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Clinical Trial
. 2011 Nov 1;17(21):6858-66.
doi: 10.1158/1078-0432.CCR-11-0995. Epub 2011 Sep 9.

Phase II study of oral capsular 4-hydroxyphenylretinamide (4-HPR/fenretinide) in pediatric patients with refractory or recurrent neuroblastoma: a report from the Children's Oncology Group

Judith G Villablanca  1 , Wendy B London, Arlene Naranjo, Patrick McGrady, Matthew M Ames, Joel M Reid, Renee M McGovern, Sarah A Buhrow, Hollie Jackson, Enno Stranzinger, Brenda J Kitchen, Paul M Sondel, Marguerite T Parisi, Barry Shulkin, Gregory A Yanik, Susan L Cohn, C Patrick Reynolds
Affiliations
Clinical Trial

Phase II study of oral capsular 4-hydroxyphenylretinamide (4-HPR/fenretinide) in pediatric patients with refractory or recurrent neuroblastoma: a report from the Children's Oncology Group

Judith G Villablanca et al. Clin Cancer Res. .

Abstract

Purpose: To determine the response rate to oral capsular fenretinide in children with recurrent or biopsy proven refractory high-risk neuroblastoma.

Experimental design: Patients received 7 days of fenretinide: 2,475 mg/m(2)/d divided TID (<18 years) or 1,800 mg/m(2)/d divided BID (≥18 years) every 21 days for a maximum of 30 courses. Patients with stable or responding disease after course 30 could request additional compassionate courses. Best response by course 8 was evaluated in stratum 1 (measurable disease on CT/MRI ± bone marrow and/or MIBG avid sites) and stratum 2 (bone marrow and/or MIBG avid sites only).

Results: Sixty-two eligible patients, median age 5 years (range 0.6-19.9), were treated in stratum 1 (n = 38) and stratum 2 (n = 24). One partial response (PR) was seen in stratum 2 (n = 24 evaluable). No responses were seen in stratum 1 (n = 35 evaluable). Prolonged stable disease (SD) was seen in 7 patients in stratum 1 and 6 patients in stratum 2 for 4 to 45+ (median 15) courses. Median time to progression was 40 days (range 17-506) for stratum 1 and 48 days (range 17-892) for stratum 2. Mean 4-HPR steady-state trough plasma concentrations were 7.25 μmol/L (coefficient of variation 40-56%) at day 7 course 1. Toxicities were mild and reversible.

Conclusions: Although neither stratum met protocol criteria for efficacy, 1 PR + 13 prolonged SD occurred in 14/59 (24%) of evaluable patients. Low bioavailability may have limited fenretinide activity. Novel fenretinide formulations with improved bioavailability are currently in pediatric phase I studies.

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Figures

Figure 1
Figure 1
A. 4-HPR plasma concentrations (n = 28). Each circle represents one patient at a given timepoint B. 4-MPR plasma concentrations (n = 28).
Figure 1
Figure 1
A. 4-HPR plasma concentrations (n = 28). Each circle represents one patient at a given timepoint B. 4-MPR plasma concentrations (n = 28).
Figure 2
Figure 2
a. Progression-free survival for all eligible patients on ANBL0321 by stratum (n=62). The numbers at risk at the start of years 1–4 are given along the curves. b. Overall survival for all eligible patients on ANBL0321 by stratum (n=62). The numbers at risk at the start of years 1–4 are given along the curves.
Figure 2
Figure 2
a. Progression-free survival for all eligible patients on ANBL0321 by stratum (n=62). The numbers at risk at the start of years 1–4 are given along the curves. b. Overall survival for all eligible patients on ANBL0321 by stratum (n=62). The numbers at risk at the start of years 1–4 are given along the curves.
Figure 3
Figure 3
a. Progression-free survival by bone marrow involvement at study entry (Log-rank p=0.0078). The numbers at risk at the start of years 1–6 are given along the curves.
Figure 3
Figure 3
a. Progression-free survival by bone marrow involvement at study entry (Log-rank p=0.0078). The numbers at risk at the start of years 1–6 are given along the curves.
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References

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