Clinical Trials Register

Summary
EudraCT Number:	2016-003328-22
Sponsor's Protocol Code Number:	56022473MDS2002
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-12-06
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

Belgium - FPS Health-DGM

A.2

EudraCT number

2016-003328-22

A.3

Full title of the trial

A Phase 2 Proof-of-Concept Study to Separately Evaluate the Activity of Talacotuzumab
(JNJ-56022473) or Daratumumab in Transfusion-Dependent Subjects with Low or
Intermediate-1 Risk Myelodysplastic Syndromes (MDS) who are Relapsed or Refractory to Erythropoiesis-Stimulating Agent (ESA) Treatment

A.3.1

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

A Proof-of Concept Study to Separately Study Talacotuzumab or Daratumumab in Low-Risk Intermediate-1 Risk Myelodysplastic Syndromes (MDS) patients

A.4.1

Sponsor's protocol code number

56022473MDS2002

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	Janssen-Cilag International NV
B.1.3.4	Country	Belgium
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	Janssen Research & Development, LLC
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Janssen-Cilag International NV
B.5.2	Functional name of contact point	Clinical Registry Group
B.5.3	Address:
B.5.3.1	Street Address	Archimedesweg 29
B.5.3.2	Town/ city	Leiden
B.5.3.3	Post code	2333 CM
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+31 71 524 21 66
B.5.5	Fax number	+31 71 524 21 10
B.5.6	E-mail	ClinicalTrialsEU@its.jnj.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	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	Talacotuzumab
D.3.2	Product code	JNJ-56022473
D.3.4	Pharmaceutical form	Powder for 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	Talacotuzumab
D.3.9.2	Current sponsor code	JNJ-56022473
D.3.9.4	EV Substance Code	SUB176319
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	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)	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	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	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	Daratumumab
D.3.2	Product code	Hu-Max-CD38
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.3.9.2	Current sponsor code	JNJ-54767414 (Daratumumab)
D.3.9.3	Other descriptive name	HUMAX-CD38
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

Transfusion-Dependent Subjects with Low or Intermediate-1 Risk Myelodysplastic Syndromes (MDS) who are Relapsed or Refractory to Erythropoiesis-Stimulating Agent (ESA) Treatment

E.1.1.1

Medical condition in easily understood language

Myelodysplastic Syndromes (MDS)

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10028534
E.1.2	Term	Myelodysplastic syndrome NOS
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 the study is to evaluate the efficacy (transfusion independence [TI]) of talacotuzumab (JNJ-56022473) or daratumumab in transfusion-dependent subjects with low or intermediate-1 risk MDS whose disease has relapsed during treatment with or is refractory to ESAs.

E.2.2

Secondary objectives of the trial

- To evaluate the safety of talacotuzumab or daratumumab in the study population
- To evaluate the clinical benefit of talacotuzumab and daratumumab in this study population through:
- Time to TI and duration of TI
- Rate of HI, CR, and PR
- Overall survival (OS)
- Progression to AML
- Rate and amount of supportive care, including transfusions and myeloid growth factors
- To characterize the PK of talacotuzumab and daratumumab in the study population
- To evaluate the immunogenicity of talacotuzumab and daratumumab in subjects with MDS

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. 18 years of age
2. MDS according to World Health Organization criteria confirmed by bone marrow aspirate and biopsy within 12 weeks prior to first dose. A local laboratory report from this diagnostic bone marrow aspirate and biopsy must be approved by the sponsor.
3. IPSS low risk or intermediate-1 risk MDS
4. RBC transfusion dependent
- Received at least 4 units of RBCs over any 8 consecutive weeks during the 16 weeks prior to randomization-Pretransfusion Hb must have been ≤9.0 g/dL
Source documentation for transfusions verified by the sponsor.
5. Relapsed/refractory to ESA treatment; the sponsor must verify this diagnosis as defined by meeting any of the criteria below:
- Received at least 8 weeks of treatment with a minimum weekly dose of epoetin alfa 40,000 U, epoetin beta 30,000 U or darbepoetin alfa 150 mcg (or equivalent
agent/dose) without having achieved a Hb rise ≥1.5 g/dL or decreased RBC
transfusion requirement by at least 4 units over 8 weeks
- Transfusion dependence or reduction in Hb by ≥1.5 g/dL after hematologic
improvement, in the absence of another explanation;
- Endogenous serum EPO level >500 mU/mL
Source documentation for failure of ESA treatment verified by the sponsor
6. Adequate iron stores, defined as transferrin saturation greater than 20% and serum ferritin greater than 400 ng/mL, measured within the screening period, or adequate iron stores as demonstrated by recent (within 12 weeks prior to first dose) bone marrow examination with iron stain.
7. ECOG performance status 0, 1 or 2
8. Hematology laboratory test values within the following limits:
- ANC ≥1.0 x 10 to the 9th/L (ie, ≥1,000/mm3) independent of growth factor support. For the screening ANC to be considered growth factor independent, a 7-day period after stopping the growth factor should be observed, or 7 half-lives of growth factor used, whichever is longer.
- Platelets ≥50 x 10 to the 9th/L independent of platelet transfusion support. For the screening platelets to be considered independent of platelet transfusion support, platelet count must be stable for 3-4 days after the transfusion.
9. Biochemical laboratory test values must be within the following limits:
- Aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤2.5 times
the upper limit of normal (x ULN)
- Creatinine clearance >40 mL/min
- Total bilirubin ≤3.0 x ULN, except for subjects with Gilbert syndrome
10. Women of childbearing potential and men who are sexually active must be practicing highly effective method of contraception (failure rate of <1% per year when used consistently and correctly) during and after the study. Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for subject participating in clinical studies. Men must agree to not father a child or donate sperm during and after the study. Women must agree not to donate eggs (ova, oocytes) for the purpose of assisted reproduction. For females and males, these restrictions apply for at least 3 months after the last dose of study drug.
11. A woman of childbearing potential must have a negative highly sensitive serum
(B-human chorionic gonadotropin [B-hCG]) or urine pregnancy test at Screening.
12. Each subject (or their legally acceptable representative) must sign an informed consent form (ICF) indicating that he or she understands the purpose of and procedures required for the study and are willing to participate in the study. Subject must be willing and able to adhere to the prohibitions and restrictions specified in this protocol.

E.4

Principal exclusion criteria

1. Known allergies, hypersensitivity, or intolerance to talacotuzumab and daratumumab or their excipients
2. Received any chemotherapy, immunomodulatory or immunosuppressive therapy, corticosteroids (>30 mg/day prednisone or equivalent) within 28 days prior to randomization
3. Received other treatments for MDS within 28 days prior to first dose (eg, azacitidine, decitabine, lenalidomide, ESA (8 weeks for long-acting ESAs)
4. History of hematopoietic stem cell transplant
5. Del (5q) karyotype unless treatment with lenalidomide has failed. Failure is defined as either:
1) having received at least 3 months of lenalidomide treatment without RBC
transfusion benefit (IWG 2006);
2) progression or relapse after hematologic improvement with lenalidomide (IWG 2006);
3) discontinuation of lenalidomide due to toxicity; or
4) unable to receive lenalidomide due to a contraindication. Source documentation for lenalidomide treatment failure must be verified by the sponsor.
6. Anemia attributed to factors other than MDS (including hemolysis, chronic renal failure, hepatitis, gastrointestinal bleeding)
7. Major surgery within 4 weeks prior to first dose (excludes the placement of a vascular access device and other minor surgical procedures)
8. Active malignancy other than MDS ≤3 years before first dose, except:
- Adequately treated non-melanoma skin cancer or lentigo maligna without current evidence of disease
- Adequately treated cervical carcinoma in situ without current evidence of disease
9. Clinically significant cardiovascular disease including:
- myocardial infarction within 6 months of screening
- unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, cardiac disease meeting New York Heart Association
Class 3-4 definition)
- uncontrolled or symptomatic cardiac arrhythmias
- screening 12-lead ECG showing a baseline corrected QT interval (QTc) >470 msec
10. Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) <50% of predicted normal
11. Known moderate or severe persistent asthma within the past 2 years or uncontrolled asthma of any classification. Note that subjects who currently have
controlled intermittent asthma or controlled mild persistent asthma are allowed to participate in the study.
12. Uncontrolled active systemic infection requiring IV antibiotics
13. Known history of human immunodeficiency virus (HIV) infection
14. Active systemic hepatitis infection requiring treatment or other clinically active liver disease
15. Females who are pregnant or are breastfeeding
16. Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator’s opinion, could compromise the subject’s safety, or put the study outcomes at undue risk. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is 8-week RBC TI, defined as absence of RBC transfusion during any consecutive 56 days (8 weeks) post randomization.

E.5.1.1

Timepoint(s) of evaluation of this end point

6 months after the last subject is randomized

E.5.2

Secondary end point(s)

1.) Transfusion independence lasting 168 days (24 weeks)
2.) Time to TI
3.) Duration of TI
4.) Transfusions and myeloid growth factors usage
5.) HI (including HI-E, HI-P, HI-N), CR, PR and cytogenetic response per IWG 2006
6.) Overall survival
7.) Progression to AML

E.5.2.1

Timepoint(s) of evaluation of this end point

1.) 6 months after the last subject is randomized
2.) 6 months after the last subject is randomized
3.) 6 months after the last subject is randomized
4.) 6 months after the last subject is randomized
5.) 6 months after the last subject is randomized
6.) 12 months after the last subject is randomized
7.) 12 months after the last subject is randomized

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

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

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

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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

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

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

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

Belgium

Italy

Netherlands

Russian Federation

Spain

United States

E.8.7

Trial has a data monitoring committee

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

The end of study is defined as 1 year after the last subject is randomized or anytime the sponsor terminates the study.

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

E.8.9.2

In all countries concerned by the trial days

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)

Subjects who are continuing to derive benefit from treatment as assessed by their investigator will continue to receive treatment and be monitored for safety by the sponsor.

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

2016-12-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-02-13

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-10-05

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