A single-arm multicenter proof-of-concept study of denosumab to treat hypercalcemia of malignancy in patients who are refractory to IV bisphosphonates.

Abstract

TPS245 Background: Hypercalcemia of malignancy (HCM) is a serious complication thought to result in large part from tumor-driven increases in bone resorption. IV bisphosphonates (BP) are used for treatment of HCM, but some patients relapse after or become refractory to IV BP treatment. In addition, although severe renal impairment may worsen HCM due to reduced calcium clearance, IV BP are not recommended in these patients. Available alternative agents (eg, calcitonin, mithramycin, gallium nitrate) are now used infrequently due to efficacy and safety limitations. Thus, there is an unmet medical need in patients with HCM for whom BP treatment is ineffective or not recommended. In animal models of humoral HCM, inhibition of RANK ligand (RANKL), the primary effector of bone resorption, reversed established hypercalcemia more effectively than high‐dose BP, suggesting that RANKL inhibition is a rational therapeutic strategy for patients with HCM. Denosumab is a fully human monoclonal antibody against RANKL approved in the US for the prevention of skeletal-related events in patients with bone metastases from solid tumors. Denosumab does not interfere with renal function and does not require renal monitoring. This single-arm study is evaluating denosumab in patients with HCM who have not responded to recent BP treatment. Methods: Patients with confirmed cancer, recent IV BP treatment (between 30 to 7 days prior), and corrected serum calcium (CSC) levels of > 12.5 mg/dL, are eligible. Patients with benign hyperparathyroidism, hyperthyroidism, adrenal insufficiency, or on dialysis are ineligible. Patients receive denosumab 120 mg SC monthly with a loading dose on study days 8 and 15. The primary endpoint is the proportion of patients with a response in CSC (defined as CSC ≤ 11.5 mg/dL by day 10 of treatment. Secondary endpoints include complete response (defined as CSC ≤ 10.8 mg/dL by day 10 of treatment), response by visit, time to response, response duration, and safety. The trial began enrolling patients in November 2009, with a total of 33 patients planned. This trial is sponsored by Amgen Inc. and is registered with the ClinicalTrials.gov identifier: NCT00896454.