This study has two portions, a phase I portion and a phase II portion. The purpose of the phase I portion is to assess the maximum-tolerated dose (MTD) and to characterize dose limiting toxicity (DLT) of escalating doses of BHQ880 (up to a maximum dose of 20 mg/kg) in combination with standard chemotherapy and zoledronic acid in relapsed or refractory multiple myeloma patients. The phase II portion of the study will also be conducted in relapsed or refractory multiple myeloma patients. Patients will be treated with various doses of BHQ880 or placebo in combination standard chemotherapy. In the phase II portion of the study zoledronic acid will be added after the first 28 days of therapy with BHQ880 or placebo and standard chemotherapy. This will allow any BHQ880-related changes in bone biomarkers to be detected in a zoledronic acid-free environment. The purpose of the phase II portion of the study, is to determine one or more doses of BHQ880 for further development based on dose-efficacy modeling. Efficacy is defined as time to first skeletal-related event and change in bone markers for bone resorption and formation relative to placebo. A skeletal-related event is defined as: * Pathologic fracture * Spinal cord compression * Requirement for either radiation or surgery to bone due to: * Pain * Prevention of imminent fracture * Stabilization of a fracture Biomarker and imaging endpoints will be assessed in both phases of the study. The pharmacodynamic effects of BHQ880 will be assessed by measuring biochemical markers of bone formation, resorption, and metabolism in serum and urine. Charges in serum DKK1 levels will be characterized. The size and number of lytic bone lesions as measured by bone survey (X-ray) or MRI will be assessed. In addition, bone mineral density (BMD) will be measured by DEXA scan and at selected sites with QCT scans.
The study was originally planned to have two phases. Phase II, the dose expansion phase, was not conducted.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
28
Mayo Clinic - Arizona Cancer Clinical Research Unit
Scottsdale, Arizona, United States
Highlands Oncology Group Dept of Highlands Oncology Grp
Fayetteville, Arkansas, United States
Dana Farber Cancer Institute Deptof DanaFarberCancerInst(2)
Boston, Massachusetts, United States
MD Anderson Cancer Center/University of Texas Dept. of MD Anderson (11)
Houston, Texas, United States
Cancer Therapy & Research Center / UT Health Science Center InstituteForDrugDevelopment(4)
San Antonio, Texas, United States
Novartis Investigative Site
Bradford, United Kingdom
Novartis Investigative Site
London, United Kingdom
Novartis Investigative Site
London, United Kingdom
Novartis Investigative Site
Manchester, United Kingdom
Time to first SRE and change in bone markers for bone resorption and formation
Time frame: 9 months minimum treatment with BHQ880 or placebo in combination with zoledronic acid and std anti-myeloma therapy
Characterize acute and chronic safety and tolerability of BHQ880
Time frame: 9 months minimum treatment with BHQ880 or placebo in combination with zoledronic acid and std anti-myeloma therapy
Characterize single-dose and repeated-dose pharmacokinetic profiles of BHQ880
Time frame: 9 months minimum treatment with BHQ880 or placebo in combination with zoledronic acid and std anti-myeloma therapy
Assess the potential immunogenicity of BHQ880
Time frame: 9 months minimum treatment with BHQ880 or placebo in combination with zoledronic acid and std anti-myeloma therapy
Characterize the binding kinetics of DKK1/BHQ880 complex (free and BHQ880 bound DKK1) in serum
Time frame: 9 months minimum treatment with BHQ880 or placebo in combination with zoledronic acid and std anti-myeloma therapy
Determine the pharmacodynamic effects of BHQ880 by measuring biochemical markers of bone formation, resorption, and metabolism in serum and urine
Time frame: 9 months minimum treatment with BHQ880 or placebo in combination with zoledronic acid and std anti-myeloma therapy
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