Application of antiCD19 CAR T lymphocytes for the treatment of adult patients with B-cell acute lymphoblastic leukemia with resistance, relapse or detectable measurable residual disease. Phase I/II clinical trial (MERMAID1)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Medical University Of Warsaw

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

19 Dec 2023 → ongoing

Decision date (initial)

2025-01-30

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2024-519808-27-00

EudraCT number

2021-003409-23

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Therapy, Efficacy, Safety

The aim of the study is to evaluate the safety and efficacy of anti-CD19 CAR T cells in the treatment of acute lymphoblastic leukemia Bcell with resistance, relapse or with positive measurable residual disease (MRD+) in adults.

Secondary objectives 1

1. The secondary objective of the study is to assess the overall safety of short- and long-term therapy, response to treatment defined as achieving remission with negative minimal residual disease, duration of response, duration of B-cell aplasia, CAR T cell kinetics, percentage of patients for whom the product was developed CAR-T, PFS and OS. In addition, exploratory endpoints based on the assessment of cytokine kinetics as well as the identification of response and toxicity predictors along with the characteristics of CRS using the criteria for assessing hemophagocytic lymphohistiocytosis (HLH) were included.

Conditions and MedDRA coding

B-cell acute lymphoblastic leukemia. with resistance, relapse or detectable measurable residual disease

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. 1. Diagnosis of B-ALL on blast cells at the time of resistance, relapse, or measurable residual disease (MRD)
2. 2. Resistance, relapse, or presence of MRD defined as at least 0.01% of leukemic lymphoblasts among bone marrow cells.
3. 3. Prior use of at least two cycles of chemotherapy
4. 4. Age >18 years on screening date
5. 5. Performance status assessed in the ECOG (Eastern Cooperative Oncology Group) scale of ≤ 2
6. 6. Satisfactory organ function during screening: A. ALT / AST activity <4 x Upper Limit of Normal (ULN) and total bilirubin <2 mg / dL (<4 mg / dL in patients with Gilbert's syndrome); B. Ejection fraction (EF)> 40% confirmed by ECHO, with no significant pericardial effusion within 6 weeks prior to screening; C. Respiratory capacity: arterial blood saturation> 92% without oxygen therapy, no significant pleural effusion; D. Creatinine clearance> 30 ml / min
7. 7. Understanding and providing informed consent to participate in the study;
8. 8. Negative pregnancy test (serum) in women of childbearing age.
9. 9. In women capable of having children, a declaration to refrain from heterosexual sexual intercourse or to use an appropriate method of contraception (as in point 4.3) after signing the informed consent form for a period of 12 months after the use of CAR-T therapy. If hormonal contraception is used, the period of use must begin at least one month before the use of CAR-T therapy. If hormonal contraception is used, the period of its use must start at least one month before the use of CAR-T therapy.
10. 10. In men capable of having children, declaration of refraining from heterosexual sexual intercourse or using an appropriate method of contraception (as in point 4.3) by themselves and/or their partners (if capable of having children) after signing an informed consent for a period of 12 months from the start of therapy CAR-T.

Exclusion criteria 15

1. 1. Diagnosis of B-cell lymphoblastic lymphoma (presence of <20% leukemic blasts in blood or bone marrow at diagnosis)
2. 2. Isolated central nervous system (CNS) relapse
3. 3. History of significant diseases of the central nervous system (CNS) or significant current CNS disorders (seizures, paralysis, aphasia, CNS ischemia / hemorrhage, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, psychosis and diseases associated with incoordination or movement disorders)
4. 4. The need for systemic immunosuppressive therapy
5. 5. Allogeneic hematopoietic cells (alloHCT) transplant surgery in less than 3 months prior to screening
6. 6. Concurrent presence of another neoplasm and another neoplasm diagnosed up to 2 years prior to study enrollment
7. 7. Active bacterial, viral or fungal infections, including SARS-CoV2
8. 8. Positive serology results towards HIV (antigene and/or anti-HIV), HBV ( HbsAg and/ or anti-HbsAg) and HCV ( anti-HCV)
9. 9. Absolute neutrophil count <500/μL unless, in the opinion of the investigator, the cytopenia is potentially reversible
10. 10. Platelet count <50,000/μL unless, in the opinion of the investigator, the cytopenia is potentially reversible
11. 11. Absolute lymphocyte count <100/μL
12. 12. Other co-morbidities that have been assessed as likely to interfere with the conduct of the study, as assessed by the investigator
13. 13. Pregnancy or breastfeeding
14. 14. Women of childbearing potential or men who do not consent to the use of an effective method of contraception (as in section 4.3) while participating in the study
15. 15. Inability to give informed consent to participate in a study

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Overall response rate (ORR) to treatment, defined as complete remission (CR) and complete remission with incomplete haematopoietic recovery (CRi)
2. Percentage of patients with treatment-emergent adverse event (TEAE) Grade ≥ 3 within 12 weeks after treatment of therapies of particular interest, i.e.: o Cytokine Release Syndrome (CRS)o Neurological Adverse Events (ICANS) o Infections o Febrile neutropenia o Persistent cytopenias (i.e. more than 28 days after CAR T cell administration) o Tumor lysis syndrome (TLS)

Secondary endpoints 11

1. Percentage of patients with SAE during the observation period, taking into account their severity and the causal relationship with the applied treatment
2. Disease-free percentage at 1, 3, 6, 12, 18 and 24 months post-infusion ie complete remission (CR) or complete remission with incomplete haematopoietic recovery (CRi) with negative minimal residual disease (MRD-) cytometrically assessed
3. Progression-Free Survival (PFS); Time from CAR-T infusion to relapse or death from any cause
4. Overall Survival (OS); Time from CAR-T infusion to death from any cause
5. Cmax; cellular kinetics of CAR-T - maximum expression observed in peripheral blood after a single administration (% copies/µg) over 24 months of observation
6. Tmax; CAR-T cellular kinetics - time to maximum copy number in peripheral blood after a single administration (days) over 24 months of observation
7. AUC0-30d and 90d; CAR-T cellular kinetics - AUC from day 0 to day 30 and 90 or other days as assessed in peripheral blood (% copies/µg x days)
8. AUC0-Tmax; CAR-T cellular kinetics - AUC from day 0 to Tmax in peripheral blood (% copies/µg/days)
9. Percentage of patients enrolled in the study for whom the CAR-T product was manufactured
10. Duration of response (time from finding CR or CRi to patient progression or death from any cause)
11. Percentage of CR or CRi patients with persistent B-cell aplasia after CAR-T cell infusion over 24 months of follow-up. Absolute CD19(+) lymphocyte count < 50/µl

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Medical University Of Warsaw

Sponsor organisation

Medical University Of Warsaw

Address

Ul. Zwirki I Wigury 61

City

Warsaw

Postcode

02-091

Country

Poland

Scientific contact point

Organisation

Medical University Of Warsaw

Contact name

Grzegorz Basak

Public contact point

Organisation

Medical University Of Warsaw

Contact name

Grzegorz Basak

Locations

1 EU/EEA country · 3 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 1 · Art. 38 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 4 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications