Clinical Trials Register

Summary
EudraCT Number:	2022-003137-19
Sponsor's Protocol Code Number:	M-2022-398
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2022-12-23
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

Germany - PEI

A.2

EudraCT number

2022-003137-19

A.3

Full title of the trial

An open-label phase I/IIa, multicenter, interventional single-arm trial of MB-CART19.1 in patients with refractory SLE

A.3.1

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

MB-CART19.1 in refractory SLE

A.3.2

Name or abbreviated title of the trial where available

MB-CART19.1 in refractory SLE

A.4.1

Sponsor's protocol code number

M-2022-398

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	Miltenyi Biomedicine GmbH
B.1.3.4	Country	Germany
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	Miltenyi Biomedicine GmbH
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Miltenyi Biomedicine GmbH
B.5.2	Functional name of contact point	Head of Global Clinical Research
B.5.3	Address:
B.5.3.1	Street Address	Friedrich-Ebert-Str. 68
B.5.3.2	Town/ city	Bergisch Gladbach
B.5.3.3	Post code	51429
B.5.3.4	Country	Germany
B.5.4	Telephone number	+49220483067569
B.5.6	E-mail	biomedicine@miltenyi.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	MB-CART19.1
D.3.2	Product code	MB-CART19.1
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	not available
D.3.9.2	Current sponsor code	MB-CART19.1
D.3.9.3	Other descriptive name	T cells transduced with chimeric antigen receptor anti-CD19
D.3.10	Strength
D.3.10.1	Concentration unit	U unit(s)
D.3.10.2	Concentration type	up to
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	Yes
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

Adult patients with refractory active systemic lupus erythematosus (SLE) with organ involvement

E.1.1.1

Medical condition in easily understood language

Lupus

E.1.1.2

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10042945
E.1.2	Term	Systemic lupus erythematosus
E.1.2	System Organ Class	10028395 - Musculoskeletal and connective tissue 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

Phase I
• To establish the safety and toxicity of MB-CART19.1 and determine the recommended dose for phase IIa (RP2D)
Phase IIa
• To evaluate the treatment response after infusion of MB-CART19.1

E.2.2

Secondary objectives of the trial

Phase I and Phase IIa
• To evaluate the treatment response, duration of response and relapse after treatment with MB-CART19.1
• To assess the phenotype, expansion and persistence of MB-CART19.1
• Cellular and humoral immunogenicity associated with MB-CART19.1 therapy.
• To assess duration of B-cell aplasia and extent of immunoglobulin deficiency
• To evaluate the changes in the levels of anti-dsDNA and other SLE associated serum autoantibodies

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patients at least 18 years of age
2. Signed and dated informed consent before the conduct of any trial-specific procedure
3. SLE fulfilling the 2019 ACR/EULAR classification criteria (refer to Appendix 8)
4. One BILAG A or two BILAG B despite treatment with at least two of the following treatment options: MMF, cyclophosphamide, rituximab belimumab, anifrolumab, methotrexate, azathioprine
5. SLE with major organ involvement defined as either:
a) Presence of active lupus nephritis according to the following criteria:
o histology proven class III or IV lupus nephritis according to ISN/RPS 2003 classification;
o Urine protein-to-creatinine ratio (UPCR) >1 in 24-hour urine collection;
o Glomerular filtration rate (eGFR) of ≥30 mL/min/1.73 m2
o No history of kidney transplantation.
b) Lupus with heart involvement (e.g. myocarditis, pericarditis, endocarditis) as measured by MRI or echocardiography/ultrasound
c) Lupus with pulmonary involvement (Lupus pleuritis, pulmonary arterial hypertension (PAH)) or lung disease defined as:
o Forced Vital Capacity (FVC) ≥ 60% OR
o Forced Expiratory Volume (FEV1) ≥ 60%, Total Lung Capacity (TLC) ≥ 60% and DLCO (diffusion capacity) ≥ 60%
6. Absolute CD3+ T cell count ≥100/µl;
7. No childbearing potential or negative pregnancy test at screening and before chemotherapy in women with childbearing potential; Subjects must agree to use a contraceptive method from screening until 12 months after the administration of the IMP.
8. Fully vaccinated against SARS-CoV2 according to the recommendations of RKI or confirmed SARS-CoV-2 infection within the last 6 months.

E.4

Principal exclusion criteria

Criteria for Exclusion
Patients will be entered into this trial only if they meet none of the following criteria:

1. Active clinically significant central nervous system (CNS) dysfunction (including but not limited to uncontrolled seizure disorders, cerebrovascular ischemia or hemorrhage, dementia, paralysis);
2. Uncontrolled diabetes mellitus.
3. Therapy induced lung disease and tuberculosis
4. Forced Vital Capacity (FVC) < 60%, FEV1 < 60%, Total Lung Capacity (TLC) < 60% and DLCO (diffusion capacity) < 60%.
5. BILAG A or BILAG B for neuropsychiatric SLE
6. History of a malignancy unless disease free for ≥5 years with the exception of basal or squamous cell skin cancer;
7. Cardiac function: unstable coronary heart disease; left ventricular ejection fraction (LVEF) < 50%; no active myocarditis
8. Renal function: eGFR < 30 ml/min/1.73 m2;
9. Liver function: Severe hepatic insufficiency defined as a Child-Pugh score ≥ 10(C) (Appendix 10)
10. Known history of infection with human immunodeficiency virus or active infection with hepatitis B (hepatitis B surface antigen positive)
11. Known history of infection with hepatitis C virus unless treated and confirmed to be polymerase chain reaction (PCR) negative
12. Any active, uncontrolled bacterial, viral or fungal infection including SARS-CoV-2
13. History of hematopoietic stem cell or solid organ transplantation.
14. Irreversible organ damage.
15. Medications:
• Systemic corticosteroids >10 mg within 7 days prior to leukapheresis;
• T cell targeting drugs (e.g. mycophenolate mofetil, calcineurin inhibitors) within 21 days prior to leukapheresis,
• Prior treatment with anti-CD19 therapy;
• Previous adoptive T cell therapy or any gene therapy including CAR T cell therapy;
• Live vaccines within 30 days prior to leukapheresis,
• Current cytotoxic drugs
16. Hypersensitivity against any drug or its ingredients/impurities that is scheduled or likely to be given during trial participation, e.g. as part of the mandatory preparative chemotherapy or rescue medication/salvage therapies for treatment related toxicities;
17. Contraindication of trial related procedures as judged by the investigator
18. Women of childbearing potential (WOCBP) who do not agree to use highly effective contraceptive measures (Pearl index < 1) or practice true sexual abstinence from any heterosexual intercourse (true abstinence is only acceptable if it is in line with the preferred and usual life style of the participant.) or must have a vasectomised partner as the sole sexual partner (The vasectomised partner must have received medical assessment of the surgical success.) for at least 1 month before the study start, during the study and in the 12 months following the last dose of study treatment.
A woman is considered a WOCBP, i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. WOCBP who want to become pregnant after completing treatment should seek advice about oocyte cryoconservation prior to treatment because of possible irreversible infertility. WOCBP must refrain from egg donation throughout the study until 12 months after the last dose of study treatment.
Highly effective methods of contraception include hormonal contraceptives associated with inhibition of ovulation (oral, intravaginal, transdermal, injectable, implantable) and intrauterine devices or systems (e.g. hormonal and non-hormonal) and bilateral tubal occlusion.
Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
A post-menopausal state is defined as no menses for 12 months without an alternative medical cause.
19. Men with non-pregnant WOCBP partners who do not agree to use highly effective contraceptive measures (Pearl index < 1, e.g. spermicide and condom or other highly effective contraceptive measures (Pearl index < 1) taken by their WOCBP partner) or practice true sexual abstinence from any heterosexual intercourse (true abstinence is only acceptable if it is in line with the preferred and usual life style of the participant.), unless they are surgically sterile (meaning at least 2 consecutive analyses following vasectomy demonstrate absence of sperms in the ejaculate), during the study and in the 12 months following the last dose of study treatment.
Men should seek advice about sperm conservation prior to treatment because of possible irreversible infertility. Men must furthermore refrain from sperm donation throughout the study until 12 months after the last administration of study treatment.
20. Concurrent participation in any other interventional trial;
21. Inability to understand the procedures and risks associated with the Trial.

E.5 End points

E.5.1

Primary end point(s)

Phase I
• Determination of the recommended dose for phase IIa out of 3 dose levels, based on a Bayesian Optimal Interval (BOIN) design, using a target dose limiting toxicity (DLT) rate of 20 %, with DLT until day 28 after infusion of MB-CART19.1 (DLT is defined in section 3.3.2).
• Safety and toxicity of MB-CART19.1 per incidence of adverse event (AE), classified according to CTCAE version 5.0, and evaluation and classification of Cytokine Release Syndrome (CRS) and Immune Effector cell-associated Neurotoxicity Syndrome (ICANS).

Phase IIa
• Proportion of patients in remission at month 6 after infusion of MB-CART19.1. Remission is evaluated by fulfillment of DORIS remission criteria of SLE.

E.5.1.1

Timepoint(s) of evaluation of this end point

Phase I: 28 days (recommended dose); from infusion until EoT (AEs/CRS/ICANS)
Phase IIa: 6 months

E.5.2

Secondary end point(s)

Phase I and Phase IIa

• Safety and toxicity of MB-CART19.1 per incidence of adverse events (AE), classified according to CTCAE version 5.0;
• Treatment response measured by:
- Proportion of patients in remission at day 28, week 12, month 6, month 9, month 12 and month 24 measured by DORIS remission criteria of SLE
- Proportion of patients with reduction in SLEDAI 2K of ≥ 4 points
- Proportion of patients with LLDAS
- British Isles Lupus Assessment Group (BILAG) index
• Duration of response
• Patient reported outcomes:
- SF36
- Health Assessment Questionnaire – Disease Index (HAQ-DI)
- Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue)
• Incidence of cellular and humoral immunogenicity after MB-CART19.1 therapy
• Immunophenotyping and persistence of circulating immune cells
• Percentage of MB-CART19.1 of all T cells as well as total number of MB-CART19.1 in peripheral blood
• Cytokine levels in peripheral blood
• Occurrence and duration of B cell aplasia, immunoglobulin levels
• Levels of serum autoantibodies (Antinuclear Antibodies (ANAs) as anti-dsDNA, anti-nucleosomes, anti-Sm, anti-U1RNP, anti-Ro/SSA, anti-La/SSB, anti-histone, and other SLE specific autoantibodies such as anti-cardiolipin IgG and IgM, anti-C1q, anti-\beta2 glycoprotein IgG and IgM), anti-phosphatidylserine and incidence of sero-conversion
• Coagulation and lupus anticoagulant (if positive)
• Serum C3 and C4 levels

E.5.2.1

Timepoint(s) of evaluation of this end point

Diverse

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

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

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

First administration in condition

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

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

Day when the last participant completes the last assessment, is considered lost to follow-up, withdraws consent or dies.

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

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)

All patients irrespective of the clinical response will be followed up then for 1 more year or until the patient is lost to follow-up or has died. After completion of this last follow-up phase, patients will be rolled over to a subsequent follow-up observation for up to further 13 years.

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

2023-05-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2023-05-30

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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