Cinacalcet for Fibroblast Growth Factor 23 (FGF23)-Mediated Hypophosphatemia (Hypophosphatemic Rickets)

OBJECTIVES: The primary objective of this protocol is to evaluate the tolerability of cinacalcet in individuals with fibroblast growth factor 23 (FGF23)-mediated hypophosphatemia, using an open-label, dose-titration study of once-daily dosing. Secondary objectives are to evaluate the pharmacodynamics of cinacalcet in this subject population and to explore the efficacy of cinacalcet by comparing a) level of oral phosphate required at baseline to the level required at maximum tolerated dose (MTD) and b) change in renal phosphate handling from baseline to MTD. Tertiary objectives are to evaluate tolerability, pharmacodynamics, and efficacy of twice daily dosing of each subject s MTD of cinacalcet after completion of the once-daily dose-titration phase. A final objective is to determine the length of time it takes for subjects to return to their pre-treatment steady state once treatment is complete. STUDY POPULATION: Up to 17 subjects with FGF23-mediated hypophosphatemia will be treated. DESIGN: This study is an open-label, dose-titration study of once-daily dosing of cinacalcet, with up to 4 escalating doses given at approximately 3 week intervals. After an initial standard of care optimization period of 2-9 weeks, subjects will proceed to the cinacalcet dose-titration period. Subjects who experience extended toxicity or study drug related serious adverse events or other related, intolerable adverse events will be down titrated to a lower dose of study medication. After subjects have achieved their own maximum tolerated dose (MTD) and completed the once-daily dosing phase, they will continue the study medication for approximately 3 additional weeks with twice daily dosing at their MTD. At the end of the cinacalcet treatment phase of the study, cinacalcet will be discontinued and standard of care (SOC) medications will be adjusted/restarted on an individualized basis. Subjects will continue in this final SOC safety follow-up period for up to 4 weeks until their SOC medications have been re-equilibrated. OUTCOME MEASURES: Primary safety: Whether or not a subject discontinued the study due to a toxicity, related serious adverse event (SAE), or related intolerable adverse event (AE). Secondary safety: * \<TAB\>Maximum tolerated dose of cinacalcet * \<TAB\>Serum calcium levels * \<TAB\>Urine calcium levels * \<TAB\>Adverse events * \<TAB\>Time from cinacalcet discontinuation to return to pre-treatment standard of care dosage levels Secondary efficacy: * \<TAB\>Pharmacodynamic assessments * \<TAB\>Serum: FGF23, intact parathyroid hormone, calcium, creatinine, phosphorus * \<TAB\>Urine: phosphorus, creatinine, calcium. * \<TAB\>Tubular maximum reabsorption of phosphate/glomerular filtration rate * \<TAB\>Tubular reabsorption of phosphate * \<TAB\>Other * \<TAB\>Change in oral phosphate and calcitriol intake required to maintain adequate phosphorus and calcium serum levels * \<TAB\>Serum osteocalcin and alkaline phosphatase * \<TAB\>Serum intact parathyroid hormone (PTH) Tertiary efficacy: * \<TAB\>Twice-Daily Dosing at MTD * \<TAB\>Time from cinacalcet discontinuation of twice-daily dosing to return to pre-treatment standard of care dosage levels * \<TAB\>Dental Evaluation * \<TAB\>Visible Plaque Index (VPI) * \<TAB\>Gingival Bleeding Index (GBI) * \<TAB\>Position of Gingival Margin (PGM) * \<TAB\>Relative Attachment Level (RAL) * \<TAB\>Periodontal Probing Pocket Depth (PPD) * \<TAB\>Gingival Crevicular Fluid (GCF) Biomarkers