car20(nap)-t therapy for b cell lymphoma (carma-01 study)

Conditions: B-cell Lymphoma

Summary: 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

Keywords: car t cell b cell lymphoma cd20 hp-nap