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: Swaminathan P Iyer, Joseph Taddeus Beck, A Keith Stewart, Jatin Shah, Kevin R Kelly, Randi Isaacs, Sanela Bilic, Suman Sen, Nikhil C Munshi
• Journal: British journal of haematology (Br J Haematol) Vol. 167 Issue 3 Pg. 366-75 (Nov 2014) ISSN: 1365-2141 [Electronic] England
• PMID: 25139740 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.

Chemical References

• Anabolic Agents
• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Bone Density Conservation Agents
• DKK1 protein, human
• Diphosphonates
• Imidazoles
• Intercellular Signaling Peptides and Proteins
• Neoplasm Proteins
• Zoledronic Acid
• BHQ880

Topics

• Aged
• Anabolic Agents (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Antibodies, Monoclonal (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Antibodies, Monoclonal, Humanized
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, therapeutic use)
• Bone Density Conservation Agents (administration & dosage, adverse effects, therapeutic use)
• Bone Resorption (drug therapy, prevention & control)
• Diphosphonates (administration & dosage, adverse effects, therapeutic use)
• Drug Therapy, Combination
• Female
• Fractures, Spontaneous (etiology)
• Humans
• Hypertension (chemically induced)
• Imidazoles (administration & dosage, adverse effects, therapeutic use)
• Intercellular Signaling Peptides and Proteins (immunology)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Molecular Targeted Therapy
• Multiple Myeloma (complications, drug therapy)
• Neoplasm Proteins (antagonists & inhibitors)
• Osteolysis (blood, drug therapy, etiology)
• Recurrence
• Spinal Cord Compression (etiology)
• Zoledronic Acid