Loncastuximab tesirine plus rituximab as bridging therapy before CAR-T for relapsed or refractory large B‑cell lymphoma

A Phase 2 Study of Loncastuximab Tesirine and Rituximab as Bridging Therapy Prior to Standard-of-care CD19 CAR T-cell Therapy in Patients With Large B-cell Lymphoma

This trial tries loncastuximab tesirine with rituximab as a bridge before commercial CD19 CAR‑T therapy for adults with relapsed or refractory large B‑cell lymphoma to see if it is safe and helps control disease before CAR‑T.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 29 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: University of Utah (Academic / other)
• Drugs / interventions: CAR-T, CAR T, chemotherapy, radiation, Loncastuximab, Rituximab, chimeric antigen receptor
• Locations: 1 site (Salt Lake City, Utah)
• Trial ID: NCT06788964 on ClinicalTrials.gov

What this trial studies

This Phase 2 study gives patients with relapsed or refractory large B‑cell lymphoma loncastuximab tesirine combined with rituximab while they await commercial CD19-directed CAR‑T cell therapy (axi‑cel or liso‑cel). Eligible adults must need bridging therapy as determined by their treating physician and have measurable disease by PET‑CT or CT/MRI. The trial monitors safety, tumor response by imaging, and whether disease control is achieved prior to leukapheresis and CAR‑T infusion. Treatment is offered at the Huntsman Cancer Institute and responses are followed to see how bridging affects subsequent CAR‑T delivery and early outcomes.

Who should consider this trial

Good fit: Adults (≥18 years) with relapsed or refractory diffuse large B‑cell lymphoma, transformed follicular lymphoma, primary mediastinal B‑cell lymphoma, or high‑grade B‑cell lymphoma who are planned for commercial CD19 CAR‑T therapy and require physician‑deemed bridging therapy are ideal candidates.

Not a fit: Patients who do not need bridging, are not eligible for commercial CD19 CAR‑T, or who have contraindications to loncastuximab tesirine or rituximab are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, this approach could reduce tumor burden and disease progression before CAR‑T, potentially improving the chances of receiving CAR‑T and its effectiveness.

How similar studies have performed: Loncastuximab tesirine has shown single‑agent activity and is approved for relapsed/refractory large B‑cell lymphoma, but combining it with rituximab specifically as a standardized bridge to CAR‑T is a relatively new approach.

Eligibility criteria

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. 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.

Where this trial is running

Salt Lake City, Utah

• Huntsman Cancer Institute at University of Utah — Salt Lake City, Utah, United States (Recruiting)

Study contacts

• Principal investigator: Narendranath Epperla, MD, MS, FACP — Huntsman Cancer Institute/ University of Utah
• Study coordinator: Rachel Kingsford

Conditions Relapsed or Refractory Large B-cell Lymphoma