Clinical Trials Register

Summary
EudraCT Number:	2019-003038-17
Sponsor's Protocol Code Number:	CART19-BE-02
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-11-25
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

Spain - AEMPS

A.2

EudraCT number

2019-003038-17

A.3

Full title of the trial

Phase 2 study of the infusion of differentiated autologous T-cells from peripheral blood, expanded and transduced with a lentivirus to express a chimeric antigen receptor with anti-CD19 specificity (A3B1) conjugated with the co-stimulatory regions 4-1BB and CD3z (ARI-0001 cells) in patients with CD19+ acute lymphoid leukemia resistant or refractory to therapy.

Estudio fase 2 de la infusión de linfocitos T diferenciados autólogos de sangre periférica expandidos y transducidos con un lentivirus para expresar un receptor antigénico quimérico con especificidad anti-CD19 (A3B1) conjugado con las regiones coestimuladoras 4-1BB y CD3z (células ARI-0001) en pacientes con leucemia linfoblástica aguda CD19+ resistente o refractaria a tratamiento

A.3.1

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

Phase 2 study of the infusion of ARI-0001 cells in patients with CD19 + acute lymphoid leukemia resistant or refractory to therapy.

Estudio fase 2 de la infusión de células ARI-0001 en pacientes con leucemia linfoblástica aguda CD19+ resistente o refractaria a tratamiento.

A.4.1

Sponsor's protocol code number

CART19-BE-02

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 d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
B.1.3.4	Country	Spain
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	Instituto de Salud Carlos III
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	CTU Clínic-FCRB
B.5.2	Functional name of contact point	Sara Varea
B.5.3	Address:
B.5.3.1	Street Address	Calle Casanova 150
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08036
B.5.3.4	Country	Spain
B.5.4	Telephone number	+349322754003343
B.5.5	Fax number	+34932279877
B.5.6	E-mail	svarea@clinic.cat

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	ARI-0001 Cells
D.3.4	Pharmaceutical form	Solution for injection
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	Células ARI0001
D.3.9.2	Current sponsor code	ARI-0001
D.3.9.3	Other descriptive name	PEI 16-187
D.3.10	Strength
D.3.10.1	Concentration unit	Other
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	100000 to 3000000
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	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

CD19+ acute lymphoid leukemia resistant or refractory to treatment

Leucemia linfoblástica aguda CD19+ resistente o refractaria a tratamiento

E.1.1.1

Medical condition in easily understood language

Adult acute lymphoid leukemia resistant or refractory

Leucemia linfoblástica aguda en adultos resistente o refractaria

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	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10060555
E.1.2	Term	Acute lymphoid leukemia
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 assess the efficacy (in terms of response rate and duration) of the infusion of ARI-0001 cells (Adult differentiated autologous T-cells from peripheral blood, expanded and transducted with a lentivirus to express a chimeric antigen receptor with anti-CD19 specificity [A3B1] conjugated to the 4-aBB and CD3z co-stimulatory regions) in patients with resistant or refractory CD19+ acute lymphoid leukemia

Evaluar la eficacia (tasa de respuesta y duración de esta) de la infusión de células ARI-0001 (linfocitos T diferenciadas adultas autólogas de sangre periférica expandidas y transducidas con un lentivirus para expresar un receptor antigénico quimérico con especificidad anti-CD19 [A3B1] conjugado con las regiones coestimuladoras 4-1BB y CD3z) en pacientes con leucemia linfoblástica aguda CD19+ resistente o refractaria

E.2.2

Secondary objectives of the trial

• Assess adverse events occurring at 3 months and per year
• To assess overall survival after infusion of ARI-0001
• To evaluate the duration of ARI-0001 cells in peripheral blood and bone marrow after administration

• Evaluar los acontecimientos adversos ocurridos a los 3 meses y al año
• Evaluar la supervivencia global tras la infusión de ARI-0001
• Evaluar la duración de las células ARI-0001 en sangre periférica y médula ósea tras su administración

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Diagnoses of CD19+ acute lymphoid leukemia, with a life expectancy of less than 2 years that meet the following conditions:
 Relapsed/refractory not candidate for transplantation (due to associated diseases or absence of donor)
 in allogenic post-transplant relapse.
2. Measurable disease understood as the presence of measurable residual disease by flow cytometry in bone marrow or peripheral blood
3. Age less than 70 years (from 18 to 70).
4. ECOG functional status from 0 to 2
5. Life expectancy of at least 3 months.
6. Adequate venous access to perform a lymphapheresis. Absence of contraindications for it.
7. Signature of informed consent (patient or legal guardian).

1. Diagnóstico de leucemia linfoblástica aguda CD19+ del adulto, con un pronóstico vital inferior a 2 años por cumplir una de las siguientes condiciones:
o Recaída/refractaria no candidato a trasplante (por enfermedad refractaria o ausencia de donante)
o Recaída tras trasplante alogénico
2. Enfermedad medible, entendido como tal la presencia de, al menos, enfermedad medible residual por citometría de flujo en médula ósea o sangre periférica en el momento de la inclusión.
3. Edad superior a 18 e inferior a 70 años
4. Estado funcional ECOG de 0-2
5. Esperanza de vida superior a 3 meses
6. Acceso venoso adecuado para realizar una linfoaféresis. Ausencia de contraindicaciones para la misma
7. Firma del consentimiento informado.

E.4

Principal exclusion criteria

1. Treatment with any experimental or non-marketed substance within four weeks prior to recruitment, or actively participating in another therapeutic trial.
2. Previous treatment with CART therapy (commercial or experimental)
3. Diagnosis of another neoplasm, past or present. Patients may be included in complete remission for more than 3 years, or have a history of non-melanoma skin cancer or in-situ carcinoma resected completely.
4. Relief of central nervous system (CNS-3) at the time of inclusion. Inclusion will be permitted in patients with a lower grade (CNS-2) or CNS-3 who have responded to intrathecal chemotherapy.
5. Isolated extramedullary involvement (i.e. in the absence of minimal residual disease in peripheral blood, or bone marrow)
6. Early relapse after transplantation (less than 3 months for mononuclear cell apheresis, less than 6 months for infusion of ARI-0001)
7. Active immunosuppressive treatment for graft-versus-host disease and other diseases. The use of corticosteroids to control leukaemia at the time of inclusion should be limited as much as possible and should be discontinued prior to infusion of ARI-0001 cells.
8. Active infection requiring systemic medical treatment such as chronic kidney infection, chronic lung infection or tuberculosis.
9. HIV infection.
10. Positive serology for hepatitis B, defined as a positive test for HBsAg. In addition, if the patient is HBsAg negative but has anti-HBc antibodies it will be necessary to perform a DNA test of the hepatitis B virus, and if the result is positive the patient will be excluded
11. Positive serology for hepatitis C, defined as a positive test for anti-VHC antibodies confirmed by RIBA
12. Concurrent uncontrolled medical illnesses including cardiac, renal, hepatic, gastrointestinal, endocrine, pulmonary, neurological or psychiatric diseases that in the opinion of the investigator are potential risk factors to the patient.
13. Severe organ involvement, defined as cardiac ejection fraction <40%; DLCO <40%; calculated glomerular filtrate <30 ml/min; or bilirubin > 3 times the upper limit of normality (unless Gilbert syndrome).
14. Pregnant or lactating women. Woman of childbearing potential should have a negative pregnancy test in the screening phase.
15. Women of childbearing potential, including those whose last menstrual cycle was in the year prior to screening, who are unable or unwilling to use highly effective contraceptive methods* from the start of the study to the completion of the study.
16. Men who cannot or do not wish to use highly effective contraceptive methods* from the beginning of the study until the end of the study.

* Hormonal contraceptives, intrauterine device, intrauterine systems of hormonal release, sexual abstinence, vasectomy of the partner or bilateral tubal occlusion

1. Tratamiento con cualquier sustancia experimental o no comercializada en las cuatro semanas previas al reclutamiento
2. Tratamiento previo con CART (comercial o experimental)
3. Diagnóstico de otra neoplasia, pasada o actual. Podrán incluirse pacientes que lleven en remisión completa más de 3 años, o con antecedentes de cáncer cutáneo no melanoma o carcinoma in situ resecado completamente.
4. Afectación franca del sistema nervioso central (SNC-3) en el momento de la inclusión. Se permitirá la inclusión con pacientes con un grado menor (SNC-2) o con SNC-3 que haya respondido a quimioterapia intratecal.
5. Afectación extramedular aislada (es decir, en ausencia de enfermedad medible residual en sangre periférica o médula ósea)
6. En caso de recaída tras trasplante alogénico, deberán haber pasado al menos 3 meses desde el trasplante para la aféresis de células mononucleadas y al menos 6 meses desde el trasplante para la infusión de ARI-0001.
7. Tratamiento inmunosupresor activo por enfermedad injerto contra receptor y otras enfermedades. Se limitará en lo posible el uso de corticoides para el control de la leucemia en el momento de la inclusión, y deberán suspenderse antes de la infusión de las células ARI-0001.
8. Infección activa que requiere tratamiento médico sistémico como, por ejemplo, infección renal crónica, infección pulmonar crónica o tuberculosis.
9. Infección por VIH.
10. Serología positiva para hepatitis B, definida como prueba positiva para HBsAg. Además, si el paciente es HBsAg negativo, pero tiene anticuerpos anti-HBc será necesario realizar un test de ADN del virus de la hepatitis B, y si el resultado es positivo el paciente será excluido.
11. Serología positiva para hepatitis C, definida como prueba positiva para anticuerpos anti-VHC que se confirma mediante RIBA.
12. Enfermedades médicas concurrentes e incontroladas incluyendo enfermedades cardiacas, renales, hepáticas, gastrointestinales, endocrinas, pulmonares, neurológicas o psiquiátricas que en opinión del investigador supongan un riesgo para el paciente.
13. Afectación orgánica grave, definida como fracción de eyección cardíaca <40%; DLCO <40%; filtrado glomerular calculado <30 ml/min; o bilirrubina > 3 veces el límite superior de la normalidad (a menos que se deba a un síndrome de Gilbert).
14. Mujeres embarazadas o lactando. Las mujeres en edad fértil deberán tener una prueba de embarazo negativa en la fase de cribado.
15. Mujeres en edad fértil, incluyendo aquellas cuyo último ciclo menstrual fue en el año previo al cribado, que no puedan o no deseen emplear métodos anticonceptivos altamente eficaces* desde el inicio del estudio hasta la finalización de este.
16. Varones que no puedan o no deseen emplear métodos anticonceptivos altamente eficaces* desde el inicio del estudio hasta la finalización de este.

* anticonceptivos hormonales, dispositivo intrauterino, sistemas intrauterinos de liberación hormonal, abstinencia sexual, vasectomía de la pareja o oclusión tubárica bilateral

E.5 End points

E.5.1

Primary end point(s)

Response rate with measurable residual disease negative by multiparametric flow cytometry 28 days after infusion of ARI-0001 cells

Tasa de respuestas con enfermedad medible residual negativa por citometría de flujo multiparamétrica a los 28 días de la infusión de las células ARI-0001

E.5.1.1

Timepoint(s) of evaluation of this end point

28 days after infusion of ARI-0001 cells.

a los 28 días de la infusión de las células ARI-0001

E.5.2

Secondary end point(s)

1. Duration of response
2. Progression-free survival
3. Overall Survival (OS)
4. Assessment of ARI-0001 cell toxicity considering special interest in the following adverse events: CRS (cytokine release syndrome), encephalopathy associated with CARs (ICANS) and cerebral edema. Mortality related to study procedures and adverse events grade 3-4
5. In vivo survival of ARI-0001 cells in peripheral blood and bone marrow, to be determined by flow cytometry and quantitative transgene PCR

1. Duración de la respuesta
2. Supervivencia libre de progresión
3. Supervivencia global (SG)
4. Toxicidad de las células ARI-0001, considerando con efectos adversos de especial interés el síndrome de liberación de citocinas (SLC), la encefalopatía asociada a CARs (ICANS) y el edema cerebral. Se evaluará la mortalidad relacionada con el procedimiento y los acontecimientos adversos grado 3-4.
5. Supervivencia in vivo de las células ARI-0001 en sangre periférica y médula ósea, lo que se determinará mediante citometría de flujo y PCR cuantitativa del transgén.

E.5.2.1

Timepoint(s) of evaluation of this end point

1. At 36 months
2. At 6 months and 1 year of the infusion and after the signature of informed consent.
3. At 1 year of the infusion and after the informed consent form signature.
4. Will be evaluated at month 3 and year 1. Intensity will be assessed using CTCAE version 5.0 scale. To evaluate CRS and neurotoxicity ASTCT criteria will be used.
5. Screening, day +3, day +7, day +14, day +21, day +28, day +35, day +42, day +56, day +70, day +84, day +100, month 4, month 5 and month 6 and thereafter quarterly up to 2 years of infusion.

1. A los 36 meses
2. A los 6 meses y al año de la infusión y de la firma del consentimiento informado
3. Al año de la infusión y de la firma del consentimiento informado
4. A los 3 meses y al año según criterios CTC versión 5.0. Para el SLC y la neurotoxicidad se empleará la clasificación de ASTCT
5. en cribado, día +3, día +7, día +14, día +21, día +28, día +35, día +42, día +56, día +70, día +84, día +100, mes 4, mes 5 y mes 6 y posteriormente trimestralmente hasta cumplir 2 años de la infusión

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

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

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

Última visita del último paciente en seguimiento

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

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.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

Ninguno

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

2020-09-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-09-16

P. End of Trial
P.	End of Trial Status	Ongoing

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