Clinical Trials Register

Summary
EudraCT Number:	2017-000900-38
Sponsor's Protocol Code Number:	FT01CARCIK
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-01-07
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2017-000900-38

A.3

Full title of the trial

Open label, single arm, multicenter, dose escalation Phase I-IIa, trial to determine the safety of Allogeneic (donor derived) Cytokine Induced Killer (CIK) cells transduced with a transposon CD19 Chimeric Antigen Receptor (CAR) gene (CARCIK.CD19) in adult and pediatric patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL), after Hematopoietic Stem Cell Transplantation (HSCT)

Studio multicentrico di Fase I-IIa, in aperto, a braccio singolo, a dosi crescenti, per determinare la fattibilit¿ e la sicurezza di una singola dose di Cellule CIK (Cytokine Induced Killer ) Allogeniche (provenienti da donatore ) trasdotte con un trasposone contenente il recettore chimerico CAR) anti-CD19 denominate cellule CARCIK-CD19, in pazienti adulti e pediatrici con leucemia linfoblastica acuta (LLA) a precursori B, in recidiva o refrattaria, dopo trapianto di cellule staminali ematopoietiche (TCSE)

A.3.1

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

Transposon-manipulated Allogeneic CARCIK-CD19 cells in Pediatric and Adult Patients with r/r ALL post HSCT

CARCIK-CD19 Cellule Allogeniche modificate tramite Trasposone in Pazienti Pediatrici e Adulti con r/r LLA dopo TCSE

A.3.2

Name or abbreviated title of the trial where available

Transposon-manipulated Allogeneic CARCIK-CD19 cells in Pediatric and Adult Patients with r/r ALL pos

CARCIK-CD19 Cellule Allogeniche modificate tramite Trasposone in Pazienti Pediatrici e Adulti con r

A.4.1

Sponsor's protocol code number

FT01CARCIK

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	FONDAZIONE TETTAMANTI M.DE MARCHI ONLUS
B.1.3.4	Country	Italy
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	Fondazione Tettamanti M.De Marchi
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	FONDAZIONE MBBM
B.5.2	Functional name of contact point	UNITA' RICERCA CLINICA
B.5.3	Address:
B.5.3.1	Street Address	VIA PERGOLESI, 33
B.5.3.2	Town/ city	MONZA
B.5.3.3	Post code	20900
B.5.3.4	Country	Italy
B.5.4	Telephone number	0392333525
B.5.5	Fax number	0392336827
B.5.6	E-mail	e.marrocco@asst-monza.it

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	CARCIK-CD19
D.3.2	Product code	PTG-CARCIK-CD19
D.3.4	Pharmaceutical form	Suspension 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.3.9.2	Current sponsor code	PTG-CARCIK-CD19
D.3.9.3	Other descriptive name	CARCIK-CD19
D.3.10	Strength
D.3.10.1	Concentration unit	Other
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	10000000 to 1000000000
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.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

Relapsed or Refractory B cell Acute Lymphoblastic Leukemia after Haematopoietic Stem Cell Transplantation

Leucemia Linfoblastica Acuta a cellule B refrattaria o recidivata dopo trapianto di cellule staminali ematopoietiche

E.1.1.1

Medical condition in easily understood language

B-cell acute lymphoblastic leukemia (ALL)

Leucemia Linfoblastica Acuta a cellule B refrattaria o recidivata

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	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10063625
E.1.2	Term	Acute lymphoblastic leukemia recurrent
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

1. To determine the Maximum Tolerated Dose (MTD) and the Recommended Phase 2 Dose (RP2D) of CARCIK-CD19 infusion
2. To assess the safety of CARCIK-CD19 infusion

1. Determinare la Massima Dose Tollerata (MTD) e la Dose Raccomandata di Fase 2 (RP2D) di infusione di CARCIK-CD19
2. Valutare la sicurezza dell¿infusione di CARCIK-CD19.

E.2.2

Secondary objectives of the trial

1. To evaluate activity of CARCIK-CD19 administration as Overall Remission Rate (ORR) which includes Complete Remission (CR) and CR with incomplete blood count recovery (CRi)
2. To evaluate the duration of remission (DOR).
3. To evaluate relapse-free survival (RFS), event-free survival (EFS) and overall survival (OS).
4. To characterize the in vivo cellular pharmacokinetic (PK) profile (levels, persistence, trafficking) of CARCIK-CD19 cells in target tissues (blood, bone marrow, and other tissues if available).
5. To describe the levels of B and T cells (peripheral blood and bone marrow) prior to and following CARCIK-CD19 infusion for safety monitoring.
6. To describe the prevalence and incidence of immunogenicity to CARCIK-CD19.¿

1. Valutare l¿attivit¿ della somministrazione di CARCIK-CD19 in termini di Overall Remission Rate (ORR) che comprende la Risposta Completa (CR) e la CR con incompleto recupero di conte (CRi)
2. Valutare la durata della remissione (DOR).
3. Valutare la sopravvivenza libera da recidiva (RFS), la sopravvivenza libera da evento (EFS) e la sopravvivenza globale (OS).
4. Caratterizzare il profilo cellulare di farmacocinetica (PK) in vivo (livelli, persistenza, trafficking) delle cellule CARCIK-CD19 in tessuti target ( sangue, midollo osseo e altri tessuti se disponibile).
5. Descrivere i livelli di cellule B e T ( sangue periferico e midollo osseo) prima e dopo l¿infusione di CARCIK-CD19 per monitoraggio di safety.
6. Descrivere la prevalenza e l¿ incidenza dell¿ immunogenicit¿ a CARCIK-CD19.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Children and adults (1-75 years old);
2. Relapsed or refractory adult and pediatric B-cell precursor ALL after HSCT;
3. Evidence of CD19 tumor expression in bone marrow and/or peripheral blood by flow cytometry;
4. Bone marrow with = 5% lymphoblasts by morphologic assessment at screening ;
5. No evidence of overall aGVHD > Grade I or chronic GVHD (cGVHD) greater than mild at time of enrollment and in the previous 30 days;
6. No longer taking immunosuppressive agents for at least 30 days prior to enrollment;
7. No evidence of concomitant life-threatening infectious disease;
8. Life expectancy > 60 days;
9. Lansky/Karnofsky scores > 60;
10. Absence of severe renal disease (creatinine > x 3 normal for age);
11. Absence of severe hepatic disease (direct bilirubin > 3 mg/dl or SGOT > 500);
12. Patient/guardian able to give informed consent.

1. Bambini e adulti (1-75 anni);
2. LLA a cellule B recidivata o refrattaria dopo TCSE;
3. Evidenza di espressione tumorale di CD19 nel midollo e/o nel sangue periferico mediante citometria di flusso;
4. Presenza di una quota di Linfoblasti nel Midollo Osseo = 5% all’esame morfologico allo screening;
5. Non evidenza di GVHD acuta > Grado I o GVHD cronica (cGVHD) superiore al grado lieve all’arruolamento e nei precedenti 30 giorni;
6. Nessuna assunzione di agenti immunosoppressivi per almeno 30 giorni prima dell’arruolamento;
7. Nessuna evidenza di infezioni concomitanti life-threatening;
8. Aspettativa di vita > 60 giorni;
9. Lansky/Karnofsky scores > 60;
10. Assenza di grave patologia renale (creatinina > x 3 normale per età);
11. Assenza di grave patologia epatica (bilirubina diretta > 3 mg/dl o SGOT > 500);
12. Paziente/tutore in grado di fornire il consenso informato.

E.4

Principal exclusion criteria

1. Patients with GVHD Grades II-IV;
2. Any cell therapy in the last 30 days;
3. Patient with concomitant life-threatening infectious disease ;
4. Lansky/Karnofsky score <60;
5. Patients with hepatic or renal disease as specific above;
6. Pregnant or breast feeding females;
7. Rapidly progressive disease that in the estimation of the investigator and sponsor would compromise ability to complete study therapy;
8. Subjects must have recovered from the acute side effects of their prior therapy, such that eligibility criteria are met.;
9. HIV/HBV/HCV Infection: Seropositive for HIV antibody. Seropositive for hepatitis C or positive for Hepatitis B surface antigen (HBsAG);
10. Uncontrolled, symptomatic, intercurrent illness including but not limited to infection, congestive heart failure, unstable angina pectoris and cardiac arrhythmia;
11. Active Central Nervous System (CNS) involvement by malignancy, defined as CNS-3 per National Comprehensive Cancer Network (NCCN) guidelines. Note: Patients with history of CNS disease that has been effectively treated will be eligible
12. Patient has received an investigational medicinal product within the last 30 days prior to screening
13. Pregnant or nursing (lactating) women. NOTE: female study participants of reproductive potential must have a negative serum or urine pregnancy test performed within 48 hours before infusion
14. Women of child-bearing potential (defined as all women physiologically capable of becoming pregnant) and all male participants, unless they are using highly effective methods of contraception for a period of 1 year after the CARCIK-CD19 infusion.

1. Pazienti con GVHD di Grado II-IV;
2. Qualsiasi terapia cellulare nei precedenti 30 giorni;
3. Pazienti con concomitanti infezioni life-threatening;
4. Lansky/Karnofsky score <60;
5. Pazienti con patologie renali o epatiche come definite sopra;
6. Donne in gravidanza o allattamento;
7. Malattia rapidamente progressiva che a giudizio dello sperimentatore e dello Sponsor potrebbe compromettere la capacità di completare la terapia in studio;
8. Effetti collaterali acuti dovuti a precedenti trattamenti devono essere regrediti in modo che i criteri di inclusione vengano soddisfatti.
9. Infezioni da HIV/HBV/HCV: Sieropositività per anticorpi HIV. Sieropositività per epatite C o positività per antigene epatite B (HBsAG);
10. Malattie concomitanti sintomatiche incluse infezioni, insufficienza cardiaca congestizia, angina pectoris instabile e aritmia;
11. Coinvolgimento della malattia al Sistema Nervoso Centrale (CNS) definito come CNS-3 secondo le linee guida National Comprehensive Cancer Network (NCCN). Nota: I pazienti che hanno una storia di malattia al CNS che è stata efficacemente trattata sono eleggibili;
12. Pazienti che hanno ricevuto un farmaco sperimentale nei 30 giorni precedenti lo screening;
13. Gravidanza o allattamento. NOTA: le pazienti di sesso femminile potenzialmente fertile devono avere un test di gravidanza su siero o urine negativo, effettuato nelle 48 ore prima dell’infusione;
14. Donne potenzialmente fertili (definite come donne fisiologicamente in grado di avere uno stato di gravidanza) e pazienti di sesso maschile che non adottino metodi contraccettivi altamente efficaci per un periodo fino a 1 anno dopo l’infusione di CARCIK-CD19.

E.5 End points

E.5.1

Primary end point(s)

1. Dose Limiting Toxicities (DLT): rate and severity of the cytokine release syndrome (CRS) grade IV at 1 month;
2. Incidence of adverse events, serious adverse events, laboratory evaluations, vital signs, physical examination, and echocardiogram/electrocardiogram results.

E.5.1.1

Timepoint(s) of evaluation of this end point

1 month

E.5.2

Secondary end point(s)

1. The overall remission rate (ORR) at 1 and 6 months after CARCIK-CD19 administration, which includes CR and CR with incomplete blood count recovery (CRi). (See Section 12.5)
2. Duration of Reponse (DOR), i.e. the time from achievement of CR or CRi, whichever occurs first, to relapse or death due to ALL
3. Relapse Free Survival (RFS), i.e. the time from achievement of CR or CRi whichever occurs first to relapse or death due to any cause during CR or CRi
4. Event Free Survival (EFS), i.e. the time from date of CARCIK-CD19 infusion to the earliest of death, relapse or treatment failure
5. Overall Survival (OS), i.e. the time from date of CARCIK-CD19 infusion to the date of death due to any reason
6. Persistence of CARCIK-CD19 cells in target tissues (blood, bone marrow, and other tissues if available).
7. Levels of B and T cells (peripheral blood and bone marrow) prior to and following CARCIK-CD19 infusion for safety monitoring.
8. Prevalence and incidence of immunogenicity and anti- CARCIK-CD19 assay titers.

1. Tasso di remissione globale (ORR) a 1 e 6 mesi dopo somministrazione di CARCIK-CD19, che comprende CR e CR con recupero incomplete delle conte (CRi).
2. Valutare la durata della remissione (DOR).
3. Valutare la sopravvivenza libera da recidiva (RFS)
4. Valutare la sopravvivenza libera da evento (EFS)
5. Valutare e la sopravvivenza globale (OS).
6. Caratterizzare la persistenza di cellule CARCIK-CD19 in vivo in tessuti target (sangue, midollo osseo, altri tessuti se disponibili).
7. Descrivere i livelli di cellule B e T ( sangue periferico e midollo) prima e dopo l¿infusione di CARCIK-CD19 per monitoraggio della safety.
8. Prevalenza e incidenza di immunogenicit¿ con titoli test anti- CARCIK-CD19

E.5.2.1

Timepoint(s) of evaluation of this end point

1,6,12 Months

1,6,12 Mesi

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

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

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

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

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.8.5.1

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

Information not present in EudraCT

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.1.1.1

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