title: A Phase IB multicentre dose-determination study of BHQ880 in combination with anti-myeloma therapy and zoledronic acid in patients with relapsed or refractory multiple myeloma and prior skeletal-related events.
abstract: Dickkopf-1 (DKK1), expressed by myeloma cells, suppresses osteoblast function and plays a key role in bone disease in multiple myeloma. BHQ880, a human neutralizing IgG1 anti-DKK1 monoclonal antibody, is being investigated for its impact on multiple myeloma-related bone disease and as an agent with potential anti-myeloma activity. The primary objectives of this Phase IB study were to determine the maximum tolerated dose (MTD) of BHQ880 and to characterize the dose-limiting toxicity (DLT) of escalating doses in combination with anti-myeloma therapy and zoledronic acid. Twenty-eight patients were enrolled and received BHQ880 at doses of 3-40 mg/kg. No DLTs were reported, therefore, the MTD was not determined. The recommended Phase II dose was declared as 10 mg/kg, based mainly on saturation data. There was a general trend towards increased bone mineral density (BMD) observed over time; specific increases in spine BMD from Cycle 12 onwards irrespective of new skeletal-related events on study were observed, and increases in bone strength at the spine and hip were also demonstrated in some patients. BHQ880 in combination with zoledronic acid and anti-myeloma therapy was well tolerated and demonstrated potential clinical activity in patients with relapsed or refractory multiple myeloma.
authors.affiliation: Houston Methodist Cancer Center, Weill Cornell Medical College, Houston, TX, USA.
authors.forename: Swaminathan P
authors.initials: SP
authors.lastname: Iyer
authors.forename: Joseph Taddeus
authors.initials: JT
authors.lastname: Beck
authors.forename: A Keith
authors.initials: AK
authors.lastname: Stewart
authors.forename: Jatin
authors.initials: J
authors.lastname: Shah
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Kelly
authors.forename: Randi
authors.initials: R
authors.lastname: Isaacs
authors.forename: Sanela
authors.initials: S
authors.lastname: Bilic
authors.forename: Suman
authors.initials: S
authors.lastname: Sen
authors.forename: Nikhil C
authors.initials: NC
authors.lastname: Munshi
mesh_terms: D000368:Aged; D045930:Anabolic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001862:Bone Resorption / Q000188:drug therapy / Q000517:prevention & control; D004164:Diphosphonates / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D005598:Fractures, Spontaneous / Q000209:etiology; D006801:Humans; D006973:Hypertension / Q000139:chemically induced; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009101:Multiple Myeloma / Q000150:complications* / Q000188:drug therapy; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D010014:Osteolysis / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D012008:Recurrence; D013117:Spinal Cord Compression / Q000209:etiology; D000077211:Zoledronic Acid
chemical_list: D045930:Anabolic Agents; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D050071:Bone Density Conservation Agents; C501126:DKK1 protein, human; D004164:Diphosphonates; D007093:Imidazoles; D036341:Intercellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D000077211:Zoledronic Acid; C557618:BHQ880
keywords: BHQ880; Phase I; multiple myeloma; skeletal-related event