Malignant gliomas, the most common of which in adults is glioblastoma multiforme, carry a grave prognosis with high morbidity and mortality. Surgery, radiotherapy and chemotherapy are only of modest value in the management of these tumors. Among novel compounds being tested against gliomas, 13 cis-retinoic acid, as single agent or in combination, has shown activity against recurrent gliomas in clinical trials. Fenretinide, a related synthetic retinoid, induces apoptosis & decreases proliferation in a variety of malignancies in vitro and is well tolerated on oral administration in humans. Fenretinide inhibits proliferation of glioma cells by induction of apoptosis at 3 - 5 muM concentration (Puduvalli et al 1999). Data from Phase I trials indicate that fenretinide is well tolerated and concentrations of approximately10?M are achievable at a dose of 1200 mg/m2 twice daily. Based on these data, we hypothesize that fenretinide administered at this dose will result in glioma tissue concentrations sufficient to induce apoptosis and result in clinical efficacy in this tumor type. We also hypothesize that fenretinide can induce molecular & radiological changes that can serve as surrogate markers for the effect of this agent against gliomas. To test these hypotheses, we propose a Phase II trial (placebo-controlled) with clinical & correlative endpoints. Clinical Trial Design: 40 patients with recurrent glioblastoma due to undergo surgery will be randomized in a blinded manner to receive fenretinide or placebo orally (20 patients each group) for 7 days prior to surgery with serum samples being collected for pharmacokinetic studies. At surgery, resected tissue will be collected with concurrent serum samples for correlative studies. All 40 patients will then continue on open label fenrentinide therapy until tumor progression.
Specific Aims :
Aim 1) To determine the efficacy of fenretinide against recurrent glioblastomas as measured by 6-month progression free survival (clinical endpoint) Aim 2) To determine the levels of fenretinide in glioma tissue and correlate it with serum concentrations.
Aim 3) To determine whether fenretinide induces apoptosis in tumor tissue and correlate the degree of apoptosis with serum and tissue concentrations of 4-HPR and with clinical efficacy.
Aim 4) To identify radiological and molecular surrogate markers of fenretinide effects on glioma tissue by utilizing - a) serum & tissue markers related to retinoid signaling such as retinol, retinol binding protein, retinoid receptors (RARgamma, RARbeta & RXR alpha) and IGF-1; b) Multivoxel MR Spectroscopy (MRS) of the tumor (before and after 7 day presurgery treatment with fenretinide) to detect changes indicative of apoptosis and correlate this with apoptosis seen in MRS-targeted tissue samples; c) Oligonucleotide microarrays to determine transcriptionally altered molecules relevant to gliomas including those that mediate invasion, angiogenesis and apoptosis. Data from this study about the tissue effects of fenretinide could hence provide new insights into the mechanism of action of fenretinide at the target tissue level. Such data could be relevant not only to future trials of retinoids in gliomas but also for ongoing trials of fenretinide in other malignancies.
