Treatment of Relapsed or Refractory B-cell Lymphoma With Chimeric Antigen Receptor (CAR) T-cell Therapy Produced by a New Technology

Multicentre Phase I/IIa Study of Infusion of Autologous Peripheral Blood T Lymphocytes Expanded and Genetically Modified Using Sleeping Beauty Family Transposons to Express a Chimeric Antigenic Receptor With Anti-CD19 Specificity Conjugated to the 4-1BB Co-stimulatory Region and CD3z and huEGFRt Signal Transmission (TranspoCART19) in Patients With Relapsed or Refractory B-cell Lymphoma

The goal of this clinical trial is to to evaluate the safety and efficacy of TranspoCART19 in patients with relapsed/refractory B-lymphoma. The main questions it aims to answer are:

Maximum tolerated dose (MTD) Response rates Participants will be treated with the investigational medicinal product and will be followed for 36 months.

This clinical trial is a Phase I/II, pilot, open-label, national, prospective, multicentre, non-randomised, open-label study to evaluate the safety and efficacy of TranspoCART19 in patients with relapsed/refractory B-lymphoma whose prognosis is less than 2 years.

Phase I: Dose escalation phase with a classic 3+3 design, in which three dose levels of TranspoCART19 will be evaluated: 1 x 106 cells/kg, 3 x106 cells/kg and 5 x 106 cells/kg. The maximum number of patients included in this phase will be 18.

Phase II: an expansion cohort with the maximum tolerated dose (MTD) determined in Phase I.

Patients will be included in the expansion cohort up to a total of 27, including Phase I patients.

Inclusion Criteria:

1. Patients diagnosed with relapsed or refractory B-cell lymphoma (Diffuse large B-cell lymphoma, Primary diffuse large B-cell lymphoma of the Central Nervous System (CNS), Mantle cell lymphoma, Follicular lymphoma grades 1, 2 or 3a or Marginal lymphoma, including splenic, nodal and MALT).
2. Age over 18 years and under 80 years.
3. Functional status Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1. Patients with ECOG 2 may be included if motivated by haematological disease (Annex 3).
4. Adequate bone marrow haematopoietic reserve.
5. Life expectancy of at least 2 months.
6. Adequate venous access for lymphapheresis. Absence of contraindications for lymphapheresis.
7. Signed informed consent (patient or legal guardian).

Exclusion Criteria:

1. Patients who, in the opinion of a physician, may benefit from other approved potentially curative therapeutic options, including commercial CAR-Ts.
2. Treatment with any experimental or non-commercialised substance in the four weeks prior to recruitment, or who are actively participating in another therapeutic clinical trial.
3. Diagnosis of another neoplasm, past or present. Patients who have been in complete remission for more than 3 years, or with a history of non-melanoma skin cancer or completely resected carcinoma in situ may be included. A current or previous history of clonal T-lymphocytes is also an exclusion criterion.
4. Early relapse after allogeneic haematopoietic stem cell transplantation (less than 3 months for lymphapheresis, less than 6 months for TranspoCART19 infusion) or patients on active immunosuppressive treatment for graft-versus-recipient disease (corticosteroids or other systemic immunosuppressants).
5. Active infection requiring systemic medical treatment.
6. HIV infection.
7. Concurrent and uncontrolled medical illnesses including cardiac, renal, hepatic, gastrointestinal, endocrine, pulmonary, neurological or psychiatric illnesses that in the opinion of the investigator pose a risk to the patient.
8. Positive serology for hepatitis B, defined as a positive test for HBsAg. In addition, if the patient is HBsAg negative but has anti-HBcore antibodies, a hepatitis B virus DNA test will be required, and if the result is positive the patient will be excluded.
9. Positive serology for hepatitis C virus (HCV), defined as a positive test for anti-HCV antibodies that is confirmed by Recombinant immunoblot assay (RIBA).
10. Severe organ involvement, defined as cardiac ejection fraction <40%; diffusing capacity of the lungs for carbon monoxide (DLCO) <40%; calculated glomerular filtration rate <30 ml/min; baseline O2 saturation <92%; bilirubin > 2 times upper limit of normal (unless due to Gilbert's syndrome) or transaminases > 2.5 upper limit of normal.
11. Pregnant or lactating women. Women of childbearing age should have a negative pregnancy test at screening.
12. Women of childbearing age, including those whose last menstrual cycle was in the year prior to screening, who are unable or unwilling to use highly effective methods of contraception* from the start of the study until the end of the study.
13. Men who are unable or unwilling to use highly effective methods of contraception* from the start of the study until the end of the study.
14. Need to take glucocorticoids chronically in doses greater than 10 mg/day of prednisone (or equivalent) or other chronic immunosuppressants.
15. Previous anti-CD19 CAR-T therapy. Previous treatment with other anti-CD19 strategies is permitted, provided that CD19 expression has been confirmed in the tumour biopsy.
16. Hypersensitivity to the active substance or to any of the excipients.