Clinical Trials Register

Summary
EudraCT Number:	2008-000411-15
Sponsor's Protocol Code Number:	CBHQ880A2102
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2009-03-31
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

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A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2008-000411-15

A.3

Full 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.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

CBHQ880A2102

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	NOVARTIS FARMA
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	BHQ880
D.3.2	Product code	BHQ880
D.3.4	Pharmaceutical form	Powder for infusion*
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	BHQ880
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Information not present in EudraCT
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Information not present in EudraCT
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	Yes
D.3.11.13.1	Other medicinal product type	anticorpo monoclonale neutralizzante le IgG1 lambda umane
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	ZOMETA
D.2.1.1.2	Name of the Marketing Authorisation holder	NOVARTIS FARMA SpA
D.2.1.2	Country which granted the Marketing Authorisation	Italy
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Powder and solvent for solution for infusion
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Zoledronic acid
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	4
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Information not present in EudraCT
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Information not present in EudraCT
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Powder for infusion*
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Relapsed or refractory multiple myeloma patients with at least one prior SRE scheduled for standard anti-myeloma therapy and bisphosphonates

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	9.1
E.1.2	Level	LLT
E.1.2	Classification code	10028228
E.1.2	Term	Multiple myeloma

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main 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.2.2

Secondary objectives of the trial

Secondary objectives (Phase I and Phase II)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 pharmacokinetic profiles of intravenously administrated BHQ880, 6. determine the pharmacodynamic effects of BHQ880 by measuring biochemical markers of bone formation, resorption and metabolism 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; and: 3. To assess the potential immunogenicity of intravenously 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.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Relapsed or refractory multiple myeloma patients requiring treatment with a non-bortezomib-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 &#8804; 2 12. Absolute neutrophil count &#8805; 1500/mm3 13. Platelet count &#8805; 75,000/mm3 14. Hemoglobin (Hgb) &#8805; 9 g/dl (prior RBC transfusion, recombinant epoetin alfa, or darbepoetin alfa allowed) 15. Electrolyte levels &#8805; LLN (i.e., potassium, magnesium, phosphorus) correction with supplements allowed 16. AST and ALT &#8804; 2.5 x ULN 17. Serum bilirubin &#8804; 1.5 x ULN 18. Patients must sign the informed consent form and be willing and able to comply with the study protocol

E.4

Principal 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. 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 &#8805; CTCAE grade 2 7. 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 8. Angina pectoris &#8804; 3 months prior to starting study drug 9. Acute myocardial infarction &#8804; 6 months prior to starting study drug 10. LVEF < 45% 11. 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) 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 anti-myeloma therapy 14. Patients who have undergone major surgery &#8804; 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 &#8804; 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 &#8804; 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 (HIV testing is not mandatory) 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 &#8804; 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.5.1

Primary 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 X-ray 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.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

E.8.7

Trial 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.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects
F.1 Age Range
F.1.1	Trial has subjects under 18	No
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	No
F.1.2	Adults (18-64 years)	Yes
F.1.3	Elderly (>=65 years)	No
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	Yes
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	Yes
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	16
F.4.2	For a multinational trial
F.4.2.1	In the EEA	103
F.4.2.2	In 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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2009-04-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2009-02-26

P. End of Trial
P.	End of Trial Status	Completed

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