Evaluation of Axicabtagene Ciloleucel CAR T-Cell Therapy in Relapsed or Refractory Primary Mediastinal B-Cell Lymphoma Patients

Trial ID: 2024-510972-19-00
Protocol: UniMS23_0018
Sponsor: Universitaet Muenster

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Diseases & Conditions

Primary mediastinal large B-cell lymphoma

Objectives

The primary objective of this study is to evaluate the **efficacy** of axicabtagene ciloleucel in patients with relapsed or refractory primary mediastinal large B-cell lymphoma (r/r PMBCL), specifically by measuring the complete metabolic response (CMR) rate. This is clinically relevant as achieving a CMR is indicative of a favorable treatment response, potentially leading to improved patient outcomes in this challenging lymphoma subtype.

Secondary objectives include:

Characterizing the safety profile of axicabtagene ciloleucel in subjects with r/r PMBCL, with a particular focus on cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).
Further evaluating the efficacy of axicabtagene ciloleucel in this patient population.

Participants

The clinical trial involves participants diagnosed with **primary mediastinal large B-cell lymphoma (PMBCL)**. The study population includes both male and female subjects, all of whom are over the age of 18. Participants are required to have a good general health status, as indicated by an Eastern Cooperative Oncology Group (ECOG) performance status of less than 2, and must meet specific health criteria, including adequate bone marrow, renal, hepatic, cardiac, and pulmonary function. The trial does not include a vulnerable population. The selection process for participants is based on their medical history and current health status, ensuring they have relapsed or refractory disease after first-line chemoimmunotherapy. Lifestyle considerations such as diet and physical activity are not specified, but participants must agree to use effective contraceptive methods if they are of childbearing potential. The sponsor has not provided information regarding the total number of participants in the trial.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of **axicabtagene ciloleucel** in patients with relapsed or refractory primary mediastinal large B-cell lymphoma (PMBCL). This is a Phase II, randomized, double-blind, controlled trial. The trial is expected to commence recruitment on January 31, 2025, and conclude by January 31, 2029. The primary endpoint is the complete metabolic response (CMR) rate at three months post-infusion, assessed via PET-CT or PET-MRI according to the Deauville and Lugano Classification.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and previous treatment history. Following successful screening, participants will receive the investigational product, **YESCARTA 0.4 – 2 x 10e8 cells dispersion for infusion**, administered via infusion. Follow-up visits will be scheduled to monitor the participants' response to treatment and assess any adverse events. The end-of-study visit will occur at the conclusion of the trial or upon early termination.

The expected duration of participant involvement is approximately four years, from the initial screening to the end-of-study visit. Conditions that may lead to early termination from the study include the occurrence of significant adverse events, withdrawal of consent, or failure to comply with study procedures. Participants must meet specific inclusion criteria, such as having a histologically confirmed diagnosis of PMBCL and adequate organ function, to be eligible for the trial. The trial will not include individuals who do not meet these criteria or those with contraindications to the investigational product.

Treatment

The clinical trial involves the administration of **axicabtagene ciloleucel**, marketed under the name YESCARTA, which is a **dispersion for infusion**. This experimental medication is specifically formulated for the treatment of patients with relapsed or refractory primary mediastinal B-Cell Lymphoma (PMBCL). The pharmaceutical form is a dispersion containing 0.4 – 2 x 10⁸ cells, and it is administered via **infusion**. The maximum daily dose is 400,000 cells, with a total maximum dose of 200,000,000 cells. The treatment period is limited to a single day. Axicabtagene ciloleucel is a structurally diverse substance categorized as a cell therapy, specifically involving autologous T cells transduced with a retroviral vector encoding an anti-CD19 CD28/CD3-zeta chimeric antigen receptor, also known as KTE-C19. The product is not a pediatric formulation and has been designated as an orphan drug.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on evaluating the efficacy of axicabtagene ciloleucel in achieving a complete metabolic response in the target patient population. Participant compliance with the dosing schedule is monitored through standard clinical trial procedures, ensuring adherence to the single-day infusion protocol. The trial is conducted under the authorization of KITE PHARMA EU B.V., with the product holding the marketing authorization number EU/1/18/1299/001.

Efficacy

The efficacy of **axicabtagene ciloleucel** in patients with relapsed or refractory primary mediastinal B-cell lymphoma (PMBCL) will be assessed by measuring the complete metabolic response (CMR) rate. The primary endpoint for evaluating efficacy is the CMR rate at 3 months following the infusion of axicabtagene ciloleucel. This assessment will be conducted using disease evaluation through PET-CT or PET-MRI, adhering to the Deauville and Lugano Classification criteria. The trial is designed to provide a comprehensive evaluation of the treatment's efficacy in achieving a complete metabolic response in the specified patient population.

Inclusion and Exclusion Criteria

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Inclusion Criteria

1.Signed written informed consent form (ICF) 2. Age > 18 years 3. ECOG performance status < 2 4. Histologically confirmed primary mediastinal B-cell lymphoma (PMBCL) • based on the 2022 World Health Organization (WHO) (R. Allagio et al.) • classification by local pathology laboratory assessment 5. Patients must have received adequate first-line therapy including: • An anti-CD20 monoclonal antibody (rituximab), and • CHOP or CHOP-like chemotherapy Note: CHOP-like chemotherapy corresponds to CHOEP, ACVBP or EPOCH or COPADEM. Patients who received dose-reduced CHOP (e.g., mini-CHOP) are excluded except for dose reductions of vincristine due to peripheral neuropathy. Patients who have received additional drugs in combination with CHOP or CHOP-like regimen are eligible. 6. Relapsed or refractory disease after first-line chemoimmunotherapy, documented by PET-CT: • Relapsed disease defined as complete remission to first-line therapy followed by biopsy-proven relapse • Refractory disease defined as:  Progressive disease (PD) during first-line therapy  Stable disease (SD) as best response after at least 4 cycles of first-line therapy (e.g., 4 cycles of R-CHOP) and biopsy-proven residual disease, or  Partial response (PR) as best response after at least 6 cycles, and biopsy-proven residual disease 7. At least 2 weeks must have elapsed since any prior systemic cancer therapy at the time the patient provides consent 8. Lymphoma tissue at recurrence available for central pathologic examination, exploratory endpoints, and ancillary studies (detailed sample collection requirements are described in protocol section 8.2) 9. Patients must have at least 1 measurable lesion per the Lugano Classification on anatomical imaging such as computed tomography (CT) imaging (functional imaging such as PET may not be used to identify a measurable lesion). A measurable lesion is defined as greater than 1.5 cm LDi for lymph node and greater than 1.0 cm LDi for extranodal lesions
Patients must be eligible for CAR T-cells as defined by: • Patient deemed eligible for CAR T-cells therapy by the study physician • Adequate vascular access for leukapheresis procedure (either peripheral or central venous line) 11. Adequate bone marrow, renal, hepatic, cardiac and pulmonary function defined as: • Absolute neutrophil count (ANC) ≥ 1000 cells/μL • Absolute lymphocyte count > 100/μL • Platelets ≥ 75,000 cells/μL • Creatinine clearance (as estimated by Cockcroft Gault) ≥ 40 ml/min • Transaminases (AST and ALT) <2.5 x ULN • Total bilirubin < 1.5 x ULN unless other reason known (Gilbert-Meulengracht-Syndrome in which 3 x ULN would be acceptable) • Left ventricular ejection fraction (LVEF) ≥ 40% and no evidence of clinically significant pericardial effusion, and no significant abnormal electrocardiogram (ECG) findings • Baseline oxygen saturation > 92% on room air
Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test (females who have undergone surgical sterilization or who have been postmenopausal for at least 12 months are not considered to be of childbearing potential) 13. Sexually active men and FCBP must agree to use one of the highly effective contraceptive methods (combined oral contraceptives using two hormones, contraceptive implants, injectables, intrauterine devices, sterilized partner) together with one of the barrier methods (latex condoms, diaphragms, contraceptive caps) while on study; this should be maintained for 12 months after the last dose of study drug 14. Willingness not to drive a vehicle for 8 weeks post CAR T-cell treatment

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Exclusion Criteria

Patients who received more than one prior line of systemic therapy 2. Prior CD19-targeted therapy 3. History of another primary malignancy that has not been in remission for at least 2 years (except for non-melanoma skin cancer or carcinoma in situ (e.g., cervix, bladder, breast)). A maintenance treatment is not allowed 4. History or presence of non-malignant CNS disorder, such as seizure disorder requiring anti-convulsive therapy, cerebellar disease, any autoimmune disease with CNS involvement, posterior reversible encephalopathy syndrome (PRES), or cerebral edema with confirmed structural defects by appropriate imaging. History of stroke or transient ischemic attack within 12 months prior to enrollment. • Secondary CNS involvement of PMBCL is not an exclusion criterion 5. History of acute or chronic active hepatitis B or C infection. If there is a positive history of treated hepatitis B or hepatitis C, the viral load must be undetectable per quantitative polymerase chain reaction (PCR) and/or nucleic acid testing
Positive for human immunodeficiency virus (HIV) unless taking appropriate anti-HIV medications, with an undetectable viral load by PCR and with a CD4 count > 200 cells/µl 7. Presence of any indwelling line or drain (e.g., percutaneous nephrostomy tube, indwelling Foley catheter, biliary drain, or pleural/peritoneal catheter). Dedicated venous access catheters, such as a Port-a-Cath or Hickman catheter, are permitted 8. Uncontrolled systemic fungal, bacterial, viral or other infection despite appropriate antimicrobials at the time of enrollment 9. Presence of cardiac atrial or ventricular lymphoma involvement 10. History of any one of the following cardiovascular conditions within the past 12 months: Class III or IV heart failure as defined by the New York Heart Association, cardiac angioplasty or stenting, myocardial infarction, unstable angina, or other clinically significant cardiac disease
History of any medical condition including but not limited to autoimmune disease (e.g., Crohn’s disease, rheumatoid arthritis, systemic lupus) requiring systemic immunosuppression and/or systemic disease modifying agents within the last year. Endocrine conditions that require maintenance with physiologic dose steroids are allowed 12. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis per chest computed tomography (CT) scan at screening. History of radiation pneumonitis in the radiation field (fibrosis) is allowed 13. History of severe immediate hypersensitivity reaction to any of the agents used in this study, including aminoglycosides, cyclophosphamide, fludarabine or tocilizumab 14. Treatment with a live, attenuated vaccine within 6 weeks prior to initiation of study treatment or anticipation of need for such a vaccine during the study 15. FCBP who are pregnant or breastfeeding
In the investigator’s judgment, the patient is unlikely to complete all protocol-required study visits or procedures, including follow-up visits, or comply with the study requirements for participation 17. Adult person unable to provide informed consent because of intellectual impairment, any serious medical condition, laboratory abnormality or psychiatric illness. 18. Simultaneously active participation in another clinical trial involving an IMP within 30 days prior to enrolment into this clinical trial 19. Patients with a physical or psychiatric condition which at the investigator’s discretion may put the patient at risk, may confound the trial results, or may interfere with the patient’s participation in this clinical trial 20. Known or persistent abuse of medication, drugs or alcohol 21. Primary immunodeficiency 22. Any medical condition likely to interfere with assessment of safety or efficacy of study treatment 23. Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow up schedule