Phase I/IIa multicentre 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.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fundacion De Investigacion Biomedica De Salamanca

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

11 Mar 2024 → ongoing

Decision date (initial)

2024-10-10

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Instituto de Salud Carlos III

External identifiers

EU CT number

2024-514544-90-00

EudraCT number

2022-001040-23

ClinicalTrials.gov

NCT06378190

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Dose response

Phase I: - To evaluate the safety of TranspoCART19 cell infusion in patients with relapsed or refractory B-cell lymphoma.
- To determine the maximum tolerated dose (MTD) and/or recommended dose of TranspoCART19 cells in patients with relapsed or refractory
B-cell lymphoma.
Pase II: - To evaluate the efficacy of TranspoCART19 cell infusion in patients with relapsed or refractory B-cell lymphoma.

Secondary objectives 10

1. To assess the duration of response after infusion of TranspoCART19.
2. To assess progression-free and overall survival after TranspoCART19 infusion.
3. To assess the expansion and persistence of TranspoCART19 cells in peripheral blood after administration.
4. To assess adverse events following infusion of TranspoCART19 cells.
5. To assess the effect of TranspoCART19 treatment on patients' quality of life.
6. To assess the dynamics of disease response by PET (SUVmax, tumour metabolic volume and total lesion glycolysis).
7. To identify molecular markers of response by whole exome sequencing analysis of pre-treatment and relapse biopsy samples.
8. To follow-up of the tumour mass by liquid biopsy.
9. To identify clinical-biological factors associated with response to treatment with TranspoCART19 cells.
10. To identify serum biomarkers of TranspoCART19 cell toxicity (CRS/neurological toxicity).

Conditions and MedDRA coding

Relapsed or refractory B-cell lymphoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Patients diagnosed with relapsed or refractory B-cell lymphoma who meet the following conditions: • Diffuse large B-cell lymphoma with relapsed or refractory disease after at least 2 lines of systemic therapy and non-candidate or relapsed after autologous haematopoietic stem cell transplantation. Includes follicular lymphoma grade 3b and lymphomas transformed from any indolent entity, primary mediastinal lymphoma and high-grade B lymphoma (double/triple Hit and high-grade lymphoma NOS). • Primary diffuse diffuse large B-cell CNS lymphoma refractory or relapsed after 1 or more lines of systemic therapy including a high-dose methotrexate regimen. • Refractory mantle cell lymphoma with disease or relapsed after at least one line of treatment (including an anthracycline or bendamustine based regimen, anti-CD20 monoclonal antibody and BTKi treatment: ibrutinib, acalabrutinib...). • Follicular lymphoma (grades 1, 2 or 3a) histologically confirmed in the 6 months prior to screening (and after the last line of treatment received), refractory or relapsed, who have received at least 2 systemic treatment regimens (one of them including an antiCD20 such as rituximab, obinutuzumab). Post-transplant relapsed patients and patients with follicular lymphoma after one line of if they are POD24 or meet GELF criteria for treatment (see Annex II) may be included. • Marginal lymphoma, including splenic, nodal and MALT, histologically confirmed within 6 months prior to screening (and after the last line of treatment), refractory or relapsed, having received at least 2 systemic treatment regimens (one of them including an antiCD20 rituximab, obinutuzumab and an alkylating agent, or relapsed after autologous transplantation.
2. Age over 18 years and under 80 years.
3. Functional status ECOG 0-1. Patients with ECOG 2 may be included if motivated by haematological disease (Protocol Annex III).
4. Adequate bone marrow haematopoietic reserve.
5. Life expectancy of at least 2 months.
6. Adequate venous access for lymphapheresis. Absence of contraindications for the procedure.
7. Signature of informed consent (patient or legal guardian).

Exclusion criteria 15

1. Patients who may benefit from other approved therapeutic options.
2. Treatment with any experimental or non-marketed substance in the four weeks prior to recruitment, or actively participating in another therapeutic clinical trial.
3. Diagnosis of another neoplasm, past or present. Patients 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.
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-host 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-HBc 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, defined as a positive test for anti-HCV antibodies that is confirmed by RIBA.
10. Severe organ impairment, defined as cardiac ejection fraction <40%; 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 in the screening phase.
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 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 chronic glucocorticoids in doses higher than 10 mg/day of prednisone (or equivalent) or other chronic immunosuppressants.
15. Previously received CAR-T antiCD19 therapy. Previous treatment with other antiCD19 strategies is allowed, provided that CD19 expression has been confirmed in the tumour biopsy.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Phase 1: To determine the Maximum Tolerated Dose and to assess the safety of TranspoCART19 cell infusion based on the following parameters: - Rate of patients developing cytokine release syndrome and/or neurological toxicity in the first month after administration of TranspoCART19 and the number of investigational drug-related grade III/IV adverse events at 1 month and 3 months.
2. Phase 2: Determine the efficacy of TranspoCART19 cell infusion based on the best response rate achieved within 3 months after infusion (overall and complete). The Lugano Criteria will be used.

Secondary endpoints 10

1. Procedure-related mortality (PRM) at 1 and 3 months, defined as any death not directly caused by lymphoma. For the estimation of MRP, disease relapse or progression will be considered as a competing event.
2. Assessment of toxicity at 1 and 3 months, defined as number of grade II-IV adverse events using the CTC (Common Toxicity Criteria) version 5.0.
3. Toxicity assessment at 1 and 3 years, defined as number of grade III-IV adverse events using the CTC (Common Toxicity Criteria) version 5.0..
4. Response rate (overall and complete) at one month, three months and one year. The Lugano criteria will be used.
5. Best response rate achieved (overall and complete). The Lugano criteria will be used.
6. Duration time of the overall response and of the complete response.
7. Progression-free survival (PFS) at 1 and 2 years post-procedure, defined as the time between TranspoCART19 infusion and disease progression or death. Patients alive and in complete remission will be censored at the time of last follow-up.
8. Overall survival (OS) at 1 and 2 years, defined as the time between TranspoCART19 infusion and death of the patient from any cause. Living patients will be censored at the time of last follow-up.
9. In vivo survival of TranspoCART19 cells in peripheral blood, which will be determined by flow cytometry on a weekly basis for the first month, monthly for the first 6 months and quarterly thereafter until 2 years after infusion.
10. Quality of life of the patients included, assessed by means of a questionnaire to be completed by patients or their legal guardians prior to treatment, at 3 and 6 months and one year after infusion.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fundacion De Investigacion Biomedica De Salamanca

Sponsor organisation

Fundacion De Investigacion Biomedica De Salamanca

Address

Paseo De San Vicente 58-182

City

Salamanca

Postcode

37007

Country

Spain

Scientific contact point

Organisation

Fundacion De Investigacion Biomedica De Salamanca

Contact name

Esperanza Lopez Franco

Public contact point

Organisation

Fundacion De Investigacion Biomedica De Salamanca

Contact name

Esperanza Lopez Franco

Locations

1 EU/EEA country · 9 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 6 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications