Loncastuximab Tesirin a Rituximab jako překlenovací terapie před standardní péčí CD19 CAR T-buněčnou terapií u pacientů s velkým B-lymfomem (CORAL)

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.