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    Summary
    EudraCT Number:2008-000411-15
    Sponsor's Protocol Code Number:CBHQ880A2102
    National Competent Authority:Greece - EOF
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2009-10-19
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGreece - EOF
    A.2EudraCT number2008-000411-15
    A.3Full title of the trial
    A Phase Ib 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.
    A.3.2Name or abbreviated title of the trial where available
    NA
    A.4.1Sponsor's protocol code numberCBHQ880A2102
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberNA
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNovartis Pharma Services AG
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code BHQ880
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeBHQ880
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product Yes
    D.3.11.13.1Other medicinal product typea neutralizing human IgG1 lambda monoclonal antibody
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Zometa
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameZometa
    D.3.4Pharmaceutical form Powder and solvent for solution for infusion
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNzoledronic acid
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Patients with relapsed or refractory multiple myeloma and at least one prior skeletal related event will either be treated in the phase I or phase II portion of the study following a 28-day screening period. The phase I/II study is designed to determine the MTD of BHQ880 in the phase I portion and to establish the dose-efficacy relationship for doses not exceeding the MTD in combination with zoledronic acid and standard anti-myeloma therapy in the phase II portion.
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10028228
    E.1.2Term Multiple myeloma
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Escalation phase (Phase I):
    1. To determine 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 anti-myeloma therapy and zoledronic acid.

    Expansion phase (Phase II):
    1. To determine one or more doses of BHQ880 for further development based on dose efficacy modeling, where efficacy is relative to placebo in terms of time to first SRE from randomization and change in bone markers for bone resorption and formation in combination with zoledronic acid plus standard anti-myeloma therapy
    E.2.2Secondary objectives of the trial
    In relapsed or refractory multiple myeloma patients in combination with zoledronic acid plus standard anti-myeloma therapy, to:
    1. characterize acute and chronic safety and tolerability of various doses of BHQ880
    2. characterize single-dose and repeated-dose PK profiles of iv administrated BHQ880
    6. determine the PD effects of BHQ880 by measuring biochemical markers of bone formation, resorption, and metabolism in serum and urine
    7. assess the effect of BHQ880 on the Ca2+ and P+ metabolism
    8. monitor preliminary evidence of anti-tumor activity of BHQ880
    9. investigate the effect of BHQ880 in combination on the radiographic size and number of lytic bone lesions as measured by bone survey

    3. To assess the potential immunogenicity of iv infused BHQ880
    4. To characterize the binding kinetics of DKK1/BHQ880 complex in serum
    5. To characterize changes in serum DKK1 levels during treatment
    E.2.3Trial contains a sub-study Yes
    E.3Principal inclusion criteria
    1. Relapsed or refractory multiple myeloma patients requiring treatment with a nonbortezomib-
    containing regimen (prior treatment with bortezomib is acceptable)
    2. The diagnosis of symptomatic multiple myeloma as defined by the following criteria
    (International Myeloma Working Group):
    • M-protein in serum or urine
    • Clonal bone marrow plasma cells or plasmacytoma
    • Presence of related organ or tissue impairment (ROTI)
    3. 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™)
    4. 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
    5. Stable renal function defined as two serum creatinine determinations of < 2.5 mg/dl or
    calculated (Cockroft-Gault formula) creatinine clearance (CrCl) < 60 mL/min.
    • Cockcroft-Gault formula (Cockcroft and Gault 1976):
    • CrCl = [140-age (years)] x weight (kg) (x 0.85 for female patients)
    [72 x serum creatinine (mg/dL)]
    6. Current or planned treatment with zoledronic acid
    7. No symptoms of hyperviscosity, amyloidosis or recurrent infection
    8. Corrected serum calcium < 12 mg/dl or ionized calcium < 6.5 mg/dL within 14 days prior
    to registration
    9. Life expectancy of at least 12 months.
    10. Ambulatory patients aged 18 years or older
    11. ECOG performance status ≤ 2
    12. Absolute neutrophil count ≥ 1500/mm3
    13. Platelet count ≥ 75,000/mm3
    14. Hemoglobin (Hgb) ≥ 9 g/dl (prior RBC transfusion, recombinant epoetin alfa, or
    darbepoetin alfa allowed)
    15. Electrolyte levels ≥ LLN (i.e., potassium, magnesium, phosphorus) correction with
    supplements allowed
    16. AST and ALT ≤ 2.5 x ULN
    17. Serum bilirubin ≤ 1.5 x ULN
    18. Patients must sign the informed consent form and be willing and able to comply with the
    study protocol
    E.4Principal exclusion criteria
    1. Known concomitant disease(s) known to influence Ca2+ metabolism including
    hyperparathyroidism, hyperthyroidism and/or Paget’s disease of bone.
    2. Current active dental problems including
    • Ongoing infection of the teeth or jawbone
    • 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
    3. Prior radiation therapy to treat diseases of the mouth
    4. Patients who are allergic to/ intolerant of bisphosphonate therapy
    5. Acute or chronic liver disease
    6. Patients with any peripheral neuropathy ≥ CTCAE grade 2
    7. Other concurrent severe and/or uncontrolled concomitant medical conditions that could
    cause unacceptable safety risks or compromise compliance with the protocol
    8. Angina pectoris ≤ 3 months prior to starting study drug
    9. Acute myocardial infarction ≤ 6 months prior to starting study drug
    10. LVEF < 45%
    11. Other clinically significant heart disease
    12. A past medical history of clinically significant ECG abnormalities or a family history of a prolonged QT-interval syndrome
    13. Patients who have not recovered from significant grade 3-4 side effects of previous antimyeloma therapy
    14. Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from the side-effects of surgery
    15. Patients who have received any investigational drug ≤ 5 half lives prior to starting study drug or who have not recovered from side effects of such therapy. Or patients who have received previous investigational monoclonal antibody or radioimmunotherapy drug ≤ 60 days prior to starting study drug or who have not recovered from side effects of such
    therapy
    16. Known diagnosis of human immunodeficiency virus (HIV) infection
    17. Women of child-bearing potential (WCBP) who are pregnant or breast feeding. WCBP, defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 24 consecutive months (i.e., who have had menses any time in the preceding 24 consecutive months), must have a negative serum pregnancy test ≤ 48 hours prior to starting study treatment. In addition, all sexually active WCBP and male patients must agree to use adequate contraceptive methods (oral,
    injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device;
    barrier contraceptive with spermicide; or vasectomized partner) throughout the study.
    18. Patients with a history of another primary malignancy that is currently clinically
    significant or currently requires active intervention
    19. Patients unwilling or unable to comply with the protocol
    E.5 End points
    E.5.1Primary end point(s)
    Safety endpoints:
    • Occurrence of treatment-related dose-limiting toxicity (DLT) (if
    observed for doses up to 20 mg/kg) (Escalation phase –
    phase I)
    • Occurrence of adverse drug reactions
    • Changes in the calcium and phosphate metabolism (PTH,
    Ca++, PO4
    --, Vit D3, calcitonin)
    • Immunogenicity
    Efficacy endpoints:
    • Time to first SRE from randomization
    • Percent change from baseline in bone markers for bone
    resorption, metabolism, and formation
    • Anti-myeloma effect: changes in monoclonal protein in blood
    and urine, changes in urinary light chain excretion, changes in
    serum free light chain, changes in plasma cells in bone
    marrow (pre- vs. postreatment)
    • Change in number and size of lytic bone lesions on X-ray
    and/or MRI (pre- vs. postreatment)
    • Change in bone mineral density assessed by dual energy Xray
    absorptiometry and QCT (exploratory)
    • Change in bone strength in normal bone and osteolytic
    lesions assessed by QCT with finite element analysis
    (exploratory)
    • Change in circulating levels of TNF, IL-6, M-CSF and sCSF-
    1R (exploratory)
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Information not present in EudraCT
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Information not present in EudraCT
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Information not present in EudraCT
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Information not present in EudraCT
    E.8.1.6Cross over Information not present in EudraCT
    E.8.1.7Other Information not present in EudraCT
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned Information not present in EudraCT
    E.8.4 The trial involves multiple sites in the Member State concerned Information not present in EudraCT
    E.8.5The trial involves multiple Member States Yes
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Information not present in EudraCT
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 267
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2009-07-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-09-08
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2011-12-09
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