Clinical Trials Register

Summary
EudraCT Number:	2014-000584-41
Sponsor's Protocol Code Number:	BP-004
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-04-15
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2014-000584-41

A.3

Full title of the trial

Phase I/II study of CaspaCide T cells from an HLA-partially matched family donor after negative selection of TCR αβ+ T cells in pediatric patients affected by hematological disorders

Studio di fase I/II sull’impiego di cellule T CaspaCide derivate da donatore familiare parzialmente compatibile sottoposto a procedura di T deplezione αβ, in pazienti pediatrici affetti da disordini ematologici dopo trapianto aploidentico.

A.3.1

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

Phase I/II study of CaspaCide T cells from an HLA-partially matched family donor after negative selection of TCR αβ+ T cells in pediatric patients affected by hematological disorders

Studio di fase I/II volto alla valutazione della sicurezza e della efficacia della somministrazione di cellule T BPX-501 dopo trapianto aploidentico da donatore familiare parzialmente compatibile sottoposto a procedura di T deplezione αβ in pazienti pediatrici.

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	Bellicum Pharmaceuticals, Inc.
B.5.2	Functional name of contact point	Martha French
B.5.3	Address:
B.5.3.1	Street Address	2130 W. Holcombe Blvd. Suite 850
B.5.3.2	Town/ city	Houston
B.5.3.3	Post code	TX 77030
B.5.3.4	Country	United States
B.5.6	E-mail	mfrench@bellicum.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	BPX-501 cells
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
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.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	No
D.2.5.1	Orphan drug designation number
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	No
D.3.7	Routes of administration for this IMP	Intravenous use
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)

Patologie neoplastiche ematologiche

E.1.1.1

Medical condition in easily understood language

Hematological disorders

Patologie neoplastiche ematologiche

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	16.1
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 Phase1 study evaluating the safety and feasibility of BPX-501 T cells infused after partially mismatched, related, T cell-depleted HSCT in pediatric patients. The purpose of this clinical trial is to determine whether BPX-501 infusion can enhance immune reconstitution and retain the graft-versus-leukemia (GvL) effect, with the potential for reducing the severity and duration of severe acute GvHD. The trial will evaluate the treatment of GvHD by the infusion of dimerizer drug (AP1903) in those subjects who present with Grade III-IV acute GVHD, as well as those subjects with Grade II gut/liver GvHD or with Grade I/II GvHD (skin only) who progress or do not respond within 7 days to standard of care treatment.

Valutare la sicurezza dell’infusione di BPX-501 in 3 differenti escalating doses (2.5 x 10^5, 5 x 10^5, 1 x 10^6 cellule/kg di peso ideale del ricevente), somministrate in giornata + 10 dopo il trapianto aploidentico da donatore familiare parzialmente compatibile (HSCT);Valutare la sicurezza dell’infusione dell’agente dimerizzante, AP1903, nei soggetti che abbiano ricevuto BPX-501 e abbiano sviluppato GvHD acuta di grado III/IV o GvHD di grado II con interessamento intestinale/epatico o GvHD di grado I/II (ad esclusivo coinvolgimento cutaneo) che progrediscano o non rispondano entro 7 giorni al trattamento standard;Determinare gli effetti sulla ricostituzione immunologica post trapianto in ciascuna delle 3 coorti

E.2.2

Secondary objectives of the trial

Disease-free survival rates after transplantation;Cumulative incidence of relapse;
Cumulative incidence of neutrophil and platelet engraftment; Kinetics of donor cell engraftment; Cumulative incidence of both primary and secondary graft failure; Cumulative incidence and severity of acute and chronic GvHD;Time to resolution of acute GVHD after administration of AP1903; Rates of infectious complications, with particular regards to HCMV reactivation or other
viral or invasive fungal infections. In detail, we will estimate the rate of patients
experiencing any HCMV reactivation, as well as that of patients who will need antiviral treatment because of a viral load (measured as HCMV DNA in blood) greater than 5,000copies/mL;Duration of hospitalization;T-cell immune reconstitution (as measured by time to reach an alpha/beta positive CD3+
cell count greater than 200/μl; CD8+ cell count greater than 200/μl;diversity of T cell receptor repertoire,and response to polyclonal activators.

Incidenza cumulativa della mortalità non correlata alla recidiva della patologia di base (NRM) al giorno 180 e ad un anno; Probabilità di sopravvivenza libera da malattia post trapianto; Incidenza cumulativa di recidiva; Incidenza cumulativa dell’attecchimento di neutrofili e piastrine; Cinetica dell’attecchimento delle cellule del donatore; Incidenza cumulativa di graft failure primaria e secondaria; Incidenza cumulativa e severità della GvHD acuta e cronica;Numero di giorni necessari per la risoluzione della GvHD acuta dopo somministrazione di AP1903;Incidenza di complicanze infettive, in particolare verrà valutata la percentuale di pazienti che presenteranno riattivazione da HCMV, così come quelli che necessiteranno di trattamento farmacologico per la presenza di un viral load (HCMV DNA si sangue) superiore a 5000 copie/ml;
Ricostituzione immunologica del comparto T- cellulare ...

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Males or females;Age < 21 years and > 3 months; Life expectancy > 10 weeks;
Deemed eligible for allogeneic stem cell transplantation; Children with life-threatening hematological malignancies (high-risk ALL in 1st CR,ALL in 2nd or subsequent CR, high-risk AML in 1st CR, AML in 2nd or subsequentCR,myelodysplastic syndromes, non-Hodgkin lymphomas in 2nd or subsequent CR);Non-malignant disorders amenable to be cured by an allograft:
a. primary immune deficiencies,b. severe aplastic anemia not responding to immune suppressive therapy,c. osteopetrosis,d. selected cases of hemoglobinopathies ande. congenital/hereditary cytopenia, including Fanconi Anemia before any clonalmalignant evolution (MDS, AML);Lack of suitable conventional donor (HLA identical sibling or HLA phenotipically identical relative or 9-10/10 unrelated donor evaluated using high resolution molecular typing) or presence of rapidly progressive disease not permitting time to identify an unrelated donor; A minimum genotypic identical match of 5 / 1 0 is required.
The donor and recipient must be identical, as determined by high resolution typing, at least one allele of each of the following genetic loci: HLA-A, HLA-B, HLA-Cw, and HLADRB1;Lansky/Karnofsky score > 50, WHO > 4;Signed written informed consent

Sesso maschile o femminile;Età compresa tra i 3 mesi e i 21 anni;Aspettativa di vita superiore a 10 settimane;Pazienti affetti da patologie ematologiche maligne a rischio di vita, eleggibili a trattamento mediante trapianto allogenico di cellule staminali emopoietiche; Pazienti affetti da patologie non maligne suscettibili di trattamento attraverso trapianto allogenico di cellule staminali (immunodeficienze primitive;anemia aplastica severa non responsive alla terapia immunosoppressiva;osteopetrosi;casi selezionati di emoglobinopatie e citopenie congenite/ereditarie, inclusa l’Anemia di Fanconi, prima di un’evoluzione clonale maligna (MDS, AML).);Indisponibilità di un donatore convenzionale (germano HLA identico o donatore familiare HLA fenotipicamente identico o donatore non familiare con compatibilità pari a 9-10/10 valutata mediante tipizzazione molecolare ad alta risoluzione) o condizioni di urgenza trapiantologica che non consentano l’identificazione di un donatore non familiare compatibile (È necessaria una compatibilità genotipica minima di 5/10; il donatore ed il ricevente devono risultare HLA identici, come determinato dalla tipizzazione ad alta risoluzione, almeno per un allele di ciascuno dei seguenti loci genici: HLA-A, HLA-B, HLA-Cw e HLA-DRB1);Lansky/Karnofsky score >50, WHO > 4;Acquisizione per iscritto del consenso informato.

E.4

Principal exclusion criteria

Age < 3 months or >21 years;Greater than grade II acute GvHD or chronic extensive GvHD due to a previous allograft at the time of inclusion; Patient receiving an immunosuppressive treatment for GvHD treatment at the time of
inclusion;Dysfunction of liver (ALT/AST > 5 times normal value, or bilirubin > 3 times normal value), or of renal function (creatinine clearance < 30 ml / min); Severe cardiovascular disease (arrhythmias requiring chronic treatment, congestive heart failure or left ventricular ejection fraction <40%); Current active infectious disease (including positive HIV serology or viral RNA);Serious concurrent uncontrolled medical disorder;Pregnant or breast feeding female patient; Lack of parents’ informed consent. Patients who have received more than 1 x 105 T cells/Kg with the graft infusion will be excluded.

Età inferiore ai 3 mesi o superiore ai 21 anni;GvHD acuta di grado superiore al II o GVHD cronica estesa al momento dell’inclusione nello studio quali complicanze di un precedente trapianto allogenico; Pazienti in terapia immunosoppressiva per trattamento della GvHD quale complicanza di un precedente trapianto allogenico al momento dell’inclusione nello studio;Alterazione della funzionalità epatica (concentrazione plasmatica di ALT/AST > 5 volte i valori normali, o bilirubinemia > 3 volte i valori normali) o della funzionalità renale (clearance della creatinina < 30 ml/min);Patologie cardiovascolari di grado severo (aritmie che richiedano trattamento farmacologico cronico, insufficienza cardiaca congestizia o frazione di eiezione del ventricolo sinistro < 40%);Infezioni in fase attiva (inclusa positività alla sierologia per HIV o RNA virale);Gravi comorbidità concomitanti;Gravidanza o allattamento nelle pazienti di sesso femminile;Mancanza del consenso informato da parte dei genitori;Verranno inoltre esclusi dallo studio pazienti che abbiano ricevuto un numero di linfociti T αβ/Kg superiore a 1 x 10^5.

E.5 End points

E.5.1

Primary end point(s)

To evaluate the safety of infusion of BPX-501 at 3 different escalating doses (2.5 x 105/kg, 5 x105 and 1 x 106cells/kg recipient ideal body weight) to be administered within 14 + 4days aftertransplantation of partially mismatched T cell depleted hematopoietic stem cell transplant(HSCT). To determine the pediatric maximum tolerated and/or recommended phase 2 dose of BPX-50. To evaluate the safety of the infusion of dimerizer drug, AP1903, to subjects who
received BPX 501 and have developed Grade III-IV acute GVHD, as well as to those subjects with Grade II gut/liver acute GvHD or with Grade I/II GvHD (skin only) who progress or do not respond within 7 days to standard of care treatment.To determine the optimal dose resulting in improved immune reconstitution without a significant impact on incidence on GHVD.

E.5.1.1

Timepoint(s) of evaluation of this end point

Up to 24 months post-transplant

Fino a 24 mesi dopo il trapianto

E.5.2

Secondary end point(s)

Disease-free survival rates after transplantation; Cumulative incidence of relapse;Cumulative incidence of neutrophil and platelet engraftment; Kinetics of donor cell engraftment; Cumulative incidence of both primary and secondary graft failure; Cumulative incidence and severity of acute and chronic GvHD;
Time to resolution of acute GVHD after administration of AP1903; Rates of infectious complications, with particular regards to HCMV reactivation or other
viral or invasive fungal infections. In detail, we will estimate the rate of patients
experiencing any HCMV reactivation, as well as that of patients who will need antiviral treatment because of a viral load (measured as HCMV DNA in blood) greater than 5,000 copies/mL;Duration of hospitalization; T-cell immune reconstitution (as measured by time to reach an alpha/beta positive CD3+
cell count greater than 500/l; CD4+ cell count greater than 200/μl; CD8+ cell countgreater than 200/μl;Research evaluations will include: diversity of T cell receptor repertoire, virus specific immunity, quantitation of sjTREC and KREC, and response to polyclonal activators or nominal antigens will be the objective of ancillary biological studies.

Incidenza cumulativa della mortalità non correlata alla recidiva della patologia di base (NRM) al giorno 180 e ad un anno; Probabilità di sopravvivenza libera da malattia post trapianto; Incidenza cumulativa di recidiva; Incidenza cumulativa dell’attecchimento di neutrofili e piastrine; Cinetica dell’attecchimento delle cellule del donatore; Incidenza cumulativa di graft failure primaria e secondaria; Incidenza cumulativa e severità della GvHD acuta e cronica;
Numero di giorni necessari per la risoluzione della GvHD acuta dopo somministrazione di AP1903;Incidenza di complicanze infettive, in particolare verrà valutata la percentuale di pazienti che presenteranno riattivazione da HCMV, così come quelli che necessiteranno di trattamento farmacologico per la presenza di un viral load (HCMV DNA si sangue) superiore a 5000 copie/ml;
Ricostituzione immunologica del comparto T- cellulare valutata come giorni necessari per raggiungere una conta di CD3 αβ+ superiore a 500/ml; CD4+ superiore a 200/µl; CD8+ superiore a 200/ µl;Durata dell’ospedalizzazione; tasso di infezioni e di terapie antivirali;diversità del repertoire del T - cell receptor, immunità virus specifica, risposta ad antigeni attivatori policlonali o ad antigeni nominali.

E.5.2.1

Timepoint(s) of evaluation of this end point

For a period of 15 years.

Per un periodo di 15 anni

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

Yes

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

Phase I/II

Fase I/II

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

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.

Lo studio verrà chiuso dopo la valutazione della sopravvivenza globale e la sopravvivenza libera da malattia per tutti pazienti arruolati a 24 mesi dopo il trapianto.

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:

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

Bambini

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.4.2.2

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

Non previsto

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

2014-10-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-04-09

P. End of Trial
P.	End of Trial Status	Completed

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