Clinical Trials Register

Summary
EudraCT Number:	2017-003951-44
Sponsor's Protocol Code Number:	ΕΑΕ-2017/ΜΜ01
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:	2017-11-28
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

Greece - EOF

A.2

EudraCT number

2017-003951-44

A.3

Full title of the trial

A Prospective, Multicenter, Non-comparative, Open-label, Phase II Study to Evaluate the Effects of Daratumumab Monotherapy on Bone Parameters in Patients with Relapsed and /or Refractory Multiple Myeloma who Have Received at least 2 Prior Lines of Therapy including Lenalidomide and a Proteasome Inhibitor

A.3.1

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

Study to evaluate Effects of Daratumumab Monotherapy on Bone Parameters in Patients with Relapsed and /or Refractory Multiple Myeloma who Have Received at least 2 Prior Lines of Therapy including Lenalidomide and a Proteasome Inhibitor

A.3.2

Name or abbreviated title of the trial where available

The REBUILD study

A.4.1

Sponsor's protocol code number

ΕΑΕ-2017/ΜΜ01

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	Hellenic Society of Hematology
B.1.3.4	Country	Greece
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	Janssen Pharmaceutica NV
B.4.2	Country	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Health Data Specialists Ireland Limited
B.5.2	Functional name of contact point	Health Data Specialists Ireland
B.5.3	Address:
B.5.3.1	Street Address	77 SIR JOHN ROGERSON'S QUAY, BLOCK C, GRAND CANAL DOCKLANDS
B.5.3.2	Town/ city	Dublin
B.5.3.3	Post code	D02 NP08
B.5.3.4	Country	Ireland
B.5.4	Telephone number	00353906480600
B.5.6	E-mail	info@heads-research.com

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	DARZALEX
D.2.1.1.2	Name of the Marketing Authorisation holder	Janssen-Cilag International N.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	Yes
D.2.5.1	Orphan drug designation number	EU/3/13/1153
D.3 Description of the IMP
D.3.1	Product name	Daratumumab
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
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	DARATUMUMAB
D.3.9.1	CAS number	945721-28-8
D.3.9.4	EV Substance Code	SUB175772
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	20
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	Yes
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	human monoclonal antibody

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Relapsed and /or Refractory Multiple Myeloma

E.1.1.1

Medical condition in easily understood language

Multiple Myeloma

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	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10028228
E.1.2	Term	Multiple myeloma
E.1.2	System Organ Class	100000004864

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

The primary objective of this study is to evaluate changes in bone resorption markers after 4 months of daratumumab monotherapy. Namely, C-telopeptide of collagen type 1 (CTX) and tartrate-resistant acid phosphatase-5b (TRACP-5b) will be evaluated at baseline and then every 2 months of therapy.

E.2.2

Secondary objectives of the trial

Secondary objectives are the following:
Increases of serum markers of bone formation after 4, 8 and 12 months of daratumumab monotherapy (or at the end of therapy).
Reductions of serum markers of bone resorption after 8 and 12 months of daratumumab monotherapy (or at the end of therapy).
Reductions of circulating receptor activator of nuclear factor kappa-B ligand (RANKL), RANKL/ osteoprotegerin (OPG) ratio, C-C motif chemokine ligand 3 (CCL3), dickkopf-1 (Dkk1), sclerostin (SOST) and activin-A after 4, 8 and 12months of therapy (or at the end of therapy).
Changes in Bone Mineral Density (BMD) of the lumbar spine measured after 6 and 12 months of therapy.
The evaluation of the immunomodulatory effects of daratumumab on T cells.
Progression Free Survival (PFS), Time to Next Treatment (TtNT) and Overall Survival (OS).
Skeletal-related events (SRE); pathological fractures, need for radiotherapy or surgery to the bones, and spinal cord compression.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Males and females at least 18 years of age.
2.Voluntary written informed consent before performance of any study-related procedure.
3.Subject must have documented relapsed and / or refractory multiple myeloma as defined by the criteria below:
a)Measurable disease as defined by any of the following:
oSerum monoclonal paraprotein (M-protein) level ≥ 1.0 g/dL (except for IgA subtype: ≥ 0.5 g/dL) or urine M-protein level ≥ 200 mg/24 hours; or
oLight chain multiple myeloma for patients without measurable disease in the serum or urine by SPEP/UPEP: Serum immunoglobulin free light chain ≥ 10 mg/dL and abnormal serum immunoglobulin kappa lambda free-light-chain ratio.
4.Prior treatment with at least two lines of treatment including lenalidomide and a PI for MM (induction followed by any planned high dose therapy or consolidation or maintenance would be considered as one regimen).
5.Documented evidence of progressive disease (PD) as defined by the modified IMWG criteria on or after the last regimen.
6.Karnofsky Performance Status score of ≥ 70.
7.All of the following laboratory test results during screening:
•Absolute neutrophil count (ANC) of ≥ 1.0 x 109/L.
•Platelet count of ≥ 75 x 109/L in patients in whom <50% of bone marrow nucleated cells are plasma cells and ≥50 x 109/L in patients in whom ≥ 50% of bone marrow nucleated cells are plasma cells.
•Hemoglobin level > 7.5 g/dL
•Alanine aminotransferase < 2.5 times the upper limit of normal (ULN).
8.Adequate renal function: estimated Glomerular Filtration Rate (eGFR) ≥ 30 mL/min by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI).
9.Willingness and ability to participate in study procedures.
10.Reproductive Status:
a.Women of childbearing potential (WOCBP) must have two negative serum or urine pregnancy tests, one 10-14 days prior to start of the study drug and one within 24 hours prior to the start of study drug.
b.Women must not be breastfeeding.
c.WOCBP must agree to follow instructions for effective methods of contraception for 4 weeks before the start of treatment with study drugs, for the duration of treatment with study drugs, and for 3 months after cessation of study treatment.
d.Male patients must use a latex or synthetic condom during any sexual contact with females of reproductive potential, even if they have undergone a successful vasectomy. They must also agree to follow instructions for methods of contraception for 4 weeks before the start of treatment with study drugs, for the duration of treatment with study drugs, and for a total of 3 months post-treatment completion. The additional contraception of female partners of childbearing potential should also be considered.

Highly effective methods of contraception have a failure rate of < 1% when used consistently and correctly. Subjects must agree to the use of two methods of contraception, with one method being highly effective (tubal ligation, intrauterine device [IUD], hormonal [birth control pills, injections, hormonal patches, vaginal rings or implants] or partner’s vasectomy) and the other method being additionally effective (male latex or synthetic condom, diaphragm, or cervical cap).

E.4

Principal exclusion criteria

1.Patient has received any of the following therapies:
•Radiotherapy or systemic therapy within 2 weeks of baseline.
•Prior Allogeneic hematopoietic stem cell transplantation; or Autologous stem cell transplantation within 12 weeks of baseline.
•Prior Treatment with any CD38-antibody (i.e. daratumumab, isatuximab).
2.Clinically significant cardiac disease, including:
a)Myocardial infarction within 6 months, or unstable or uncontrolled condition (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV).
b)Cardiac arrhythmia (CTCAE Grade 3 or higher) or clinically significant ECG abnormalities.
c)ECG showing a baseline QT interval as corrected >470 msec.
3.Chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) <50% of predicted normal. Note that FEV1 testing is required for subjects suspected of having COPD and subjects must be excluded if FEV1 <50% of predicted normal.
4.Any of the following:
a)Known active hepatitis A.
b)Patient is seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR.
c)Patient is known to be seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy).
5.Patient is known to be seropositive for human immunodeficiency virus (HIV)

6.Significant neuropathy (Grades 3–4, or Grade 2 with pain) within 14 days prior to enrolment.
7.Hypersensitivity to the active substance or to any of the excipients.
8.Any concurrent medical or psychiatric condition or disease (e.g., active systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) that is likely to interfere with subject’s ability to give informed consent, the study procedures or results, or that in the opinion of the investigator, would constitute a hazard for participating in this study.
9.Pregnant or breastfeeding women.

E.5 End points

E.5.1

Primary end point(s)

Change from baseline in bone resorption markers CTX and TRACP-5b after 4 months of daratumumab monotherapy

E.5.1.1

Timepoint(s) of evaluation of this end point

4 months of daratumumab monotherapy

E.5.2

Secondary end point(s)

• Change from baseline in bone formation markers bALP, OC and PINP after 4, 8 and 12 months of daratumumab monotherapy (or at the end of therapy).
• Change from baseline in bone resorption markers CTX and TRACP-5b after 8 and 12 months of daratumumab monotherapy (or at the end of therapy).
• Change from baseline in RANKL, RANKL/OPG ratio, CCL3, Dkk1, SOST and activin-A after 4, 8 and 12months of daratumumab monotherapy (or at the end of therapy).
• Change in Bone Mineral Density (BMD) of lumbar spine measured by DXA after 6 and 12 months of daratumumab monotherapy.
• Immunomodulatory effects of daratumumab on T cells by comprehensive molecular and phenotypic studies and correlations with bone markers.
• PFS, OS.
• Time to next treatment.
• Skeletal related events.
• Safety (adverse events).

E.5.2.1

Timepoint(s) of evaluation of this end point

For the entire duration of the study.

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

E.8.1.1

Randomised