Axicabtagene Ciloleucel CAR T-cells in Patients With Relapsed or Refractory Primary Mediastinal B-cell Lymphoma

This phase II study will evaluate the efficacy, safety and tolerability of second-line treatment with axicabtagene ciloleucel in primary mediastinal B-cell lymphoma patients (PMBCL).

Patients who are refractory or relapse after first-line therapy of PMBCL have poor outcomes when treated with standard salvage therapy consisting of high-dose therapy and autologous stem cell transplantation. Recent studies and real-world data on CAR T-cells in patients with early relapsed or refractory aggressive B-cell lymphoma, particularly diffuse large cell B-Cell lymphoma, showed improved event free survival and overall survival with axicabtagene ciloleucel compared with the previous standard of care. These reports suggest comparable efficacy with similar toxicity profiles for CAR T-cells in PMBCL. However, larger studies with CAR T-cells in patients who are refractory to first-line therapy or who relapse after an initial response are urgently needed.

Eligibility Criteria:
Inclusion Criteria:

1. Signed written informed consent form (ICF) according to ICH/EU GCP and national regulations
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
10. 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
    * No evidence of Grade 2 (per Common Terminology Criteria for Adverse Events \[CTCAE\] 5.0) or greater pleural effusion or ascites (subjects with Grade 1 ascites or pleural effusion are eligible)
    * Baseline oxygen saturation \> 92% on room air
12. 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

Exclusion Criteria:

1. 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
6. 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
11. 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
16. 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. History of deep vein thrombosis or pulmonary embolism requiring therapeutic anticoagulation within 6 months of enrollment
22. Primary immunodeficiency
23. Any medical condition likely to interfere with assessment of safety or efficacy of study treatment
24. Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow up schedule