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

B-cell Lymphoma Recurrent Clinical Trial

— TranspoCART19  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06378190
• Other study ID #: TranspoCART19
• Secondary ID: 2022-001040-23
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: March 11, 2024
• Est. completion date: October 2028

Study information

• Verified date: February 2024
• Source: Instituto de Investigación Biomédica de Salamanca
• Contact: Esperanza López_Franco, PhD
• Phone: 923 291200
• Email: uicec.coordinacion[@]ibsal.es
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 27
• Est. completion date: October 2028
• Est. primary completion date: April 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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.

Related Conditions & MeSH terms

• B-cell Lymphoma Recurrent
• Lymphoma
• Lymphoma, B-Cell
• Refractory B-Cell Lymphoma

Intervention

Biological:
• CAR-T cells therapy
CAR-T cells therapy

Locations

Country	Name	City	State
Spain	Hospital Clínic	Barcelona
Spain	Virgen de la Arrixaca University Hospital	El Palmar	Mur
Spain	Institut Català d'Oncologia Hospital	Hospitalet de Llobregat	Barcelona
Spain	Fundación Jiménez Díaz Hospital	Madrid
Spain	Clínica Universidad de Navarra	Pamplona	Navarra
Spain	University Hospital of Navarra	Pamplona	Navarra
Spain	Salamanca University Health Care Complex	Salamanca
Spain	Virgen del Rocio Hospital	Sevilla

Sponsors (4)

Lead Sponsor	Collaborator
Instituto de Investigación Biomédica de Salamanca	Fundación Canaria de Investigación Sanitaria, Fundación para la Investigación Biomédica del Hospital 12 de Octubre, Spanish Clinical Research Network - SCReN

Country where clinical trial is conducted

Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Molecular and cell biology exploratory objectives: Response dynamics	Assess disease response dynamics by Positron Emission Tomography (PET); - Calculate SUVmax value	days +28, +100, +180; 9 months - 12 months - 18 months - 24 months - 30 months - 36 month. Biopsy: days 7, 14, 28, 56, 100 and 180 - 6 months - 9 months - 12 months -18 months - 24 months - 36 month.
Other	Molecular and cell biology exploratory objectives: Response dynamics	Assess disease response dynamics by Positron Emission Tomography (PET); - Calculate tumour metabolic volume (mL)	days +28, +100, +180; 9 months - 12 months - 18 months - 24 months - 30 months - 36 month. Biopsy: days 7, 14, 28, 56, 100 and 180 - 6 months - 9 months - 12 months -18 months - 24 months - 36 month.
Other	Molecular and cell biology exploratory objectives: Response dynamics	Assess disease response dynamics by Positron Emission Tomography (PET); - Calculate total lesion glycolysis (mL)	days +28, +100, +180; 9 months - 12 months - 18 months - 24 months - 30 months - 36 month. Biopsy: days 7, 14, 28, 56, 100 and 180 - 6 months - 9 months - 12 months -18 months - 24 months - 36 month.
Other	Molecular and cell biology exploratory objectives: In vivo survival of TranspoCART19 cells in peripheral blood	Evaluation of time (days) for TranspoCART19 cell survival determined by flow cytometry	36 month
Other	Molecular and cell biology exploratory objectives: Analysis of molecular markers which are possibly related to the tumor response to TranspoCART19 cells	The tumour biopsy sample obtained prior to infusion of TranspoCART19 cells will be analysed by whole exome study in order to identify possible molecular markers related to the tumor response/resistance to the TranspoCART19 cells.	Screening and relapse (in case of)
Other	Molecular and cell biology exploratory objectives: Evaluation of serum biomarkers of toxicity induced by TranspoCART19 cells (cytokine release syndrome and neurotoxicity)	Cytokine analyses by ELISA will be performed on the samples collected in order to correlate the obtained data with the development of either cytokine release syndrome or neurotoxicity.	screening, day 0, +1, +7, +14, +21, +28+, 56 and +100.
Other	Molecular and cell biology exploratory objectives: Epigenetic studies on mononuclear bone marrow cells.	Epigenomic studies including Conventional and advanced technologies in profiling DNA methylation, histone modifications and ncRNAs.	screening, +28, +100 and relapse (in caso of)
Primary	Maximum tolerated dose (MTD)	Determine the maximum tolerated dose (MTD) and/or recommended dose of TranspoCART19 cells in patients with relapsed or refractory B-cell lymphoma.	1 month
Primary	Efficiency	Determine best response rate achieved (overall and complete).	3 month
Secondary	Procedure-related mortality (PRM)	Rate of mortality, defined as any death not directly caused by lymphoma.	1 month - 3 month
Secondary	Toxicity assessment	Number of grade II-IV adverse events using Common Toxicity Criteria (CTC) version 5.0	1 month - 3 month - 12 month - 36 month
Secondary	Response (overall and complete)	Best response rate achieved (overall and complete) following Lugano classification (PET-CT treatment response)	1 month - 3 month - 12 month - 36 month
Secondary	Duration of response	Time (month) in overall response and complete response.	36 month
Secondary	Progression-free survival (PFS)	Time (month) between infusion of TranspoCART19 and disease progression or death.	12 month - 24 month
Secondary	Overall survival (OS)	Time (month) between infusion of TranspoCART19 and death of the patient from any cause.	12 month - 24 month
Secondary	Perceived general well-being	Evaluation of quality of life using EuroQol-5 Dimension-5 levels (EQ-5D-5L) questionnaire [score range from 0 (the worst health status for that dimension) to 100 (the best health status)]	3 month -6 month -12 month