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Phase II trial of fenretinide in patients with recurrent malignant gliomas - A North American Brain Tumor Consortium study

Al Musella's Comments: (This is his personal views and are not necessarily the views of the Musella Foundation!)


Posted on: 06/14/2003

39th ASCO Annual Meeting • Chicago, IL • May 31-June 3, 2003 (Abstract No. 419)

Phase II trial of fenretinide in patients with recurrent malignant gliomas - A North American Brain Tumor Consortium study

V. K. Puduvalli, W. K. A. Yung, M. Prados, J. Kuhn, K. Hess, M. Groves, V. Levin, S. Chang, J. Zwiebel, T. Cloughesy

and North American BrainTumor Consortium; UT MD Anderson Cancer Center, Houston, TX

The synthetic retinoid, fenretinide (4-hydroxyphenyl retinamide, 4HPR) induces apoptosis in several malignant cell lines including gliomas and has been well tolerated in phase I trials in humans.

Based on preclinical evidence of activity, a phase II trial of fenretinide was conducted in adults with recurrent malignant gliomas with a KPS³70 who had failed radiation therapy and £2 prior chemotherapy regimens.

A Simon two-stage design with separate arms for anaplastic gliomas (AG) and glioblastomas (GBM) was used, with the primary endpoint being 6-month progression free survival (PFS).

Fenretinide was given as 600 mg/m2 BID, orally, for 1 week, followed by 2 weeks of rest (6 weeks=1 cycle).

Of the 22 patients enrolled in the first stage of the AG arm, 21 were evaluable for response and toxicity.

Six patients (28%) had stable disease at 6 months.

No responses were noted.

Median PFS was 6 weeks (95% CI - 6, 12) and 6 month PFS was 10% (3, 36). Toxicity was limited to grades 1 or 2, most commonly fatigue, anemia and hyboalbuminemia.

In the GBM arm, the 23 patients enrolled in the first stage were evaluable for response and all but 1 for toxicity.

Two (9%) patients were stable at 6 months; and the remainder progressed. Median PFS was 6 weeks (95% CI, 5, 6) and 6-month PFS was 0%.

One patient who was on anticoagulants developed an uncontrollable nasal bleed (INR>6.0) while on treatment with 4HPR and died.

The other patients in this arm manifested grade 1 or 2 toxicities, most commonly fatigue and dryness of skin.

The trial was closed after the first stage due to the inadequate activity seen with this agent.

Pharmacokinetic data were available for 26 patients at a 600 mg/m2 BID dosage; mean serum Cmax was 833.9±347.2 ng/ml for fenretinide and 240.8±133.4 ng/ml for its major metabolite, 4MPR.

In 4 AG patients, treated with 900 mg/m2 BID, mean serum Cmax = 1213±260.5 ng/ml for fenretinide and 337±112.7 ng/ml for 4MPR.

Our results suggest that fenretinide is not active against recurrent malignant gliomas at the dosage utilized in this trial.

© Copyright 2003 American Society of Clinical Oncology All rights reserved worldwide

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