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

Sponsor

Uppsala University (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT06002659

Collaborator

Elicera Therapeutics (Other), Uppsala University Hospital (Other), Karolinska University Hospital (Other)

Enrollment

Locations

Arm

Anticipated Duration (Months)

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
B-cell Lymphoma	Biological: CAR20(NAP)-T Drug: Cyclophosphamide Drug: Fludarabine	Phase 1/Phase 2

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

18 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase I/IIa Multicenter Study Evaluating the Safety and Efficacy of CAR20(NAP)-T in Patients With Relapsed/Refractory B Cell Lymphoma (CARMA-01 Study)

Anticipated Study Start Date :

Dec 1, 2023

Anticipated Primary Completion Date :

Dec 30, 2027

Anticipated Study Completion Date :

Dec 30, 2027

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment CAR20(NAP)-T treatment	Biological: CAR20(NAP)-T Autologous CAR-T cells targeting CD20 and upon target recognition express and secrete NAP Other Names: ELC-301 Drug: Cyclophosphamide pre-conditioning chemotherapy Drug: Fludarabine pre-conditioning chemotherapy

Arm

Intervention/Treatment

Experimental: Treatment

CAR20(NAP)-T treatment

Biological: CAR20(NAP)-T

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

Other Names:

ELC-301

Drug: Cyclophosphamide

pre-conditioning chemotherapy

Drug: Fludarabine

pre-conditioning chemotherapy

Outcome Measures

Primary Outcome Measures

Incidence of dose limiting toxicity [First infusion up to 30 days]
The incidence of dose limiting toxicity (DLT). Number of Participants Experiencing Adverse Events (AEs) Defined as Dose Limiting Toxicities (DLTs)
Adverse events [24 months]
The nature, frequency, severity, and tolerability of adverse events (AEs) including clinically significant laboratory data, and their relation to dosage.
Pharmacodynamic (PD) and pharmacokinetic (PK) [Either 24 month or 15 years during long-term follow up if clinically indicated]
PD is assessed by determine circulating B cell level; PK is assessed by determine circulating CAR20(NAP)-T cells.

Secondary Outcome Measures

Objective response rate [ORR] [24 months]
ORR is defined as the incidence of a complete response or a partial response by the revised Lugano classification as determined by the study investigators. All patients that do not meet the criteria for an objective response by the analysis cutoff date will be considered non-responders.
Progression free survival [PFS] [24 months]
PFS is defined as the time from the IMP treatment date to the date of disease progression per the revised Lugano classification or death from any cause.
Best Objective Response [24 months]
the incidence of complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), or unevaluable (UE) as best response to treatment.
Duration of Response (DOR) [24 months]
DOR is defined as the date of their first objective response (which is subsequently confirmed) to disease progression per the revised Lugano classification or death regardless of cause. Patients not meeting the criteria for progression or death by the analysis data cutoff date will be censored at their last evaluable disease assessment date and their response will be noted as ongoing.
Overall Survival (OS) [either 24 months or 15 years during long-term follow up if clinically indicated]
defined as the time from IMP treatment to the date of death. Patients alive by the analysis data cutoff date will be censored at their last contact date. The overall survival rate will be reported at different cut-off time points.

Other Outcome Measures

Anti-NAP response [either 24 months or 15 years during long-term follow up if clinically indicated]
Determine anti-NAP immune response
Bystander immunity activation [either 24 months or 15 years during long-term follow up if clinically indicated]
Assess induced tumor specific endogenous T-cell immune response

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Key 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