Clinical trial NCT06788964: Loncastuximab Tesirine and Rituximab as Bridging Therapy Prior to Standard-of-care CD19 CAR T-cell Therapy in Patients With Large B-cell Lymphoma
Official title: 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
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Relapsed or Refractory Large B-cell Lymphoma
Lead sponsor: University of Utah
Sponsor class: OTHER
Collaborators: name: ADC Therapeutics S.A.
First posted: 2025-01-23
Enrollment: 29
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.


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.

Primary outcomes:
measure: The complete response (CR) rate at D30 (+/- 7 days) post CAR-T administration per Lugano 2014 criteria.
timeFrame: 1 month
measure: Duration of cytopenias post CAR-T (as defined by the NIH CTCAE, version 5.0) D30 (+/- 7 days).
timeFrame: 1 month
measure: Severity of cytopenias post CAR-T (as defined by the NIH CTCAE, version 5.0) D30 (+/- 7 days).
timeFrame: 1 month
measure: Rate of infections D30 (+/- 7 days).
timeFrame: 1 month
Secondary outcomes:
measure: 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)
timeFrame: 5 years
measure: ORR defined as the proportion of subjects achieving a confirmed PR or CR at D30 (+/- 7 days) post CAR-T per Lugano 2014 criteria1.
timeFrame: 1 month
measure: Best response rate per Lugano 2014 criteria following CAR-T (based on imaging up until D90 post CAR-T)
timeFrame: 3 months
measure: ORR defined as the proportion of subjects achieving a confirmed PR or CR post lonca-R (pre-CAR-T)
timeFrame: 5 years
measure: 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
timeFrame: 5 years
measure: The frequency of adverse events (AEs) and serious adverse events (SAEs) characterized by severity (as defined by the NIH CTCAE, version 5.0)
timeFrame: 5 years
measure: The frequency of adverse events (AEs) and serious adverse events (SAEs) characterized by seriousness.
timeFrame: 5 years
measure: The frequency of adverse events (AEs) and serious adverse events (SAEs) characterized by duration.
timeFrame: 5 years
measure: The frequency of adverse events (AEs) and serious adverse events (SAEs) characterized by relationship to study treatment.
timeFrame: 5 years
Other outcomes:
Locations:
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute at University of Utah
state: Utah
Study officials:
References: