CAR20(NAP)-T Therapy for B Cell Lymphoma (CARMA-01 Study)

NCT ID: NCT06002659

Last Updated: 2024-05-09

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 18 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-05-01
• Study Completion Date: 2027-12-30

Brief Summary

The purpose is to study the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of CAR20(NAP)-T for patients with B-cell malignancies.

Detailed Description

A cancer patient's T cells can be isolated and engineered to express a chimeric antigen receptor (CAR), which re-directs the T cells to recognize and kill tumor cells expressing that particular antigen. CD19-targeted CAR-T cell therapy has shown good effects for B cell malignancies, even cure, in otherwise therapy refractory patients.

Antigen escape, i.e., the downregulation of the antigen targeted by the CAR due to the selective pressure caused by the CAR-T cell therapy is a challenge. For patients treated with CD19 CAR-T cell therapy, about 30% of the patients are resistant to treatment and about 20% of patients relapse after an initial response.

CAR20(NAP)-T cells target CD20 and upon target recognition secrete a bacterial-derived pluripotent immune-stimulating factor named NAP (Helicobacter pylori Neutrophil-activating protein). Secretion of NAP in the tumor microenvironment can induce an endogenous bystander immune response, that counteracts antigen escape and thereby improves the therapeutic outcome.

CAR20(NAP)-T is an investigational agent not yet approved by authorities.

Design:

The study is designed as 3+3 dose escalation phase I, and a dose expansion Phase IIa. The safety, tolerability, PK/PD, and efficacy will be evaluated.Dose escalation is to be based on the incidence of dose-limiting toxicity (DLTs). The investigator or sub-investigator will decide if the AE is related to IMP-treatment on a case-by-case basis depending on the character of the DLT symptoms. Investigator or sub-investigator has a possibility to classify various toxicity observed in patient as DLT.The Recommended phase II dose (RP2D) is decided based on safety, PK/PD data as well as preliminary clinical activity data from the Phase I dose escalation. After setting the RP2D, additional patients will be treated at RP2D to make sure at least 6 patients will be treated at RP2D dose level already at the phase I part.

Protocol treatment:

The enrolled patient will undergo a leukapheresis procedure to harvest enough T cells for IMP production. During CAR20(NAP)-T manufacturing, the patient may receive bridging therapy to control tumor burden. All patients will receive pre-conditioning chemotherapy (cyclophosphamide and fludarabine) followed by one dose of CAR20(NAP)-T cell infusion intravenously. The patient will then be followed by doctor/study nurse for evaluation of the health status and side effects. At follow-up visits, blood samples will be obtained and CT imaging will be performed. Patient will actively participate in the study for about 24 months when the final follow-up visit will be scheduled.

Conditions

B-cell Lymphoma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Treatment

CAR20(NAP)-T treatment

Group Type: EXPERIMENTAL

CAR20(NAP)-T

Intervention Type: BIOLOGICAL

Autologous CAR-T cells targeting CD20 and upon target recognition express and secrete NAP

Cyclophosphamide

Intervention Type: DRUG

pre-conditioning chemotherapy

Fludarabine

Intervention Type: DRUG

pre-conditioning chemotherapy

Interventions

CAR20(NAP)-T

Autologous CAR-T cells targeting CD20 and upon target recognition express and secrete NAP

Intervention Type: BIOLOGICAL

Cyclophosphamide

pre-conditioning chemotherapy

Intervention Type: DRUG

Fludarabine

pre-conditioning chemotherapy

Intervention Type: DRUG

Other Intervention Names

ELC-301

Eligibility Criteria

Inclusion Criteria

• Signed informed consent.
• Relapsed or refractory CD20+ diffuse large B-cell lymphoma, mantle cell lymphoma or indolent lymphoma.
• The patient should have been treated with at least two lines of therapy and have no curative treatment option, specifically

• Relapsed or refractory CD20+ B-cell lymphoma that are not eligible to receive clinically approved CD19-directed CAR T cell treatment.
• Relapsed or refractory CD20+ B-cell lymphoma who are CD19 negative.
• Relapsed or refractory B-cell lymphoma who relapse after CD19 CAR T cell treatment.
• In phase I age >18 years, in phase II all ages
• Measurable disease per Lugano classification.
• Performance status ECOG 0-2.
• Adequate bone marrow function as evidenced by:

• Absolute neutrophil count (ANC) ≥ 1x10^9/l/L
• Platelet ≥ 50x 10^9/l
• Absolute lymphocyte count ≥ 0,1x10^9/L
• Adequate renal, hepatic, cardiac, and pulmonary function as evidenced by:

• Creatinine clearance (Cockcroft Gault) ≥ 30 mL/min
• Serum Alanine aminotransferase/Aspartate aminotransferase (ALT/AST) ≤ 2.5 Upper limit of normal (ULN) and S-Bilirubin <1.5x UNL
• Cardiac ejection fraction ≥ 40%
• Functional venous for administration of IMP.
• Fertile individuals must consent to use contraceptives during participation in the trial.

Exclusion Criteria

• Other CD20-positive lymphomas i.e Burkitt lymphoma, primary CNS lymphoma, plasmablastic lymphoma or CLL transformed to DLBCL/HGBL (Richter transformation)
• Any significant medical or psychiatric illness that would prevent the subject from giving informed consent or from following the study procedures.
• Known human immunodeficiency virus (HIV) infection.
• Impending organ-compromising disease.
• Rapidly progressing disease
• Active and/or severe infection (e.g., tuberculosis, sepsis and opportunistic infections, active hepatitis B virus (HBV) or active hepatitis C virus (HCV) infection.
• Other serious underlying medical conditions, which, in the Investigator's judgment, could impair the ability of the subject to perform the treatment.
• Treatment with an investigational product within 30 days prior to enrolment
• Potential sign of hypersensitivity reaction to tocilizumab or any of the agents used in this study
• Systemic corticosteroid treatment (>10mg/day) <5 days prior to IMP treatment or <7 days prior leukapheresis.
• Pregnancy

• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Elicera Therapeutics

UNKNOWN

Sponsor Role: collaborator

Uppsala University Hospital

OTHER

Sponsor Role: collaborator

Karolinska University Hospital

OTHER

Sponsor Role: collaborator

Uppsala University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Di Yu, PhD

Role: STUDY_DIRECTOR

Uppsala University

Locations

Karolinska University Hospital

Stockholm, , Sweden

Site Status: ACTIVE_NOT_RECRUITING

Uppsala University Hospital

Uppsala, , Sweden

Site Status: RECRUITING

Countries

Sweden

Central Contacts

Gunilla Enblad, MD/PhD

Role: CONTACT

gunilla.enblad@igp.uu.se

+46186110000

Di Yu, PhD

Role: CONTACT

di.yu@igp.uu.se

+46707204196

Facility Contacts

Gunilla Enblad

Role: primary

References

Jin C, Ma J, Ramachandran M, Yu D, Essand M. CAR T cells expressing a bacterial virulence factor trigger potent bystander antitumour responses in solid cancers. Nat Biomed Eng. 2022 Jul;6(7):830-841. doi: 10.1038/s41551-022-00875-5. Epub 2022 Apr 4.

Reference Type: BACKGROUND

PMID: 35379957 (View on PubMed)

Other Identifiers

2022-004157-31

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

ELC301-CARMA-01

Identifier Type: -

Identifier Source: org_study_id