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

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

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.

Eligibility Criteria:
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