Phase II study of fenretinide (NSC 374551) in adults with recurrent malignant gliomas: A North American Brain Tumor Consortium study

Abstract

Purpose: Fenretinide induces apoptosis in malignant gliomas in vitro. This two-stage phase II trial was conducted to determine the efficacy of fenretinide in adults with recurrent malignant gliomas.

Patients and methods: Twenty-two patients with anaplastic gliomas (AG) and 23 patients with glioblastoma (GBM) whose tumors had recurred after radiotherapy and no more than two chemotherapy regimens were enrolled. Fenretinide was given orally on days 1 to 7 and 22 to 28 in 6-week cycles in doses of 600 or 900 mg/m(2) bid.

Results: Six of 21 (29%) patients in the AG arm and two of 23 (9%) patients in the GBM arm had stable disease at 6 months. One patient with AG treated at 900 mg/m(2) bid dosage had a partial radiologic response. Median progression-free survival (PFS) was 6 weeks for the AG arm and 6 weeks for the GBM arm. PFS at 6 months was 10% for the AG arm and 0% for the GBM arm. Grade 1 or 2 fatigue, dryness of skin, anemia, and hypoalbuminemia were the most frequent toxicities reported. The trial was closed after the first stage because of the inadequate activity at the fenretinide doses used. The first-administration mean plasma C(max) for fenretinide was 832 +/- 360 ng/mL at the 600 mg/m(2) bid dosage and 1,213 +/- 261 ng/mL at the 900 mg/m(2) bid dosage.

Conclusion: Fenretinide was inactive against recurrent malignant gliomas at the dosage used in this trial. However, additional studies using higher doses of the agent are warranted based on the tolerability of the agent and the potential for activity of a higher fenretinide dosage, as suggested in this trial.

Conflict of interest statement

Authors’ Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

Figures

Fig 1

Kaplan-Meier curve for progression-free survival (PFS) for patients in the anaplastic glioma stratum.

Fig 2

Fenretinide-induced response in a patient with biopsy-proven recurrent anaplastic astrocytoma after radiation therapy failed a year before enrollment and temozolomide (TMZ) plus marimastat (MMT) subsequently. The patient has completed 13 cycles of fenretinide (900 mg/m2 bid) and remained progression free 18 months after initiation of therapy. AA, anaplastic astrocytoma; 4HPR, 4-hydroxyphenyl-retinamide.

Fig 3

Kaplan-Meier curve for progression-free survival (PFS) for patients in the glioblastoma stratum.

Fig 4

Pharmacokinetic profiles of fenretinide (4-HPR) and N-(4-methoxyphenyl)-retinamide (4-MPR) in 26 patients. Plasma samples were obtained on day 1, course 1 at 0, 1, 3, 6, 9, and 12 hours, and trough levels at 24 hours, days 14 (336 hours) and 21 (504 hours) after the first administration of fenretinide at a dose of 600 mg/m2.