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Bridging Therapy with Loncastuximab Tesirine and Rituximab for the Treatment of Relapsed/Refractory Large B-cell Lymphoma in Patients Undergoing CD19 CAR T-cell Therapy
Trial Status: active
This phase II trial studies how well bridging therapy with loncastuximab tesirine and rituximab (lonca-R) works in treating patients that are undergoing standard of care (SOC) CD19 chimeric antigen receptor (CAR) T-cell therapy for large B-cell lymphoma that has come back after a period of improvement (relapsed) or that does not respond to treatment (refractory). CD19 CAR T-cell therapy is a treatment that uses T-cells that have been engineered to contain a CAR that specifically targets the CD19 antigen. Bridging therapy is often given before CAR T-cell therapy to help transition the patient to the CAR T-cell therapy or to maintain their health or status until they are a candidate for the CAR T-cell therapy. Loncastuximab tesirine is a monoclonal antibody, called loncastuximab, linked to a drug, called pyrrolobenzodiazepine (PBD). Loncastuximab is a form of targeted therapy because it attaches to specific molecules (receptors) on the surface of cancer cells, known as CD19 receptors, and delivers PBD to kill them. Rituximab is a monoclonal antibody. It binds to a protein called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. Giving bridging therapy with lonca-R may be effective in treating patients undergoing SOC CD19 CAR T-cell therapy for relapsed/refractory (R/R) large B-cell lymphoma.
Inclusion Criteria
Subject aged ≥ 18 years
Intended to receive commercial CD19-directed CAR-T cell therapy (axicabtagene ciloleucel [axi-cel] and lisocabtagene maraleucel [liso-cel])
Need for bridging therapy as deemed clinically necessary by the treating physician
Relapsed or refractory diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma (tFL) or primary mediastinal large B-cell lymphoma (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
Eastern Cooperative Oncology Group (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
Absolute neutrophil count (ANC) ≥ 1000/mm^3
Platelet count ≥ 75,000/mm^3
Hemoglobin ≥ 8 g/dL
Bilirubin ≤ 1.5 x upper limit of normal (ULN) or ≤ 3 x ULN with document liver involvement and/ or Gilbert’s disease
Transaminases (aspartate aminotransferase [AST] or alanine aminotransferase [ALT]) ≤ 3 x ULN or ≤ 5 x ULN with documented liver involvement
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
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 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 central nervous system (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
** QT interval corrected (QTc) prolongation defined as a QT interval corrected using Fridericia equation (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 deoxyribonucleic acid (DNA) polymerase chain reaction (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 hepatitis (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 anti-drug antibody (ADA) to a CD19 antibody
Subjects taking prohibited medications as described. 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
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT06788964.
I. To evaluate the efficacy of SOC CAR T-cell therapy in patients with R/R large B-cell lymphoma following bridging with lonca-R.
II. To evaluate toxicities post CAR-T.
SECONDARY OBJECTIVES:
I. To assess the safety and tolerability of lonca-R in the study population.
II. To determine whether CD19 expression is reduced in patients who receive bridging with lonca-R prior to CAR-T.
III. To evaluate the level of disease control provided by bridging lonca-R.
EXPLORATORY OBJECTIVES:
I. To describe the number of cycles of lonca-R administered compared to the efficacy of CAR-T.
II. Time to event analyses post CAR-T.
III. To evaluate post-CAR-T cytokine release syndrome (CRS) and immune-effector cell-associated neurotoxicity syndrome (ICANS).
OUTLINE:
Patients receive loncastuximab tesirine intravenously (IV) over 30 minutes followed by rituximab IV on day 1 of each cycle. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, computed tomography (CT) and positron emission tomography (PET) or PET/CT throughout the study. Patients may also undergo tissue biopsy or bone marrow aspiration throughout the study.
After completion of study treatment, patients who are unable to receive CAR T-cell therapy are followed up at 7 and 60 days, patients who receive CAR T-cell therapy are followed up at 7 and 30 days and prior to initiation of lymphodepletion chemotherapy and then every 3 months for up to 1 year after CAR-T administration.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationHuntsman Cancer Institute/University of Utah
