bone marrow (BM) tumor (morphology). RESULTS:Fourteen (6.9%) complete response (CR) and 14 (6.9%) partial response (PR) occurred among 203 patients evaluable for response. Five-year progression-free survival (PFS) was 16 ± 3%; overall survival (OS) was 27 ± 3%. Disease sites at enrollment included MIBG-avid lesions (100% MIBG trials; 84% non-MIBG trials), measurable CT/MRI lesions (48%), and BM (49%). By multivariable analysis, Curie score of 0 (P < 0.001), lower Curie score (P = 0.003), no measurable CT/MRI lesions (P = 0.044), and treatment on peripheral blood stem cell (PBSC) supported trials (P = 0.005) were associated with achieving CR/PR. Overall response of stable disease (SD) or better was associated with better OS (P < 0.001). In multivariable analysis, MYCN amplification (P = 0.037) was associated with worse PFS; measurable CT/MRI lesions (P = 0.041) were associated with worse OS; prior progressive disease (PD; P < 0.001/P < 0.001), Curie score ≥ 1 (P < 0.001; P = 0.001), higher Curie score (P = 0.048/0.037), and treatment on non-PBSC trials (P = < 0.001/0.003) were associated with worse PFS and OS. CONCLUSIONS:NANTRCv1.0 response of at least SD is associated with better OS in patients with recurrent/refractory neuroblastoma. Patient and tumor characteristics may predict response and outcome. Identifying these variables can optimize Phase 1/2 trial design to select novel agents for further testing.

Dataset Information

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.

Publications

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.

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