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

Br J Haematol. 2014 Nov;167(3):366-75. doi: 10.1111/bjh.13056. Epub 2014 Aug 19.

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.

Keywords: BHQ880; Phase I; multiple myeloma; skeletal-related event.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • 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