Clinical Trials Register

Summary
EudraCT Number:	2016-000296-24
Sponsor's Protocol Code Number:	CL1-68587-002
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-10-20
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

France - ANSM

A.2

EudraCT number

2016-000296-24

A.3

Full title of the trial

Phase I, open label, dose-escalation study to evaluate the safety, expansion and persistence of a single dose of UCART19 (allogeneic engineered T-cells expressing anti-CD19 chimeric antigen receptor), administered intravenously in patients with relapsed or refractory CD19 positive B-cell acute lymphoblastic leukaemia (B-ALL)).

A.3.1

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

A study to evaluate the safety and tolerability of ascending doses of UCART19 given as a single infusion in patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukaemia (B-ALL) and to determine the maximum tolerated dose (MTD).

A.3.2

Name or abbreviated title of the trial where available

CALM study

A.4.1

Sponsor's protocol code number

CL1-68587-002

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02746952

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	Institut de Recherches Internationales Servier (I.R.I.S)
B.1.3.4	Country	France
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	ADIR
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Institut de Recherches Internationales Servier
B.5.2	Functional name of contact point	Clinical Studies Department
B.5.3	Address:
B.5.3.1	Street Address	50 Rue Carnot
B.5.3.2	Town/ city	Suresnes
B.5.3.3	Post code	92284
B.5.3.4	Country	France
B.5.4	Telephone number	+33 155 7243 66
B.5.5	Fax number	+33 155 7254 12
B.5.6	E-mail	clinicaltrials@servier.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	UCART19
D.3.2	Product code	S68587
D.3.4	Pharmaceutical form	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	CD19CAR/RQR8+_TCRαβ-_T-cells
D.3.9.2	Current sponsor code	S68587
D.3.9.3	Other descriptive name	UCART19
D.3.9.4	EV Substance Code	SUB180949
D.3.10	Strength
D.3.10.1	Concentration unit	Other
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	6.10^5 to 2.10^7
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)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Yes
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	Yes
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	Yes
D.3.11.3.5.1	CAT classification and reference number	Gene therapy medicinal product EMA/132648/2014
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	Yes
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

Patients with relapsed or refractory CD19 positive B-cell acute lymphoblastic leukaemia (B-ALL).

E.1.1.1

Medical condition in easily understood language

Patients with B-cell acute lymphoblastic leukaemia (B-ALL) that have relapsed or for whom previous treatments have not worked.

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	10060390
E.1.2	Term	Leukaemia lymphoblastic acute
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

To evaluate the safety and tolerability of ascending doses of UCART19 given as a single infusion in patients with relapsed/refractory (R/R) acute lymphoblastic leukaemia (ALL) and to determine the maximum tolerated dose (MTD).

E.2.2

Secondary objectives of the trial

To assess the anti-leukaemic activity specifically
- rate of objective response at Day 28, Day 84 and overall response
- duration of response, time to response, disease-specific survival and progression-free survival.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female participant
2. Age ≥ 16 years
3. Patient with relapsed or refractory CD19 positive B-acute lymphoblastic leukaemia (B-ALL).
4. Estimated life expectancy ≥ 12 weeks (according to investigator’s judgement).
5. Eastern Cooperative Oncology Group (ECOG) performance status < 2
6. Adequate organ functions including renal and hepatic function based on the last assessment performed within the Screening Period, defined as:
- creatinine clearance ≥ 30 mL/min (assessed as GFR using the Cockcroft & Gault formula)
- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) < 3 x ULN (upper limit of normal)
- Total bilirubin < 1.5 x ULN (Except Gilbert’s Syndrome confirmed by UGT1A1 gene mutation)
7. Women of childbearing potential must have been tested negative in a serum pregnancy test within 7 days prior to inclusion.
8. Written informed consent obtained prior any study-specific procedure.

E.4

Principal exclusion criteria

10. Women who are lactating.
35. Patients unwilling to undergo a safety follow-up for 15 years
11. Foreseeable poor compliance to the study procedures.
12. Previous treatment with investigational gene or cell therapy medicine products.
13. Use of other investigational products or other anti-leukaemic therapy within 5 half-lives or within 14 days prior to UCART19 administration, whichever is a shorter duration, participation in non-interventional registries or epidemiological studies is allowed.
14. CD19 negative B-cell leukaemia.
16. Burkitt cell (L3 ALL) or mixed lineage acute leukaemia.
36. Clinically suspected extra-medullary involvement.
19. Active CNS leukaemia.
20. Clinically active significant CNS dysfunction.
37. Previous severe neurological toxicity related to blinatumomab.
18. Radioimmunotherapy, radiotherapy, within 8 weeks (except prophylaxis of CNS involvement) before Inclusion.
21. Autologous HSCT within 6 weeks or allogeneic HSCT within 3 months prior Screening.
22. Use of rituximab and other anti CD 20 antibodies known to have the same epitope as rituximab or anti CD20 for which the epitope is unknown within 6 months prior to Screening.
23. Presence of donor-specific anti-HLA antibodies.
24. Active acute or chronic GvHD requiring therapy.
25. Patient with autoimmune disease treated with immunosuppressive agents, e.g. corticosteroids > 1 mg/kg, within 5 days prior to administration of UCART19. Infliximab must be stopped at least 45 days prior to administration of UCART19.
26. A known hypersensitivity to any of the test materials or related compounds including murine and bovine products.
27. Any known uncontrolled cardiovascular disease or any of the following in the previous 6 months before Inclusion: ventricular or atrial dysrhythmia ≥ grade 2, bradycardia ≥ grade 2, myocardial infarction, severe/unstable angina, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, pulmonary embolism, deep vein thrombosis, hypertension not adequately controlled by standard medications. In addition, left ventricular ejection fraction (LVEF) < 45% assessed by echocardiography or Multi Gated Acquisition Scan (MUGA) assessed at Screening.
28. History of hypertension crisis or hypertensive encephalopathy within 3 months prior to Screening.
29. Active bacterial, fungal, protozoal or viral infection not controlled by adequate treatment, at Inclusion, and presence of positive blood cultures within 7 days before Inclusion
30. Any major surgery within 3 months prior to Screening.
31. Abnormal findings during the Screening period, any other medical condition(s) or laboratory findings that, in the opinion of the investigator, might jeopardize the patient’s safety.
32. Any planned medical/surgical treatment that might interfere with the ability to comply with the study requirements.
33. Evidence of another malignancy within 2 years prior to Screening (except in situ basal or squamous cervix or skin cell carcinoma).
34. Any mental condition rendering the patient unable to understand the nature, scope and possible consequences of the study, and/or evidence of an uncooperative attitude.
38. Patients tested positive for human immunodeficiency virus (HIV) and/or human T-lymphotropic virus (HTLV), at Inclusion

E.5 End points

E.5.1

Primary end point(s)

DLT at Day 28 post UCART19 infusion and AE throughout the study

E.5.1.1

Timepoint(s) of evaluation of this end point

Evaluation of DLTs at Day 28

E.5.2

Secondary end point(s)

To assess the anti-leukaemic activity with:
- Response at D28, D84 and overall assessed by morphologic assessment of bone marrow, blood, lymph nodes (if applicable or available)
- duration of response, time to response, disease-specific survival and progression-free survival.

E.5.2.1

Timepoint(s) of evaluation of this end point

Throughout 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

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Analysis of safety and/or efficacy biomarkers

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

Yes

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)

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

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

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

France

United Kingdom

United States

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

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

Yes

F.1.1

Number of subjects for this age range:

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)

Yes

F.1.1.6.1

Number of subjects for this age range:

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

Yes

F.3.3.7.1

Details of other specific vulnerable populations

minors > = 16 years old

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)

After the discontinuation of the study, the participant will access to an appropriate medical care by his doctor.
After completion of EOS visit/WD, consenting patients will transition to a long term follow-up study (under a separate protocol) and will be followed-up for up to 15 years. The patient’s participation in a long term follow-up study is a requirement of the regulatory authorities in the follow-up of any patient having received a gene therapy treatment.

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

2017-10-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-04-26

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-07-28

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