Clinical Trials Register

Summary
EudraCT Number:	2018-000924-32
Sponsor's Protocol Code Number:	AGMT_MM-3
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-09-24
Trial 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

Austria - BASG

A.2

EudraCT number

2018-000924-32

A.3

Full title of the trial

Denosumab for high risk SMM and SLiM CRAB positive, early myeloma patients- a randomized, placebo controlled phase II trial “DEFENCE” (DEnosumab For the rEductioN of the smoldering myeloma transformatioN inCidence ratE)

Randomisierte, Placebo kontrollierte Phase II Studie für Patienten mit Hochrisiko Smoldering Multiplem Myelom (SMM) oder mit SLiM CRAB positivem Myelom mit Denosumab zur Verringerung der Transformationshäufigkeitsrate (AGMT_MM-3)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Denosumab for high risk SMM and SLiM CRAB positive, early myeloma patient- a randomized, placebo controlled phase II trial “DEFENCE” (DEnosumab For the rEductioN of the smoldering myeloma transformatioN inCidence ratE)

A.4.1

Sponsor's protocol code number

AGMT_MM-3

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03792763

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	AGMT gGmbH
B.1.3.4	Country	Austria
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Amgen Ltd
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AGMT gGmbH
B.5.2	Functional name of contact point	Clinical Trial Lead Manager
B.5.3	Address:
B.5.3.1	Street Address	Wolfsgartenweg 31
B.5.3.2	Town/ city	Salzburg
B.5.3.3	Post code	5020
B.5.3.4	Country	Austria
B.5.4	Telephone number	+436626404411
B.5.5	Fax number	+436626404414
B.5.6	E-mail	d.wolkersdorfer@agmt.at

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	Yes
D.2.1.1.1	Trade name	XGEVA
D.2.1.1.2	Name of the Marketing Authorisation holder	Amgen Europe B.V.
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	denosumab
D.3.9.1	CAS number	615258-40-7
D.3.9.3	Other descriptive name	DENOSUMAB
D.3.9.4	EV Substance Code	SUB29173
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	70
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)	No
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	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
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	No
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.IMP: 2
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	Yes
D.2.1.1.1	Trade name	Calcilac
D.2.1.1.2	Name of the Marketing Authorisation holder	Dermapharm GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Austria
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	Chewable tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Calcium caronate
D.3.9.1	CAS number	471-34-1
D.3.9.3	Other descriptive name	CALCIUM CARBONATE
D.3.9.4	EV Substance Code	SUB13166MIG
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	1250
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	COLECALCIFEROL
D.3.9.1	CAS number	67-97-0
D.3.9.3	Other descriptive name	Vitamin D3
D.3.9.4	EV Substance Code	SUB06794MIG
D.3.10	Strength
D.3.10.1	Concentration unit	IU international unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	400
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)	No
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	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
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	No
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	Solution for injection
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

High-risk smouldering multiple myeloma or "SLiM CRAB" positive early multiple myeloma

E.1.1.1

Medical condition in easily understood language

High-risk smouldering multiple myeloma is a precursor and "SLiM CRAB" positive early multiple myeloma is an early phase of multiple myeloma, a is a cancer of plasma cells, a type of white blood cell.

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10067386
E.1.2	Term	Multiple myeloma transformation
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10075894
E.1.2	Term	Smoldering myeloma
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Effectiveness of denosumab in delaying transformation to symptomatic, active MM or progression of disease.

E.2.2

Secondary objectives of the trial

- Effectiveness of denosumab in reduction of percentage of patients developing serological progression within 3 years
- Effectiveness of denosumab in reduction of progression rate in high risk MM patients
- Effectiveness of denosumab in reduction of progression rate in “SLiM CRAB” myeloma patients
- Effectiveness of denosumab in reduction of skeletal-related events (SRE) defining progression to active MM
- Effectiveness of denosumab in delaying time to skeletal-related events
- Effectiveness of denosumab in delaying time to symptomatic skeletal-related events
- Effectiveness of denosumab in delaying time to first anti-myeloma treatment
- Influence of denosumab regarding overall survival of patients with high-risk SMM and early ‘SLiM CRAB’ positive MM

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Age ≥ 18 years
• Able to provide written informed consent in accordance with federal, local, and institutional guidelines
• Must meet criteria of high risk smoldering MM or early "SLiM CRAB" MM based on the criteria described below:
o High-risk SMM is defined here according to the revised Mayo Clinical algorithm (2 out of 3 criteria must be fulfilled):
• Bone marrow clonal plasma cells >20%
• Serum M protein >2.0g/dL
• Serum free light chain ratio >20 measured with “Binding site Kit”
o Early ‘SLiM CRAB’ multiple myeloma (3)
Patients must present with only one of the following features
• Bone marrow clonal plasma cells ≥ 60%, or
• Serum FLC ratio ≥ 100 (k-LC leading) or ≤ 0.01 (l-LC leading), measured with “Binding site Kit”, or
• >1 Focal bone lesion of ≥5mm (not associated with osteolysis, detected by PET-CT or whole-body low-dose CT (WBLDCT))
• Time from diagnosis of high risk SMM or SLIM CRAB positive, early MM to study enrollment: <5 years

E.4

Principal exclusion criteria

• ECOG >3
• Active, symptomatic MM (fulfilling CRAB-criteria)
• Non secretory MM, extramedullary plasmacytoma, plasma cell leukemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
• MGUS
• Hypocalcemia (can be corrected by drug intervention before start of treatment)
• Second malignancy within the past 5 years except:
o Adequately treated basal cell or squamous cell skin cancer
o Carcinoma in situ of the cervix
o Prostate cancer Gleason score ≤ 6 with stable prostate-specific antigen (PSA over 12 months)
o Ductal breast carcinoma in situ with full surgical resection (i.e., negative margins)
o Treated medullary or papillary thyroid cancer
o Similar condition with an expectation of > 95% five-year disease-free survival
• Active infection within the 14 days prior to randomization requiring systemic antibiotics and/or antiviral therapy
• Known human immunodeficiency virus (HIV) seropositivity or active hepatitis C or hepatitis B infection (subjects with past hepatitis B virus [HBV] infection or resolved HBV infection defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti HBc] antibody test are eligible; subjects positive for hepatitis C virus [HCV] antibody are eligible only if polymerase chain reaction [PCR] is negative for HCV RNA.)
• Participation in another interventional study within the 28 days prior to randomization
• Any other clinically significant medical disease or social condition that, in the investigator’s opinion, may interfere with protocol adherence or a subject’s ability to give informed consent, be compliant with study procedures, or provide accurate information.
• Prior administration of denosumab
• Prior exposure to any experimental or approved anti-myeloma agent
• Use of oral bisphosphonates with a cumulative exposure of more than 1 year (wash out period for allowed bisphosphonate exposure 1 month)
• More than 1 previous dose of IV bisphosphonate administration or teriparatide (wash out period for allowed bisphosphonate exposure 1 month)
• Prior history or current evidence of osteonecrosis/osteomyelitis of the jaw
• Active dental or jaw condition which requires oral surgery, including tooth extraction
• Subject is pregnant or breast feeding, or planning to become pregnant within 7 months after the end of treatment
• Female subject of child bearing potential is not willing to use, in combination with her partner, a highly effective and in addition an effective contraception during treatment and for 5 months after the end of treatment
• Known sensitivity to denosumab (including all components of the formulation) or any of the products to be administered during the study (e.g. mammalian derived products, calcium, or vitamin D)
• Subject is receiving or is less than 30 days since ending other experimental device or drug (no marketing authorization for any indication).
• Subject will not be available for follow-up assessment

E.5 End points

E.5.1

Primary end point(s)

Time from randomization to transformation to symptomatic, active MM (defined as progression to active multiple myeloma according to IMWG diagnosis criteria 2014) or progression of disease according to IMWG response criteria 2016.

E.5.1.1

Timepoint(s) of evaluation of this end point

Monthly during the first 6 months and 3-monthly until a maximum of 3 years.

E.5.2

Secondary end point(s)

1. Percentage of patients transforming to CRAB positive multiple myeloma and/or developing serological progression (as defined by IMWG criteria 2016 for MM) within three years.
2. Percentage of high risk SMM patients progressed to active, symptomatic MM within 3 years.
3. Percentage of “SLiM”- part of “SLiM CRAB” criteria fulfilling patients at inclusion progressing to CRAB-positive MM within three years
4. Incidence of bone lesions as MM defining events
5. Time to first skeletal-related event
6. Time to symptomatic skeletal-related event
7. Time to first anti-myeloma treatment
8. Overall survival

E.5.2.1

Timepoint(s) of evaluation of this end point

Endpoints 1-3: at baseline monthly during first 6 months and 3-monthly until a maximum of 3 years

Endpoints 4-6: at baseline and every 6 months thereafter until a maximum of 3 years

Endpoints 7-8: from randomizaton until end of study (12 months after end of treatment of last patient)

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

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

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

Yes

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.8.2.4

Number of treatment arms in the trial

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

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

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

LVLS

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

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

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

2018-10-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-12-07

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2023-09-14

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