title: Denosumab for patients with persistent or relapsed hypercalcemia of malignancy despite recent bisphosphonate treatment.
abstract: Hypercalcemia of malignancy (HCM), caused primarily by tumor-induced bone resorption, may lead to renal failure, coma, and death. Although HCM can be treated with intravenous bisphosphonates, patients may not respond or may relapse on therapy. Denosumab binds the bone resorption mediator RANKL. In this single-arm, open-label, proof-of-concept study, HCM patients with albumin-corrected serum calcium (CSC) levels greater than 12.5mg/dL (Common Terminology Criteria for Adverse Events grade ≥ 3) despite recent intravenous bisphosphonate treatment received subcutaneous denosumab on days 1, 8, 15, and 29, and then every 4 weeks. The primary endpoint was the proportion of patients with CSC 11.5mg/dL or less (grade ≤ 1) within 10 days of denosumab initiation. In a prespecified interim analysis, 15 patients received denosumab (median CSC = 13.6 mg/dL). Time to response and response duration were analyzed with Kaplan-Meier methods. All statistical tests were two-sided. By day 10, 12 patients (80%; 95% exact confidence interval [CI] = 52% to 96%) responded (CSC ≤ 11.5mg/dL); median response duration was 26 days. Ten patients (67%; 95% exact CI = 38% to 88%) had complete responses (CSC ≤ 10.8 mg/dL) by day 10. Denosumab may offer a new treatment option for HCM. Clinicaltrials.gov identifier: NCT00896454.
authors.affiliation: Affiliations of authors: University of Texas MD Anderson Cancer Center, Houston, TX (MIH); Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, NY (IG); Institut Gustave Roussy, Villejuif, France (SL); Yale School of Medicine, New Haven, CT (KI); Montefiore Medical Center-Bronx, New York, NY (RG); Endocrinology Department, Medical Center for Postgraduate Education, Warsaw, Poland (WM); Peninsula Regional Medical Center, Salisbury, MD (BY); Amgen Inc., Thousand Oaks, CA, USA (WY, RKJ).
authors.forename: Mimi I
authors.initials: MI
authors.lastname: Hu
authors.forename: Ilya
authors.initials: I
authors.lastname: Glezerman
authors.forename: Sophie
authors.initials: S
authors.lastname: Leboulleux
authors.forename: Karl
authors.initials: K
authors.lastname: Insogna
authors.forename: Rasim
authors.initials: R
authors.lastname: Gucalp
authors.forename: Waldemar
authors.initials: W
authors.lastname: Misiorowski
authors.forename: Bennett
authors.initials: B
authors.lastname: Yu
authors.forename: Wendy
authors.initials: W
authors.lastname: Ying
authors.forename: Rajul K
authors.initials: RK
authors.lastname: Jain
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000627:therapeutic use*; D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000150:complications* / Q000378:metabolism; D000069448:Denosumab; D004164:Diphosphonates / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D006934:Hypercalcemia / Q000188:drug therapy* / Q000209:etiology*; D015994:Incidence; D007279:Injections, Subcutaneous; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D053245:RANK Ligand / Q000187:drug effects / Q000378:metabolism; D012008:Recurrence; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D053245:RANK Ligand; D000069448:Denosumab