Clinical Trials Register

Summary
EudraCT Number:	2014-000584-41
Sponsor's Protocol Code Number:	BP-004
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2017-03-21
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

Spain - AEMPS

A.2

EudraCT number

2014-000584-41

A.3

Full title of the trial

Phase II extension study of CaspaCIDe T cells (BPX-501) from an HLA-partially matched family donor after negative selection of TCR αβ+T cells in pediatric patients affected by hematological disorders

Estudio de extensión fase II de linfocitos T con CaspaCide (BPX-501) de un donante emparentado parcialmente compatible respecto al HLA tras selección negativa de linfocitos T TCR αβ+ en pacientes pediátricos afectados de trastornos hematológicos

A.3.1

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

A.3.2

Name or abbreviated title of the trial where available

CaspaCide TCR αβ haplo HSCT

A.4.1

Sponsor's protocol code number

BP-004

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02065869

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	Bellicum Pharmaceuticals, Inc.
B.1.3.4	Country	United States
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	Bellicum Pharmaceuticals
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	Leon Research S.L.
B.5.2	Functional name of contact point	Rocío García Cañamaque
B.5.3	Address:
B.5.3.1	Street Address	Avda Ordoño II, 37-2ºDcha
B.5.3.2	Town/ city	Leon
B.5.3.3	Post code	24001
B.5.3.4	Country	Spain
B.5.4	Telephone number	0034987261 064
B.5.5	Fax number	0034987216 243
B.5.6	E-mail	rgcanamaque@leonresearch.es

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	Yes
D.2.5.1	Orphan drug designation number	EU/3/16/1674
D.3 Description of the IMP
D.3.1	Product name	BPX-501 cells
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	Yes
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	rivogenleucleucel
D.3.9.1	CAS number	N/A
D.3.9.2	Current sponsor code	BPX-501
D.3.9.3	Other descriptive name	BPX-501
D.3.9.4	EV Substance Code	SUB171410
D.3.10	Strength
D.3.10.1	Concentration unit	Other
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1000000
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	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.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	Yes
D.2.5.1	Orphan drug designation number	EU/3/16/1666
D.3 Description of the IMP
D.3.1	Product name	AP1903
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	Yes
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	Rimiducid
D.3.9.1	CAS number	195514-63-7
D.3.9.2	Current sponsor code	AP1903
D.3.9.3	Other descriptive name	AP1903
D.3.9.4	EV Substance Code	SUB171411
D.3.10	Strength
D.3.10.1	Concentration unit	mg/kg milligram(s)/kilogram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.4
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

Hematological disorders (ALL;AML;Non-Hodgkin lymphoma;Myelodysplastic
syndromes;Congenital immune deficiencies;Severe aplastic anemia;Fanconi anemia; Osteopetrosis;Selected cases of hemoglobinopathies)

Trastornos hematológicos (ALL, AML, linfoma no Hodgkin; síndromes mielodisplásicos; inmunodeficiencias congénitas; anemia aplásica severa, anemia de Fanconi; Osteopetrosis; Casos seleccionados de hemoglobinopatías);

E.1.1.1

Medical condition in easily understood language

Hematological disorders

Desórdenes hematológicos

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.1
E.1.2	Level	HLGT
E.1.2	Classification code	10018849
E.1.2	Term	Haematological disorders NEC
E.1.2	System Organ Class	10005329 - Blood and lymphatic system disorders

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

This is a Phase II study to determine whether BPX-501 and rimiducid will improve event free survival – events defined as TRM (or NRM) at 180 days, severe GVHD (acute Grade 2-4 organ or extensive chronic GVHD) and life threatening infections (Grade 4). To evaluate the safety of the infusion of BPX-501 gene modified T cells after mismatched, T depleted allogeneic transplantation. To determine safety by evaluating the overall incidence of GVHD after infusion of AP1903.

Este es un estudio Fase II para determinar si BPX-501 y rimiducid mejorarán la supervivencia libre de acontecimientos, definidos estos como mortalidad relacionada con el trasplante (MRT) (o mortalidad sin recidiva, MSR) a los 180 días, enfermedad del injerto contra el huésped (EICH) grave (EICH aguda del órgano de grado 2-4 o crónica extendida) e infecciones potencialmente mortales (grado 4).Evaluar la seguridad de la infusión de linfocitos T modificados genéticamente BPX-501 tras un alotrasplante con reducción de linfocitos T de donante incompatible. Determinar la seguridad mediante la evaluación de la incidencia global de EICH tras la infusión de AP1903.

E.2.2

Secondary objectives of the trial

1.TRM (non-malignant) or NRM (malignant) at 100 and 180 days
2.Cumulative incidence and severity of acute (grade 2-4) and chronic GvHD at 180 days;
3.Time to resolution of acute GvHD after administration of AP1903
4.Immune reconstitution as determined by T cell subsets at day 180
a.Absolute CD3 count
b.Absolute CD4 count
c.Absolute CD8 count
5.Time to immune reconstitution
6.Disease Free/cGVHD survival at 180 days
7.Disease status of each specific disease indication at 180 days:
-Primary immune disorders as determined by CD3 T cell count >500 cells/ul and lower normal levels of IgA and IgM at 180 days
-Haemoglobinopathies as determined by incidence of RBC transfusion dependence and haemoglobin of >8.5 g/dL at 180 days
-Fanconi Anemia as determined by RBC >3,000,000 cells/ul, neutrophil count determined by 1500 cells/ul and >150,000 platelet counts at 180 days
-Leukemia as determined by PFS at 180 days

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age < 18 years and > 1 month (< 1 month upon approval by Applicant)
2. Life expectancy > 10 weeks
3. Patients deemed clinically eligible for allogeneic stem cell transplantation.
4. Patients may have failed prior allograft
5. Patients with life-threatening hematological malignancies (high-risk ALL in 1st CR, ALL in 2nd, high-risk AML in 1st CR, AML in 2nd CR;
OR
6. Non-malignant disorders deemed curable by allogeneic transplantation:
• primary immune deficiencies,
• severe aplastic anemia not responding to immune suppressive therapy,
• osteopetrosis,
• selected cases of hemoglobinopathies, for example, β0 β0 thalassemia major, sickle cell disease, Diamond- Blackfin
• congenital/hereditary cytopenia, including Fanconi Anemia before any clonal malignant evolution (MDS, AML).
7. Lack of suitable conventional donor (HLA identical sibling or HLA phenotypically identical relative or 10/10 unrelated donor evaluated using high resolution molecular typing) or presence of rapidly progressive disease not permitting time to identify an unrelated donor
8. A minimum genotypic identical match of 5/10 is required.
9. The donor and recipient must be identical, as determined by high resolution typing, on at least one allele of each of the following genetic loci: HLA-A, HLA-B, HLA-Cw, and HLA- DRB1.
10. Lansky/Karnofsky score > 50

1. Edad ≤ 18 años y ≥ 1 mes (< 1 mes tras la aprobación por el solicitante).
2. Esperanza de vida > 10 semanas.
3. Pacientes que se consideren clínicamente aptos para el alotrasplante de células madre.
4. Pacientes con un alotrasplante anterior fallido.
5. Pacientes con neoplasias hematológicas potencialmente mortales (leucemia linfocítica aguda [LLA] de alto riesgo en primera respuesta completa [RC], LLA en segunda RC, leucemia mieloide aguda [LMA] de alto riesgo en primera RC, LMA en segunda RC).
O BIEN
6. Enfermedades benignas que pueden curarse mediante alotrasplante:
• inmunodeficiencias primarias,
• anemia aplásica grave que no responde al tratamiento inmunosupresor,
• osteopetrosis,
• determinados casos de hemoglobinopatías, por ejemplo, talasemia mayor β0/β0, drepanocitemia, anemia de Diamond-Blackfan,
• citopenia congénita/hereditaria, como anemia de Fanconi, antes de una evolución clonal maligna (síndrome mielodisplásico [SMD], LMA).
7. Falta de donante convencional compatible (hermano con sistema HLA idéntico o pariente con sistema HLA idéntico desde el punto de vista fenotípico o donante no emparentado 10/10, evaluado mediante tipificación molecular de alta resolución) o presencia de enfermedad rápidamente progresiva que no ofrece margen para identificar a un donante no emparentado.
8. Se requiere una compatibilidad genotípica idéntica mínima de 5/10.
9. El donante y el receptor deben ser idénticos, según determine la tipificación de alta resolución, en al menos un alelo de cada uno de los siguientes locus genéticos: HLA-A, HLA-B, HLA-Cw y HLA-DRB1.
10. Escala de Lansky/Karnofsky > 50.

E.4

Principal exclusion criteria

1. Greater than ongoing Grade II acute GvHD or chronic extensive GvHD due to a previous allograft at the time of screening
2. Patient receiving an immunosuppressive treatment for GvHD treatment due to a previous allograft at the time of screening
3. Dysfunction of liver (ALT/AST > 5 times normal value, or bilirubin > 3 times normal value), or of renal function (creatinine clearance <30ml/min/1.73m2)
4. Severe cardiovascular disease (arrhythmias requiring chronic treatment, congestive heart failure or left ventricular ejection fraction < 40%)
5. Current active infectious disease (including positive HIV serology or viral RNA)
6. Serious concurrent uncontrolled medical disorder
7. Pregnant or breast feeding female patient

1. EICH aguda en curso de grado mayor de 2 o EICH crónica extendida debida a un alotrasplante previo en el momento de la selección.
2. Paciente que esté recibiendo tratamiento inmunosupresor para tratar la EICH debida a un alotrasplante anterior en el momento de la selección.
3. Disfunción hepática (ALT/AST > 5 veces el valor normal o bilirrubina > 3 veces el valor normal) o renal (aclaramiento de creatinina < 30 ml/min/1,73 m2).
4. Enfermedad cardiovascular grave (arritmias con necesidad de tratamiento crónico, insuficiencia cardíaca congestiva o fracción de eyección del ventrículo izquierdo < 40 %).
5. Enfermedad infecciosa activa actual (lo que incluye pruebas serológicas positivas de VIH o ARN vírico).
6. Trastorno médico grave simultáneo no controlado.
7. Paciente embarazada o lactante.

E.5 End points

E.5.1

Primary end point(s)

1. Cumulative incidence of infectious complications at 180 days
a. Cumulative Incidence of clinically significant viral reactivations at 180 days
b. Cumulative incidence of patients requiring antiviral treatment at 180 days
c. Cumulative incidence of rehospitalizations due to viral infection by day 180
d. Cumulative incidence of bacterial and fungal infections at 180 days
e. Cumulative use of non-prophylactic antibiotic and antifungal use at 180 days

1. Incidencia acumulada de complicaciones infecciosas a los 180 días
a. Incidencia acumulativa de reactivaciones virales clínicamente significativas a los 180 días
b. Incidencia acumulada de pacientes que requieren tratamiento antiviral a los 180 días
c. Incidencia acumulada de rehospitalizaciones por infección viral al día 180
d. Incidencia acumulada de infecciones bacterianas y fúngicas a los 180 días
e. Uso acumulativo de antibióticos y antifúngicos no profilácticos a los 180 días

E.5.1.1

Timepoint(s) of evaluation of this end point

180 days and up to 24 months post transplant

Hasta 180 días u hasta 24 meses después del trasplante

E.5.2

Secondary end point(s)

1.MRT (sin cáncer) o MSR (con cáncer) a los 100 y 180 días.
2.Incidencia acumulada y gravedad de la EICH aguda (grado 2-4) y crónica a los 180 días.
3.Tiempo hasta la resolución de la EICH aguda después de la administración de AP1903.
4.Reconstitución inmunitaria, determinada según los subgrupos de linfocitos T el día 180.
a.Recuento absoluto de CD3
b.Recuento absoluto de CD4
c.Recuento absoluto de CD8
5.Tiempo hasta la reconstitución inmunitaria.
6.Supervivencia libre de enfermedad/EICH crónica a los 180 días.
7.Estado de la enfermedad en función de cada enfermedad específica a los 180 días:
-Enfermedades autoinmunitarias primarias, determinado por un recuento de linfocitos T CD3 > 500 células/μl y niveles inferiores a los normales de IgA e IgM a los 180 días.
-Hemoglobinopatías, determinado por la incidencia de dependencia de transfusiones de eritrocitos y valores de hemoglobina > 8,5 g/dl a los 180 días.
-Anemia de Fanconi, determinado por un recuento de eritrocitos > 3 000 000 células/μl, un recuento de neutrófilos determinado por 1500 células/μl y recuentos de plaquetas > 150 000 a los 180 días.
-Leucemia, determinado por la SLP a los 180 días.

E.5.2.1

Timepoint(s) of evaluation of this end point

180 days

180 dias

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.8.3

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

E.8.6.2

Trial being conducted completely outside of the EEA

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 study will be closed after evaluation of overall survival and disease free survival for all patients enrolled at 24 months after transplantation. The 15 year follow up data will be collected separately from the clinical trial data.

El estudio se cerrará tras la evaluación de la supervivencia global y la supervivencia libre de enfermedad para todos los pacientes incluidos a los 24 meses después del trasplante. Los datos de seguimiento de 15 años se recogerán por separado de los datos de los ensayos clínicos.

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

Yes

F.1.1

Number of subjects for this age range:

170

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)

Yes

F.1.2.1

Number of subjects for this age range:

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

Yes

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Children

Niños

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

175

F.4.2.2

In the whole clinical trial

175

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

2017-06-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-05-11

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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