CLINICAL TRIAL: PASIREOTIDE IN PATIENTS WITH PERSISTENT OR RECURRENT CUSHING'S D

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Pasireotide is a novel cyclohexapeptide, somatostatin analogue developed as a follow-up to octreotide (SMS 201-955, Sandostatin) with a superior endocrine profile. Pasireotide exhibits a unique binding profile with a high affinity binding to four of the five known human somatostatin receptors (sst-1-5). Pasireotide binds with a 30 to 40 fold higher affinity than octreotide to the hsst1 and -5 receptor subtypes and a fivefold higher affinity to sst-3. Primary Objectives: o To assess the efficacy in terms of response to pasireotide 600 mg s.c. b.i.d. and 900 mg s.c. b.i.d. independently in patients with Cushing's disease as measured by UFC <1.5 X ULN and >50% reduction of urinary free cortisol (UFC) from baseline after 6 months of treatment. Study Design: After a 2-4 week screening period, patients who fulfill the entrance criteria will be randomized in a double-blinded manner to receive pasireotide s.c. at a dose of either 600 or 900 mg s.c. b.i.d. for three months via an Interactive Voice Response System (IVRS). After the first three months of treatment, patients who have responded to the assigned blinded treatment dose (UFC 1.5 X ULN and >50% reduction of UFC) will continue to receive the same dose for the following 3 months. Patients who have not responded will be unblinded by the investigator. Patients who received the 600 mg s.c. b.i.d. dose will be required to have their dose increased to 900 mg s.c. b.i.d. for the following 3 months. Patients in the 900 mg s.c. b.i.d. dose group who did not respond will be permitted to have their dose increased to 1200 mg s.c. b.i.d.. Those not electing to increase the dose will be discontinued from the study. The primary analysis will be performed after six months of treatment. Should both dose levels provide evidence of pasireotide treatment success at month 6, the primary efficacy analysis will be complete. Otherwise, a sequential step-down analysis may be performed. There will be a 6-month open-label period thereafter when patients will continue with the same pasireotide dose. Patients receiving the 600 mg s.c. b.i.d., can have their dose increased to receive 900 mg s.c. b.i.d. at any time during the open-label period if the response is not maintained. In the same way, patients receiving 900 mg s.c. b.i.d. will be permitted to have their dose increased to 1200 mg s.c. b.i.d. at any time during the open-label period if the response is not maintained, and if they have tolerated the 900 mg s.c. b.i.d. dose.