A PHASE-I TRIAL OF HUMAN CORTICOTROPIN-RELEASING FACTOR (HCRF) IN PATIENTS WITH PERITUMORAL BRAIN EDEMA

Background: Human corticotropin-releasing factor (hCRF) is an endogeno us peptide responsible for the secretion and syn thesis of corticoster oids. In animal models of peritumoral brain edema, hCRF has significan t anti-edematous action. This effect, which appears to be independent of the release of adrenal steroids, appears mediated by a direct effec t on endothelial cells. We conducted a feasibility and phase I study w ith hCRF given by continuous infusion to patients with brain metastasi s. Patients and merl?ods: Peritumoral brain edema documented by MRI an d the use of either no steroids or stable steroid doses for more than a week were required, MRIs were repeated at completion of infusion and estimations by dual echo-image sequence (Proton density and T2-weight ed images) of the amount of peritumoral edema were performed. The stud y was performed in two stages. In the feasibility part, patients were randomized to receive either 0.66 or 1 mu g/kg/h of hCRF or placebo ov er 24 hours. The second part was a dose finding study of hCRF over 72 hours at escalating doses. Results: Seventeen patients were enrolled; only one was receiving steroids (stable doses) at study entrance; dose -limiting toxicity (hypotension:) was observed at 4 mu g/kg/h x 72 hou rs in two out of four patients, while zero of five patients treated at 2 mu g/kg/h developed dose-limiting toxicities. Flushing and hot flas hes were also observed. Improvement of neurological symptoms and/or ex am were seen in 10 patients. Only small changes were detected by MRI. Improvement in symptoms did not correlate with changes in cortisol lev els, and changes in cortisol levels were not correlated with changes i n peritumoral edema. Conclusions: hCRF is well tolerated in doses up t o 2 mu g/kg/h by continuous infusion x 72 hours. Hypotension limits ad ministration of higher doses, The observation of clinical benefit in t he absence of corticosteroids suggests hCRF may be an alternative to s teroids for the treatment of patients with peritumoral brain edema. Fu rther exploration of this agent in efficacy studies is warranted.