Pilot Study on the Infusion of ARI-0001 Cells in Patients With CD19+ Leukemia or Lymphoma Refractory to Therapy (CART19-BE-01)

• ClinicalTrials.gov Identifier: NCT03144583
• Recruitment Status: Completed
• First Posted: May 9, 2017
• Last Update Posted: August 28, 2023
• Sponsor: Sara V. Latorre
• Collaborator: Instituto de Salud Carlos III
• Information provided by (Responsible Party): Sara V. Latorre, Institut d'Investigacions Biomèdiques August Pi i Sunyer

Tracking Information

• First Submitted Date: April 26, 2017
• First Posted Date: May 9, 2017
• Last Update Posted Date: August 28, 2023
• Actual Study Start Date: June 15, 2017
• Actual Primary Completion Date: September 13, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 4, 2017)

• Procedure-related mortality (PRM) [ Time Frame: Year 1 ]
  Any death not caused directly by leukemia / lymphoma. For the estimation of PRM, relapse or progression of the disease will be considered as a competitive event.
• Procedure-related mortality (PRM) [ Time Frame: Year 3 ]
  Any death not caused directly by leukemia / lymphoma. For the estimation of PRM, relapse or progression of the disease will be considered as a competitive event.
• Assessment of toxicity [ Time Frame: Month 3 ]
  number of adverse events grade III-IV using CTC (common toxicity criteria)
• Assessment of toxicity [ Time Frame: Year 1 ]
  number of adverse events grade III-IV using CTC (common toxicity criteria)

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: May 4, 2017)

• Response rate (overall and complete) [ Time Frame: Month 3 and Year 1 ]
  Defined differently for each disease:

  • On chronic lymphoid and acute lymphocytic leukemia, the usual criteria NCCN and IWCLL will be used.
  • On non-Hodgkin's lymphoma, the Lugano criteria will be used-
  • On patients with leukemia will be quantified the persistence of minimal residual disease, in bone marrow and peripheral blood, using multiparametric cytometry and new generation sequencing techniques.
• Progression-free survival [ Time Frame: Year 2 after procedure ]
  Time lag between infusion of ARI-0001 and the progression of disease or death. Patients alive and in complete remission will be censored at the last follow-up
• Overall survival (OS) at 2 years [ Time Frame: 3 years ]
  Time lag between the infusion of ARI-0001 and the death of the patient from any cause. Living patients will be censored at the the last follow-up.
• In vivo survival of ARI-0001 cells in peripheral blood, bone marrow and cerebrospinal fluid [ Time Frame: months 1,2,3,4,5,6 ]
  Determined monthly during the first 6 months by flow cytometry and quantitative transgene PCR.
• In vivo survival of ARI-0001 cells in peripheral blood, bone marrow and cerebrospinal fluid [ Time Frame: months 9,12,15,18,21,24 ]
  Determined quarterly from month 6 until the 2 years after infusion, by flow cytometry and quantitative transgene PCR.
• Quality of life of included patients [ Time Frame: Month 3, 6, 12 ]
  Evaluated by a questionnaire completed by patients or their legal guardians
• Toxicity assessment [ Time Frame: Month 3 and year 1 ]
  defined as number of adverse events of any type occurring throughout the study using the common toxicity criteria

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Pilot Study on the Infusion of ARI-0001 Cells in Patients With CD19+ Leukemia or Lymphoma Refractory to Therapy
• Official Title: Pilot Study on the Infusion of Differentiated Autologous T-cells From Peripheral Blood, Expanded and Transduced With a Lentivirus to Express a Chimeric Antigen Receptor With Anti-CD19 Specificity Conjugated With the Co-stimulatory Regions 4-1BB and CD3z in Patients With CD19+ Leukemia or Lymphoma Refractory to Therapy
• Brief Summary: To assess the infusion of ARI-0001 cells (Adult differentiated autologous T-cells from peripheral blood, expanded and transduced with a lentivirus to express a chimeric antigen receptor with anti-CD19 specificity [A3B1] conjugated with the co-stimulatory regions 4-1BB and CD3z ) safety on patients with leukemia or lymphoma CD19+ resistant or refractory to treatment and with a prognosis of less than 2 years.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1

Study Design

Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Masking Description:

Open label

Primary Purpose: Other

Condition

• Leukemia
• Lymphoma

Intervention

Biological: Adult differentiated autologous T-cells

After pretreatment, adult differentiated autologous T-cells with a chimeric antigen receptor with anti-CD19 specificity will be transfused.

Study Arms

Experimental: Adult differentiated autologous T-cells

Adult differentiated autologous T-cells from peripheral blood, expanded and transduced with a lentivirus to express a chimeric antigen receptor with anti-CD19 specificity (A3B1) conjugated with the co-stimulatory regions 4-1BB and CD3z. Such cells will be administered in a single infusion intravenously at a total ARI-0001 cell dose of 0.5-10 x 106 / kg body weight.

Intervention: Biological: Adult differentiated autologous T-cells

Publications *

• Ortiz-Maldonado V, Rives S, Castella M, Alonso-Saladrigues A, Benitez-Ribas D, Caballero-Banos M, Baumann T, Cid J, Garcia-Rey E, Llanos C, Torrebadell M, Villamor N, Gine E, Diaz-Beya M, Guardia L, Montoro M, Catala A, Faura A, Gonzalez EA, Espanol-Rego M, Klein-Gonzalez N, Alsina L, Castro P, Jordan I, Fernandez S, Ramos F, Sune G, Perpina U, Canals JM, Lozano M, Trias E, Scalise A, Varea S, Saez-Penataro J, Torres F, Calvo G, Esteve J, Urbano-Ispizua A, Juan M, Delgado J. CART19-BE-01: A Multicenter Trial of ARI-0001 Cell Therapy in Patients with CD19+ Relapsed/Refractory Malignancies. Mol Ther. 2021 Feb 3;29(2):636-644. doi: 10.1016/j.ymthe.2020.09.027. Epub 2020 Sep 20.
• Castella M, Caballero-Banos M, Ortiz-Maldonado V, Gonzalez-Navarro EA, Sune G, Antonana-Vidosola A, Boronat A, Marzal B, Millan L, Martin-Antonio B, Cid J, Lozano M, Garcia E, Tabera J, Trias E, Perpina U, Canals JM, Baumann T, Benitez-Ribas D, Campo E, Yague J, Urbano-Ispizua A, Rives S, Delgado J, Juan M. Point-Of-Care CAR T-Cell Production (ARI-0001) Using a Closed Semi-automatic Bioreactor: Experience From an Academic Phase I Clinical Trial. Front Immunol. 2020 Mar 20;11:482. doi: 10.3389/fimmu.2020.00482. eCollection 2020.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 10, 2019): 50
• Original Estimated Enrollment (submitted: May 4, 2017): 10
• Actual Study Completion Date: September 13, 2022
• Actual Primary Completion Date: September 13, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Diagnosis of leukemia or CD19 + lymphoma, with a life expectancy less than 2 years that meet the following conditions:- Adult acute lymphoid leukemia in second or third response, not candidate for transplantation due to age, associated diseases or lack of donor, or in relapse post allogeneic transplant.- Pediatric acute lymphoid leukemia in second or third response, refractory or non-transplant candidate due to donor absence, or in relapse post allogeneic transplant, or with minimal residual residual disease (0.1% or greater) after two or more lines of treatment. - Symptomatic follicular lymphoma, which has received at least 2 treatment regimens (one of them including rituximab) and a progression-free interval of less than 2 years. Patients not candidates for transplantation or post-transplant relapse may be included.- Symptomatic chronic lymphocytic leukemia, which has received at least 2 treatment regimens (one of them including rituximab) and a progression-free survival of less than 2 years. Patients with a 17p deletion or TP53 mutation may be included after the first line of treatment. - Mantle cell lymphoma in the first relapse (or higher) when it is not a candidate for transplantation, or second post-transplant relapse (or higher). - Diffuse large cell lymphoma in first relapse (or higher) when it is not a candidate for transplantation, or second post-transplant relapse (or higher).
• Age greater than 2 years and less than 80.
• ECOG functional status from 0 to 2
• Life expectancy of at least 3 months.
• Appropriate venous access to perform an apheresis procedure. Absence of contraindications for it.
• Signature of informed consent (patient or legal guardian).

Exclusion Criteria:

• Treatment with any experimental or non-marketed substance within four weeks prior to recruitment, or actively participating in another therapeutic clinical trial.
• Diagnosis of another past or present neoplasm. Patients may be included in complete remission for more than 3 years, or with a history of non-melanoma skin cancer or completely resected in-situ carcinoma.
• Central nervous system involvement (CNS-3) at inclusion. Inclusion will be permitted with patients with a lower grade (CNS-2) or with CNS-3 who have responded to intrathecal chemotherapy.
• Early relapse after allogeneic transplantation (less than 3 months for apheresis of mononuclear cells, less than 6 months for infusion of ARI-0001) or patients on active immunosuppressive therapy for graft-versus-host disease (corticosteroids or other systemic immunosuppressants ).
• Active infection requiring systemic medical treatment such as chronic kidney infection, chronic lung infection or tuberculosis.
• HIV infection.
• Concurrent and uncontrolled medical illnesses including cardiac, renal, hepatic, gastrointestinal, endocrine, pulmonary, neurological or psychiatric diseases which in the opinion of the researcher represent a risk to the patient.
• 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 it will be necessary to perform a DNA test of the hepatitis B virus, and if the result is positive the patient will be excluded.
• Positive serology for hepatitis C, defined as a positive test for anti-HCV antibodies confirmed by RIBA.
• Severe organ failure, defined as a cardiac ejection fraction <40%; DLCO <40%; calculated glomerular filtrate rate <30 ml / min; Or bilirubin> 3 times the upper limit of normal (unless it is due to CLL or Gilbert syndrome).
• Pregnant or lactating women. Women of childbearing potential should have a negative pregnancy test in the screening phase.
• 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 contraceptive methods from the start of the study to the end of the study.
• Men who are unable or unwilling to use highly effective contraceptive methods from the start of the study to the completion of the study.
• The need to take glucocorticoids in a chronic manner at doses higher than 10 mg / day of prednisone (or equivalent) or other chronic immunosuppressants. Hormonal contraceptives, intrauterine device, intrauterine systems of hormonal release, sexual abstinence, vasectomy of the couple or bilateral tubal occlusion.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 2 Years to 80 Years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Spain

Administrative Information

• NCT Number: NCT03144583
• Other Study ID Numbers: CART19-BE-01
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Sara V. Latorre, Institut d'Investigacions Biomèdiques August Pi i Sunyer
• Original Responsible Party: Same as current
• Current Study Sponsor: Sara V. Latorre
• Original Study Sponsor: Same as current
• Collaborators: Instituto de Salud Carlos III

Investigators

• Principal Investigator: Julio Delgado González, PhD MD; Hospital Clinic of Barcelona

• PRS Account: Institut d'Investigacions Biomèdiques August Pi i Sunyer
• Verification Date: August 2023