Clinical Trials Register

Summary
EudraCT Number:	2015-003862-10
Sponsor's Protocol Code Number:	Dara-Atra
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-01-19
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

Netherlands - Competent Authority

A.2

EudraCT number

2015-003862-10

A.3

Full title of the trial

A phase 1 and phase 2 study of daratumumab in combination with all-trans retinoic acid in relapsed/refractory multiple myeloma

A.3.1

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

Daratumumab in combination with ATRA in patients with relapsed/ refractory multiple myeloma

A.3.2

Name or abbreviated title of the trial where available

Dara-Atra study

A.4.1

Sponsor's protocol code number

Dara-Atra

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02751255

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	VU University Medical Center
B.1.3.4	Country	Netherlands
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 Pharmaceuticals
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	VUmc
B.5.2	Functional name of contact point	Trial office dept. of Hematology
B.5.3	Address:
B.5.3.1	Street Address	De Boelelaan 1117
B.5.3.2	Town/ city	Amsterdam
B.5.3.3	Post code	1081 HV
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+31204449193
B.5.5	Fax number	+31204442601
B.5.6	E-mail	hemtrial@vumc.nl

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	Name: Darzalex INN or common name : daratumumab
D.2.1.1.2	Name of the Marketing Authorisation holder	Janssen-Cilag International NV
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.3.2	Product code	HuMax-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
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.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	Vesanoid
D.2.1.1.2	Name of the Marketing Authorisation holder	Cheplapharm Arzneimittel GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Tretinoin
D.3.2	Product code	L01XX14
D.3.4	Pharmaceutical form	Capsule
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	tretinoine
D.3.9.2	Current sponsor code	ATRA
D.3.9.4	EV Substance Code	SUB11246MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	15 to 45
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

relapsed/refractory multiple myeloma

E.1.1.1

Medical condition in easily understood language

relapsed/refractory 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	16.1
E.1.2	Level	HLT
E.1.2	Classification code	10028229
E.1.2	Term	Multiple myelomas
E.1.2	System Organ Class	100000004851

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Evaluation of the effect of daratumumab in combination with ATRA in patients with relapsed/refractory multiple myeloma.
In Phase 1: to determine the maximum tolerated dose (MTD) and recommended phase 2 dose level (RDL) of daratumumab combined with ATRA.
For Phase 2: to investigate the efficacy of daratumumab combined with ATRA at the RDL, as determined by the (s)CR+VGPR+PR rate.

E.2.2

Secondary objectives of the trial

- To evaluate toxicity.
- To evaluate progression-free survival
- To evaluate overall survival
- To evaluate prognostic factors for response and survival
- To evaluate the effects of daratumumab and daratumumab plus ATRA on CD38 expression levels, complement-inhibitory proteins, and immune cells by using flow cytometric analysis and CYTOF
- To analyze the prognostic value of myeloma gene expression profiles
- To assess the prognostic value of mutations as determined by sequencing.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age 18 years and older
2. Subject must have documented multiple myeloma as defined by the criteria below:
•Monoclonal plasma cells in the bone marrow ≥10% at some point in their disease history or presence of a biopsy proven plasmacytoma.
•Measurable disease as defined by any of the following:
o Serum monoclonal paraprotein (M-protein) level ≥5 g/L (0.5 g/dL); or urine M-protein level ≥200 mg/24 hours; or serum immunoglobulin free light chain ≥100 mg/L (10 mg/dL) and abnormal serum immunoglobulin kappa lambda free light chain ratio (See Appendix A)
3. Relapsed from or refractory to 2 or more different prior therapies, including IMiDs (eg, thalidomide, lenalidomide) and proteasome inhibitors, chemotherapy-based regimens, or ASCT and without further established treatment options.
--Relapse is defined as progression of disease after an initial response (MR or better) to previous treatment, more than 60 days after cessation of treatment
--Refractory disease is defined as < 25% reduction in M-protein or progression of disease during treatment or within 60 days after cessation of treatment
4. WHO performance 0, 1, or 2
5. Life expectancy at least 3 months
6. Written informed consent

E.4

Principal exclusion criteria

1. Subject has received daratumumab or other anti-CD38 therapies, within 6 months before start of treatment.
2. Non-secretory myeloma
3. Systemic AL amyloidosis or plasma cell leukemia (>2.0x109/L circulating plasma cells by standard differential) or Waldenstrom’s macroglobulinemia
4. Subject has known meningeal involvement of multiple myeloma
5. Subject has received anti-myeloma treatment within 2 weeks or 5 pharmacokinetic half-lives of the treatment, whichever is longer, before start of treatment. This included subjects who have received a cumulative dose of corticosteroid greater than or equal to the equivalence of 140 mg prednisone or a single dose of corticosteroid greater than or equal to the equivalence of 40 mg/day dexamethasone within the 2-week period before start of treatment.
6. Subject has previously received an allogeneic stem cell transplantation within 1 year before the date of registration and has not used immunesuppressive drugs within one months before the date of registration.
7. Inadequate marrow reserve as defined by a platelet count <50 x 109/L or an absolute neutrophil count <1.0 x 109/L
8. a) Subject has known chronic obstructive pulmonary disease (COPD) with an Forced Expiratory Volume in 1 second (FEV1) < 50% of predicted normal. Note that FEV1 testing is required for patients suspected of having COPD and subjects must be excluded if FEV1 <50% of predicted normal.
b) Subject has known moderate or severe persistent asthma within the past 2 years, or currently has uncontrolled asthma of any classification. (Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study).
9. Subject has clinically significant cardiac disease, including:
•Myocardial infarction within 6 months before Cycle 1, Day 1, or unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable
angina, congestive heart failure, New York Heart Association Class III-IV)
• Cardiac arrhythmia (Common Terminology Criteria for Adverse Events [CTCAE] Version 4 Grade 2 or higher) or clinically significant ECG abnormalities.
• Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) >470 msec.
10. Significant hepatic dysfunction (total bilirubin ≥ 3 times normal value or transaminases ≥ 3 times normal value), unless related to myeloma
11. Creatinine clearance <30 ml/min.
12. Known hypersensitivity to components of the investigational product or severe allergic or anaphylactic reactions to humanized products.
13. Subject has any concurrent severe and/or uncontrolled medical condition (e.g.uncontrolled diabetes, infection, hypertension, etc.) that is likely to interfere with study procedures or results, or that in the opinion of the investigator would constitute a hazard for participating in this study.
14. Subject is known to be seropositive for human immunodefiency virus (HIV) or have active hepatitis B or hepatitis C.
15. History of active malignancy during the past 5 years, except squamous cell and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy that in the opinion of the local investigator, with concurrence with the principal investigator, is considered cured with minimal risk of recurrence within 5 years.
16. Subject is known or suspected of not being able to comply with the study protocol
(eg, because of alcoholism, drug dependency, or psychological disorder) or the subject has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (eg, compromise their well-being) or that could prevent, limit, or confound the protocol-specified assessments.
17. Pregnant or lactating females
18. Women of childbearing potential not willing to use adequate contraception, defined as hormonal birth control or intrauterine device, during the trial and for 1 year after the last dose of daratumumab. For patients in the US, the use of a double-barrier method is also considered adequate.
19. Sensory or motor neuropathy of ≥grade 3.

E.5 End points

E.5.1

Primary end point(s)

Phase 1: Dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended phase 2 dose (RDL) of daratumumab combined with ATRA.

Phase 2: Overall response rate of treatment with daratumumab combined with ATRA. In this analysis we will consider the best response obtained during treatment

E.5.1.1

Timepoint(s) of evaluation of this end point

for phase 1: up to 1.5 years.

For phase 2: up to 5 years.

E.5.2

Secondary end point(s)

For phase 1:
Safety and toxicity as defined by type, frequency and severity of adverse events as defined by the National Cancer Institute (NCI) Common Terminology Criteria for
Adverse Events (CTCAE), version 4.

For Phase 2:
Overall response rate of treatment with daratumumab monotherapy. In this analysis
we will consider the best response obtained during treatment
♦ Safety and toxicity as defined by type, frequency and severity of adverse events as
defined by the National Cancer Institute (NCI) Common Terminology Criteria for
Adverse Events (CTCAE), version 4
♦ Progression free survival (PFS; i.e. time from registration to progression or death from
any cause, whichever comes first)
♦ Overall survival measured from registration, measured until death from any cause.
Patients still alive or lost to follow up are censored at the date they were last known to
be alive
♦ Prognostic factors for response and survival
♦ Effects of daratumumab plus ATRA on CD38, CD55, and CD59 expression levels.
♦ Immunomodulatory effects of daratumumab plus ATRA by evaluation of diverse
immune subsets including T cells, NK cells, Tregulatory cells, and MDSCs.

E.5.2.1

Timepoint(s) of evaluation of this end point

For phase 1: up to 1.5 years.

For phase 2: up to 5 years.

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

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)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

dose finding.

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

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.8.3

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

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

2016-01-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-04-01

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2022-10-18

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