Clinical Trials Register

Summary
EudraCT Number:	2021-000937-15
Sponsor's Protocol Code Number:	HO161
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-09-08
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

Netherlands - Competent Authority

A.2

EudraCT number

2021-000937-15

A.3

Full title of the trial

A phase II non-inferiority design study comparing point-of-care produced CAR T-cell to commercial CAR T-cells in patients with relapsed/refractory Non-Hodgkin Lymphoma

A.3.1

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

A study evaluating the safety and efficacy of a in-house manufactured CAR T-cell treatment in patients with relapsed/refractory Non-Hodgkin Lymphoma

Een onderzoek naar de veiligheid en werkzaamheid van in het ziekenhuis geproduceerde CAR T- cellen als behandeling voor patiënten met een B-cel Non-Hodgkin lymfoom waarbij de ziekte is teruggekeerd of niet heeft gereageerd op de eerdere behandeling(en).

A.3.2

Name or abbreviated title of the trial where available

HOVON 161 CAR T

A.4.1

Sponsor's protocol code number

HO161

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	UMCG
B.1.3.4	Country	Netherlands
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	Zorginstituut Nederland
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Erasmus MC, HOVON Data Center
B.5.2	Functional name of contact point	HOVON Data Center
B.5.3	Address:
B.5.3.1	Street Address	Dr. Molenwaterplein 40
B.5.3.2	Town/ city	Rotterdam
B.5.3.3	Post code	3015 GD
B.5.3.4	Country	Netherlands
B.5.6	E-mail	hdc@erasmusmc.nl

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
D.3.2	Product code	ARI-0001
D.3.4	Pharmaceutical form	Dispersion for 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	ARI-0001
D.3.9.3	Other descriptive name	Autologous T cells transduced with lentiviral vector expressing a chimeric antigen receptor directed against CD19
D.3.9.4	EV Substance Code	SUB216979
D.3.10	Strength
D.3.10.1	Concentration unit	Other
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	1.0 to 2.0
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	Comparator
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	Yes
D.2.1.1.1	Trade name	Yescarta
D.2.1.1.2	Name of the Marketing Authorisation holder	Kite Pharma EU B.V.
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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/3/14/1393
D.3 Description of the IMP
D.3.1	Product name	axicabtagene ciloleucel
D.3.4	Pharmaceutical form	Dispersion for 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	Axicabtagene ciloleucel
D.3.9.2	Current sponsor code	Ax-cel Yescarta
D.3.9.3	Other descriptive name	Axicabtagene ciloleucel
D.3.9.4	EV Substance Code	SUB188282
D.3.10	Strength
D.3.10.1	Concentration unit	Other
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	0.4 to 2.0
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. Doc Ref. EMA/CAT/360525/2015
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

B-Cell Non Hodgkin Lymphoma

E.1.1.1

Medical condition in easily understood language

B-Cell Non Hodgkin Lymphoma

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	HLGT
E.1.2	Classification code	10025320
E.1.2	Term	Lymphomas non-Hodgkin's B-cell
E.1.2	System Organ Class	10005329 - Blood and lymphatic system disorders

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 compare progression free survival (PFS) of patients randomized to investigational point-of-care (PoC) ARI-0001 CAR T-cells versus PFS of patients randomized to commercial standard-of-care (SoC) (axicabtagene ciloleucel (Axi cel, Yescarta)) CAR T-cells inpatients with R/R DLBCL.

E.2.2

Secondary objectives of the trial

• To evaluate response rates
• To evaluate safety and toxicity of ARI-0001 and Axi-cel
• To assess overall survival
• To evaluate quality of life
• To assess costs associated with both treatment regimens (ARI-0001 vs Axi-cel)
• To evaluate CAR T-cell expansion, persistence, and T-cell characteristics in both treatment arms (ARI-0001 vs Axi-cel)
• To evaluate PoC CAR T-cell production characteristics (e.g. number of viable T-cells, transduction efficiency, T-cell subsets (activated T-cells, memory T-cells)), including the functional characteristics between the different production sites.
• To evaluate the association of the functional characteristics of ARI-0001 CAR T-cells with CAR T-cell expansion, persistence, adverse events, response rates and PFS.
• To assess the proportion of successful batches between the different production sites
• To evaluate the number of days between leukapheresis and infusion of CAR T-cells
• To evaluate fludarabine pharmacokinetics.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Histologically confirmed DLBCL and associated subtypes, defined by WHO 2016 classification: DLBCL not otherwise specified (NOS), High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology (DHL/THL) and FL3B, T-cell/histocyte rich B-cell lymphoma, Primary mediastinal B-cell lymphoma, EBV+ DLBCL, transformed lymphoma (transformed follicular) and R/R after at least 2 lines of systemic therapy
• Age ≥ 18 years
• Eastern Cooperative Oncology Group (ECOG)/WHO performance status 0-2
• If the patient has a history of central nervous system (CNS) involvement, then he/she must have:
- No signs or symptoms of CNS involvement
- No active disease on magnetic resonance imaging (MRI)
- Absence of large cell lymphoma in cerebral spinal fluid (CSF) on cytospin preparation or flow cytometry, regardless of the number of white blood cells
• Estimated life expectancy of >3 months other than primary disease
• Patients of child-bearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study and for four months after receiving the preparative regimen
• Signed and dated informed consent before conduct of any trial-specific procedure
• Patient is capable of giving informed consent

E.4

Principal exclusion criteria

• Absolute neutrophil count (ANC) <1.0x109/L
• Platelet count <50x109/L
• Absolute lymphocyte count <0.1x109/L
• Primary CNS lymphoma
• Known history of infection with hepatitis C or B virus unless treated and confirmed to be PCR negative
• Active HIV infection with detectable viral load or CD4 T-cell count below 0.20x109/L
• Known history or presence of seizure activities or on active anti- seizure medications within the previous 12 months
• Known history of CVA within prior 12 months
• Unstable neurological deficits
• Known history or presence of autoimmune CNS disease, such as multiple sclerosis, optic neuritis or other immunologic or inflammatory disease
• Active systemic autoimmune disease for which immunnosupressive therapy is required
• Presence of CNS disease that, in the judgment of the investigator, may impair the ability to evaluate neurotoxicity, baseline dementia that would interfere with therapy or monitoring, determined using mini-mental status exam at baseline
• Active systemic fungal, viral or bacterial infection
• Clinical heart failure with NYHA class ≥2 or LVEF <40%
• Resting oxygen saturation <92% on room air
• Liver dysfunction as indicated by total bilirubin, AST and/or ALT >5 x institutional ULN, unless directly attributable to the lymphoma or Gilbert disease
• GFR <40 mL/min calculated according to the modified formula of Cockcroft and Gault or by direct urine collection
• Pregnant or breast-feeding woman
• Active other malignancy requiring treatment
• Medical condition requiring prolonged use of systemic immunosuppressives with exception of prednisolon<10mg/day
• History of severe immediate hypersensitivity reaction against any drug or its Ingredients/ impurities that is scheduled to be given during trial participation e.g. as part of the mandatory lymphodepletion protocol, premedication for infusion, or rescue medication/salvage therapies for treatment related toxicities
• Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule

E.5 End points

E.5.1

Primary end point(s)

• PFS from date of IMP infusion (if applicable)

E.5.1.1

Timepoint(s) of evaluation of this end point

When applicable data of evaluable patients are available

E.5.2

Secondary end point(s)

• PFS from date of randomization
• Safety and toxicity assessment of ARI-0001 CAR T-cells and Axi-cel per AE reporting classified according to CTCAE Version 5 and CRS and ICANS classified according to the ASTCT criteria
• Overall response rate (ORR, sum of (metabolic) complete response [CR] and partial response [PR]), as well as CR, PR, stable disease (SD) and progressive disease (PD)/relapse at 4 weeks, 12 weeks, 6, 12 and 24 months after infusion of CAR T-cells
• Best overall response (BOR) rate at 4 weeks, 12 weeks, 6, 12 and 24 months after infusion of CAR T-cells
• Duration of response (DOR)
• OS from date of randomization, and from date of CAR T-cell infusion (if applicable)
• Patient Reported Outcome/Quality of Life (PRO/QOL)
• CAR T-cell expansion, persistence, and T-cell characteristics in both treatment arms (ARI-0001 vs Axi-cel)
• PoC CAR T-cell production characteristics (e.g. number of viable T-cells, transduction efficiency, T-cell subsets (activated T-cells, memory T-cells)), including the functional characteristics (eg potency tests) between the different production sites.
• The association of the functional characteristics (eg potency tests) of the CAR T-cell products (ARI-0001 CAR T-cells) with CAR T-cell expansion, persistence, adverse events, response rates and progression free survival.
• Proportion of successful batches between the different production sites
• Number of days between leukapheresis and infusion of CAR T-cells (vein-to-vein time)
• Fludarabine pharmacokinetics.

E.5.2.1

Timepoint(s) of evaluation of this end point

When applicable data of evaluable patients are available

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

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

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

Yes

E.8.2.3.1

Comparator description

registered CAR T-cel therapy (Axi-cel)

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

LPLV

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

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)

F.1.2.1

Number of subjects for this age range:

150

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

150

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

300

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

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	HOVON Foundation
G.4.3.4	Network Country	Netherlands

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-09-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-08-25

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

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