Clinical Trials Register

Summary
EudraCT Number:	2015-004293-15
Sponsor's Protocol Code Number:	UCART19_02(CL1-68587-001)
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:	2017-04-06
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

2015-004293-15

A.3

Full title of the trial

A phase 1, open label, non-comparative, study to evaluate the safety and the ability of UCART19 to induce molecular remission in paediatric patients with relapsed /refractory B-cell acute lymphoblastic leukaemia

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 efficacy of UCART19 in children with B cell lymphoblastic leukaemia that has relapsed or not responded to other treatments

A.3.2

Name or abbreviated title of the trial where available

UCART19_PALL

A.4.1

Sponsor's protocol code number

UCART19_02(CL1-68587-001)

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02808442

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	+3315572 4366
B.5.5	Fax number	+3315572 5412
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	2x10^7
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

Paediatric relapsed or refractory CD19-positive B-cell acute lymphoblastic leukemia

E.1.1.1

Medical condition in easily understood language

Children with B-cell lymphoblastic leukaemia that has relapsed or for whom previous treatment has 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

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the safety of UCART19 in paediatric patients with relapsed or refractory B-ALL.

E.2.2

Secondary objectives of the trial

To determine the ability of UCART19 to achieve molecular remission at D28 after the first UCART19 infusion

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female patients

2a. Age ranging from birth to <18 years

3a. Patients with relapsed or refractory CD19-positive B-acute lymphoblastic leukemia (B-ALL) (National Comprehensive Cancer Network (NCCN), 2017),
- Morphologically confirmed with ≥ 5% leukemic blasts in the bone marrow
- or presenting a quantifiable MRD load of 1x10-3 (by multiparameter flow cytometry and/or quantitative polymerase chain reaction) at the end of the last induction treatment
- Who have exhausted alternative treatment options

Relapsed disease is defined as:
- second or subsequent bone marrow relapse or,
- any bone marrow relapse after allo-SCT.

Refractory disease is defined by not achieving an initial complete response (CR) after 2 cycles of a standard chemotherapy regimen (primary refractory). Subjects who were refractory to subsequent chemotherapy regimens after an initial remission were considered chemo-refractory

Patients with Philadelphia chromosome positive (Ph+) ALL are eligible if they are intolerant to or have failed 2 lines of tyrosine kinase inhibitor therapy (TKI), or if TKI therapy is contraindicated.

4. Estimated life expectancy ≥ 12 weeks (according to investigator’s judgement)

6a. Lansky (age < 16 years at the time of assent/consent) or Karnofsky (age ≥ 16 years at the time of assent/consent) performance status ≥ 50

35. Adequate organ function defined as:
a. Creatinine clearance ≥ 30 mL/min (as calculated using the method standard for the institution). In equivocal cases, a 24-hour urine collection test can be used to estimate the creatinine clearance more accurately.
b. Serum ALT/AST ≤ 3 x ULN
c. Total bilirubin ≤ 1.5 x ULN (unless the patient has a history of Gilbert’s Syndrome, in which case, total bilirubin must be ≤ 2.5 ULN)
d. Left Ventricular Ejection Fraction (LVEF) ≥ 45% and no clinically significant ECG findings

44. Availability of a donor for potential allo-HSCT in the event of persistent marrow aplasia without evidence of residual leukemia

7. Written informed consent from parent(s) or legal representative and or written assent from patient when applicable obtained prior any study-specific procedure of the protocol

60 No detectable anti-CD19 CAR transgene copies in blood, by qPCR, in patients previously treated with CAR-T cell therapy.

E.4

Principal exclusion criteria

34. Patients unwilling to undergo a safety follow-up for 15 years

9. Foreseeable poor compliance to the study procedures

10a. Previous treatment with gene or gene-modified cell therapy medicine products (except autologous CAR-T cell therapy).

11a. Use of previous anti-leukemic therapy (including approved therapies and other investigational products) within 5 half-lives prior to UCART 19 administration. Inotuzumab ozogamicin must be stopped at least 28 days prior to UCART19 administration. Participation in non-interventional registries or epidemiological studies is allowed

12. CD19-negative B-cell leukaemia

15. Burkitt cell acute leukaemia (L3 ALL)

45a. Clinically suspected extramedullary involvement (except CNS and isolated skin involvement)

37a. Evidence of disease progression after cytoreduction, if administered (e.g., significant increase in peripheral blast count)

17a. Active CNS leukemia (CNS-3)

28. Clinically active significant CNS dysfunction

29a. Known history of irreversible severe neurological toxicity related to previous antileukemic treatment leading to organic central nervous system lesions

30. Primary immunodeficiency or bone marrow failure syndrome

14. Weight< 8.8 kgs

16b. Allogeneic HSCT within 3 months prior to screening; any donor lymphocyte infusions must be completed > 6 weeks prior to Screening

31. Radioimmunotherapy, radiotherapy, within 8 weeks (except prophylaxis of CNS involvement) prior to Inclusion

18. Use of rituximab and other anti CD20 antibodies known to have the same epitope as rituximab or anti CD20 for which the epitope is unknown within 3 months prior to UCART19 infusion

19. Presence of donor-specific anti-HLA antibodies directed against UCART19

20b. Active, acute or chronic graft versus host disease (GvHD) requiring systemic treatment within 4 weeks of UCART19 infusion

21a. Patients with autoimmune disease requiring systemic immunosuppression that cannot be stopped

22. A known hypersensitivity to any of the test materials or related compounds including murine and bovine products

24. Active systemic bacterial, fungal, protozoal or viral infection not controlled by adequate treatment, and presence of positive blood cultures within 7 days before Inclusion

33. Patients tested positive for human immunodeficiency virus (HIV) and/or or human T-lymphotropic
virus (HTLV)

25a. 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

26. Any planned medical/surgical treatment that might interfere with the ability to comply with the study requirements

27a. Risk of pregnancy or non compliance with contraception (if applicable) .Girls of childbearing potential must have been tested negative in a pregnancy test within 7 days prior to inclusion. Within the frame of this study, female participants of childbearing potential and male participants with partners of childbearing potential must use an effective method of birth control, as well as their partners, from the screening period up to 12 months after the last dose of Investigational Medicinal Product (IMP) administration.

36. Any known contraindication to any of the drugs that will be used for the lymphodepletion (fludarabine, cyclophosphamide) or other drugs proposed for safety issues (including tocilizumab, rituximab).

59. Corticosteriods (topical, inhaled or nasal corticosteroids are permitted) within 5 days before administration of UCART19

61. Known history of CRS grade 4 related to previous CAR-T cell therapy.

ELIGIBILITY CRITERIA FOR UCART19 ADMINISTRATION (WITHIN 24 HOURS PRIOR TO INFUSION)

38a. Adequate organ functions including renal and hepatic function based on the last assessment performed within the lymphodepletion period, defined as:
- Creatinine clearance ≥ 30 mL/min (as calculated using the method standard for the institution. In equivocal cases, a 24-hour urine collection test can be used to estimate the creatinine clearance more accurately.
- Serum ALT/AST ≤ 3 x ULN
- Total bilirubin ≤ 1.5 x ULN (unless the patient has a history of Gilbert’s Syndrome, in which case, total bilirubin must be ≤ 2.5 ULN)

39. No clinical signs of cardiac failure

40. No active systemic bacterial, fungal, protozoal or viral infection not controlled by adequate treatment, and absence of positive blood cultures within 7 days before UCART19 administration

41a. No evidence of disease progression after lymphodepletion (e.g., significant increase in peripheral blast count)

42. Baseline oxygen saturation level > 92% in room air

43a. No Abnormal findings during the lymphodepletion period, neither any other medical condition(s) or laboratory findings that, in the opinion of the investigator, might jeopardize the patient’s safety

E.5 End points

E.5.1

Primary end point(s)

- Adverse events graded according to the National Cancer Institute Common Toxicity Criteria for Adverse Event (NCI-CTCAE) version V4.3 June 14, 2010, throughout the study, except CRS, TLS and acute GvHD events that will be graded according to the grading systems of Lee, Cairo and Harris, respectively ;

- Clinical examination and cardiac evaluation (ECG, echocardiography) ;

- Vital signs (blood pressure, heart rate, body temperature, respiratory rate, oxygen saturation level),

- Laboratory data assessments: haematology, biochemistry, coagulation parameters ;

- Viral / bacterial / protozoal infection monitoring,

E.5.1.1

Timepoint(s) of evaluation of this end point

safety will be evaluated on an on-going basis throughout the trial

E.5.2

Secondary end point(s)

1- The activity of UCART19 will include a careful examination and valuation of the blood and the marrow if indicated.
2- MRD evaluation by multiparameter flow cytometry and/or qPCR

E.5.2.1

Timepoint(s) of evaluation of this end point

1: Day 28 after the first UCART19 infusion
2: During the screening period, at D-1, (D14), D28, D56, D84, M4, M6, M9, M12

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

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.8.5

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

France

Spain

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)

Yes

F.1.1.4.1

Number of subjects for this age range:

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

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)

F.1.3

Elderly (>=65 years)

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

minors subjects

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)

After the discontinuation of the study, the participant will access to an appropriate medical care by his doctor.
After completion of the study or at time of premature discontinuation, patients will be rolled-over to a separate long-term follow-up study and will be followed for 15 years.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2017-06-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-07-31

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-11-04

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