a dose escalating study of cd19/cd22/bcma car-t therapy in relapsed or refractory b cell non-hodgkin lymphoma(nhl)

Conditions: Non-Hodgkin Lymphoma, B-cell

Summary: this is a single arm, open-label, dose escalation clinical study to evaluate the safety and tolerability of autologous chimeric antigen receptor t (car-t) cells targeting cd19/cd22/bcma in patients with relapsed or refractory b cell non-hodgkin lymphoma.

this is a single arm, open-label, dose escalation investigator initiated (iit) study, the primary objective is to evaluate the safety and tolerability of cd19/cd22/bcma car-t therapy in patients with b cell non-hodgkin lymphoma, and determine the maximum tolerated dose (mtd). for the secondary objectives, pharmacokinetics(pk), survival of car-t cells in vivo, pharmacodynamics (pd) and efficacy in r/r b cell nhl will be evaluated. this study flow comprises of a screening phase( ≤28 days prior to apheresis), apheresis phase (occur upon enrollment, ≤10 days prior to infusion), lymphodepletion phase (from day -5 to day -3) ,infusion of cd19/cd22/bcma car-t cells on day0, dlt assessments phase from day1 to day 28 and post-treatment follow-up phase (day 29 and up to end of the study).

Eligibility criteria:
key inclusion criteria: * patients who are diagnosed with relapsed/refractory b cell non-hodgkin lymphoma , especially * diffuse large b cell lymphoma, not other specified (dlbcl,nos), * primary mediastinal large b cell lymphoma (pmbcl) * transformation follicular lymphoma (tfl) * high grade b-cell lymphoma(hgbcl) * high grade b-cell lymphoma (hgbcl) with myc(myelocytomatosis oncogene) and bcl2(b-cell lymphoma2) /bcl6 (b-cell lymphoma6) rearrangement * refractory diseases are defined as one of the following * no response to last line of therapy: i. progressive disease (pd) as best response to most recent therapy regimen; ii. stable disease (sd) as best response to most recent therapy regimen * not candidate for autologous stem cell transplant (asct) or refractory post-asct: i. disease progression (pd) or relapsed ≤12 months of asct (must have biopsy proven recurrence in relapsed individuals) ii. if salvage therapy is given post-asct, the individual must have had no response to or relapsed after the last line of therapy * individuals must have received adequate prior therapy including at a minimum: * anti-cd20 monoclonal antibody unless investigator determines that tumor is cd20-negative and * an anthracycline containing chemotherapy regimen * immunohistochemical staining shows at least two of b cell surface receptor antigen cd19,cd20, bcma are positive(including weak, medium and strong positive) * at least one measurable lesion during the screening based on the recommendation for initial evaluation, staging and response assessment of hodgkin and non-hodgkin lymphoma. * life expectancy ≥ 12 weeks * eastern cooperative oncology group (ecog) performance status of 0 or 1 * adequate renal, hepatic, pulmonary and cardiac function defined as: * renal function: serum creatinine ≤ 1.5 upper limit of normal(uln), or egfr ≥ 60 ml/min/1.73m2 \[egfr(estimated glomerular filtration rate)=186×age\^-0.203×scr\^-1.154（mg/dl）,female×0.742\] * hepatic function: i: serum alanine aminotransferase (alt)/aspartate aminotransferase (ast) ≤ 5 uln and ii: total bilirubin ≤ 2 uln, except in individuals with gilbert syndrome (in gilbert's syndrome patients, those with total bilirubin ≤ 3 uln and direct bilirubin ≤ 1.5 uln can be enrolled).iii: international normalized ratio (inr) or prothrombin time (pt) ≤1.5 uln pulmonary: have the minimum level of pulmonary reserve, defined as ≤ ctcae (common terminology criteria for adverse events) grade 1 dyspnea and the sao2(oxygen saturation)≥ 91% on room air * cardiac: left ventricular ejection fraction (lvef) ≥50% determined by echocardiogram(ecg) or multigated acquisition scan (muga) * adequate bone marrow function, define as: * absolute neutrophil count (anc) ≥1 ×10\^9/l * absolute lymphocyte count (alc)≥ 0.5 ×10\^9/l * platelets ≥50 ×109/l； * hemoglobulin ≥80 g/l; patients with bone marrow involvement can be enrolled if globulin\>60 g/l * female of child-bearing age and male participants must agree to use effective contraceptive methods until no car-t cells can be detected by pcr(polymerase chain reaction) test. key exclusion criteria: * individuals who have anticd45 or anticd3 therapy * individuals with detectable cerebrospinal fluid malignant cells, or brain metastases, or with a history of primary or secondary cns (central nervous system) lymphoma, cerebrospinal fluid malignant cells or brain metastases * presence or history of cns disorder such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with cns involvement * history of allogeneic stem cell transplantation * any of the following situations: • hbsag/ hbeag positive; hbeab/hbcab positive and hbv(hepatitis b virus) dna copies above the lower test limit; * hcv(hepatitis c virus) rna positive * hiv(human immunodeficiency virus) positive or treponema pallidum positive * presence of active or life-threatening fungal, bacterial, viral, or other infection that is uncontrolled or requiring iv antimicrobials for management. * individuals presence of unstable angina or myocardial infarction within 6 months of screening, or other severe/uncontrolled diseases during the screening (eg. unstable or uncompensated respiratory, cardiac, hepatic or renal disease) * presence of uncontrolled arrhythmia with treatment * pregnancy or breastfeeding women other protocol defined inclusion/exclusion criteria may apply.

Keywords: b cell non-hodgkin lymphoma car-t cd19 cd22 bcma