CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

* Subject aged ≥ 18 years.
* Intended to receive commercial CD19-directed CAR-T cell therapy (axi-cel and liso-cel).
* Need for bridging therapy as deemed clinically necessary by the treating physician.
* Relapsed or refractory DLBCL, tFL or PMBCL as defined by the 2016 World Health Organization classification (including patients with DLBCL transformed from indolent lymphoma), or high-grade B-cell lymphoma (HGBL), not otherwise specified, and HGBL with MYC and BCL2 and/or BCL6 rearrangements.

  --Relapsed (disease that has recurred following a response) or refractory (disease that failed to respond to prior therapy) disease following at least one multi-agent systemic treatment regimen.
* Measurable disease as defined by the 2014 Lugano Classification as assessed by positron-emission tomography (PET)- computed tomography (CT) or by CT or magnetic resonance imaging (MRI) if the tumor is not fluorodeoxyglucose (FDG)-avid on screening PET-CT.
* ECOG Performance Status ≤ 2.
* Time between prior anticancer therapy and first dose of lonca-R as below

  * Autologous hematopoietic cell transplantation - At least 30 days
  * Allogeneic hematopoietic cell transplantation - At least 60 days
  * Cytotoxic chemotherapy - At least 21 days
  * Non-cytotoxic chemotherapy (e.g., small molecule inhibitor) - At least 14 days
* Adequate organ function as defined as:

  * Hematologic:

    * Absolute neutrophil count (ANC) ≥ 1000/mm3
    * Platelet count ≥ 75,000/mm3
    * Hemoglobin ≥ 8 g/dL
  * Hepatic:

    * Bilirubin ≤1.5 x upper limit of normal (ULN) or ≤3 x ULN with document liver involvement and/ or Gilbert's disease
    * Transaminases (AST or ALT) ≤ 3 x ULN or ≤ 5 x ULN with documented liver involvement
  * Renal:

    * Estimated creatinine clearance ≥ 60 mL/min by Cockcroft-Gault formula.
* For female subjects: Negative pregnancy test or evidence of post-menopausal status. The post-menopausal status will be defined as having been amenorrheic for 12 months without an alternative medical cause or having undergone surgical sterilization (bilateral oophorectomy or hysterectomy). The following age-specific requirements apply:

  * Women \< 50 years of age:

    * Amenorrheic for ≥ 12 months following cessation of exogenous hormonal treatments; and
    * Luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution; or
    * Underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
  * Women ≥ 50 years of age:

    * Amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments; or
    * Had radiation-induced menopause with last menses \>1 year ago; or
    * Had chemotherapy-induced menopause with last menses \>1 year ago; or
    * Underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy).
* Female subjects of childbearing potential and male subjects with a sexual partner of childbearing potential must agree to use a highly effective method of contraception and the lactation requirements as described in Sections 5.41.1 and 5.4.2.
* Subjects or their legal representatives must be able to read, understand, and provide informed consent to participate in the trial.
* Willing and capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol

Exclusion Criteria:

* Previous treatment with any anti-CD19 therapy including lonca or prior CD19 CAR T-cell therapy
* Subjects receiving investigational CAR-T products
* Major surgery within 4 weeks prior to starting study therapy.
* History of bleeding diathesis (e.g., von Willebrand's disease), hemophilia, or active bleeding.
* Subjects with chronic liver disease with hepatic impairment Child-Pugh class C
* Pregnant or lactating or intending to become pregnant during the study
* Active graft-versus-host disease
* Post-transplantation lymphoproliferative disorders
* Active autoimmune disease which, in the opinion of the investigator, may negatively impact subject safety or interfere with study participation.
* The diagnosis of another malignancy which, in the opinion of the investigator, is likely to negatively impact subject safety or interfere with study participation.
* Subjects with known CNS involvement.
* Significant medical diseases or conditions including those requiring substantial changes in concomitant medications, as assessed by the investigator, that would substantially increase the risk-to-benefit ratio of participating in the study. This includes, but is not limited to the following conditions:

  * Cardiovascular disorders:

    * Congestive heart failure New York Heart Association Class III or IV, unstable angina pectoris, serious cardiac arrhythmias.
    * Myocardial infarction (MI) within 6 months before the first dose.
    * QTc prolongation defined as a QTcF \> 480 ms.
    * Congenital long QT syndrome or a corrected QT measure (QTc) interval of \>480 ms at screening (unless secondary to pacemaker or bundle branch block).
  * Severe pulmonary disease
  * Uncontrolled diabetes mellitus
  * Severely immunocompromised state
  * Any other condition that would, in the Investigator's judgment, contraindicate the subject's participation in the clinical study due to safety concerns or compliance with clinical study procedures.
* Active systemic bacterial, viral, fungal, or other infection requiring systemic treatment at time of screening
* HIV infection.
* Subjects with evidence of active hepatitis B infection, based on positive surface antigen or Hepatitis B DNA PCR are excluded. Subjects who are Hepatitis B core antibody positive must take prophylaxis with entecavir or equivalent and be willing to undergo monthly Hepatitis B DNA PCR testing. Subjects with active Hep C patients may be enrolled if other parameters precluding hepatic impairment are met and they are not undergoing active therapy for hepatitis C.
* Known prior severe hypersensitivity to a CD19 antibody, lonca (including SG3249) or any of its excipients, or history of positive serum human ADA to a CD19 antibody.
* Subjects taking prohibited medications as described in Section 6.8.1. A washout period of prohibited medications for a period of at least five half-lives or as clinically indicated should occur before the start of treatment.

主要终点：The complete response (CR) rate at D30 post CAR-T(+/- 7 days) post CAR-T administration per Lugano 2014 criteria. · To evaluate the efficacy of SOC CAR T-cell therapy in patients with R/R large B-cell lymphoma following bridging with lonca-R. · 1 month；Duration of cytopenias post CAR-T (as defined by the NIH CTCAE, version 5.0) D30 post CAR-T (+/- 7 days). · To evaluate toxicities post CAR-T · 1 month；Severity of cytopenias post CAR-T (as defined by the NIH CTCAE, version 5.0) D30 (+/- 7 days). · To evaluate toxicities post CAR-T · 1 month；Rate of infections D30 (+/- 7 days). · To evaluate toxicities post CAR-T · 1 month
次要终点：CD19 expression as measured by flow cytometry and IHC on biopsies obtained pre- and post-lonca-R (optional) and post-CAR-T (optional but strongly recommended)；ORR defined as the proportion of subjects achieving a confirmed PR or CR at D30 (+/- 7 days) post CAR-T per Lugano 2014 criteria1.；Best response rate per Lugano 2014 criteria following CAR-T (based on imaging up until D90 post CAR-T)；ORR defined as the proportion of subjects achieving a confirmed PR or CR post lonca-R (pre-CAR-T)；Level of disease control (measured as percentage) with lonca-R as evaluated by CT measurements and metabolic tumor volume on PET pre and post Lonca-R；The frequency of adverse events (AEs) and serious adverse events (SAEs) characterized by severity (as defined by the NIH CTCAE, version 5.0)；The frequency of adverse events (AEs) and serious adverse events (SAEs) characterized by seriousness.；The frequency of adverse events (AEs) and serious adverse events (SAEs) characterized by duration.

• Treatment: All Patients · EXPERIMENTAL · The study will investigate the effectiveness of Loncastuximab tesirine and Rituximab (Lonca-R) prior to standard of care CAR-T cell therapy.

The purpose of this clinical trial is to learn if the study treatment Loncastuximab tesirine and Rituximab is safe and efficient before standard of care chimeric antigen receptor T-cell (CAR-T) therapy in patients with relapsed or refractory large B-cell lymphoma.