Multiple Myeloma Bone Disease Clinical Trial
Official title:
A Phase Ib/II Multicenter Dose-determination Study, With an Adaptive, Randomized, Placebo-controlled, Double-blind Phase II, Using Various Repeated IV Doses of BHQ880 in Combination With Zoledronic Acid in Relapsed or Refractory Myeloma Patients With Prior Skeletal-related Event
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.
| Status | Completed |
| Enrollment | 28 |
| Est. completion date | December 2011 |
| Est. primary completion date | December 2011 |
| Accepts healthy volunteers | No |
| Gender | Both |
| Age group | 18 Years to 78 Years |
| Eligibility |
Inclusion Criteria: 1. Relapsed or refractory multiple myeloma patients requiring treatment with a non-bortezomib-containing regimen (prior treatment with bortezomib is acceptable) • The diagnosis of symptomatic multiple myeloma (International Myeloma Working Group) 2. Patients with multiple myeloma who do not have measurable serum M-protein or measurable urine M-protein must have measurable increased concentrations of free light chains (using FreeLite™) 3. At least one prior SRE defined as one of the following: - Pathologic fracture - Spinal cord compression - Requirement for either radiation or surgery to bone due to: - Pain - Prevention of imminent fracture - Stabilization of a fracture 4. Current or planned treatment with zoledronic acid 5. Ambulatory patients aged 18 years or older 6. Adequate organ function Exclusion Criteria: 1. Known concomitant disease(s) known to influence calcium metabolism including hyperparathyroidism, hyperthyroidism and/or Paget's disease of bone. 2. Current active dental problems including - Ongoing infection of the teeth or jawbone (maxilla or mandibula) - Current exposed bone in the mouth - Dental or fixture trauma - Current or previous osteonecrosis of the jaw - Slow healing after dental procedures - Recent (within 6 weeks) or planned dental or jaw surgery during the study (extraction, implants) 3. Patients who are allergic to/ intolerant of bisphosphonate therapy 4. Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. uncontrolled diabetes, active or uncontrolled infection, uncontrolled diarrhea) that could cause unacceptable safety risks or compromise compliance with the protocol 5. Other clinically significant heart disease (e.g. symptomatic congestive heart failure, uncontrolled arrhythmia, uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen) Other protocol-defined inclusion/exclusion criteria may apply |
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
| Country | Name | City | State |
|---|---|---|---|
| United Kingdom | Novartis Investigative Site | Bradford | |
| United Kingdom | Novartis Investigative Site | London | |
| United Kingdom | Novartis Investigative Site | London | |
| United Kingdom | Novartis Investigative Site | Manchester | |
| United States | Dana Farber Cancer Institute Deptof DanaFarberCancerInst(2) | Boston | Massachusetts |
| United States | Highlands Oncology Group Dept of Highlands Oncology Grp | Fayetteville | Arkansas |
| 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 | Mayo Clinic - Arizona Cancer Clinical Research Unit | Scottsdale | Arizona |
| Lead Sponsor | Collaborator |
|---|---|
| Novartis Pharmaceuticals |
United States, United Kingdom,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | Time to first SRE and change in bone markers for bone resorption and formation | 9 months minimum treatment with BHQ880 or placebo in combination with zoledronic acid and std anti-myeloma therapy | No | |
| Secondary | Characterize acute and chronic safety and tolerability of BHQ880 | 9 months minimum treatment with BHQ880 or placebo in combination with zoledronic acid and std anti-myeloma therapy | Yes | |
| Secondary | Characterize single-dose and repeated-dose pharmacokinetic profiles of BHQ880 | 9 months minimum treatment with BHQ880 or placebo in combination with zoledronic acid and std anti-myeloma therapy | Yes | |
| Secondary | Assess the potential immunogenicity of BHQ880 | 9 months minimum treatment with BHQ880 or placebo in combination with zoledronic acid and std anti-myeloma therapy | Yes | |
| Secondary | Characterize the binding kinetics of DKK1/BHQ880 complex (free and BHQ880 bound DKK1) in serum | 9 months minimum treatment with BHQ880 or placebo in combination with zoledronic acid and std anti-myeloma therapy | Yes | |
| Secondary | Determine the pharmacodynamic effects of BHQ880 by measuring biochemical markers of bone formation, resorption, and metabolism in serum and urine | 9 months minimum treatment with BHQ880 or placebo in combination with zoledronic acid and std anti-myeloma therapy | Yes |