CD19-CAR_Lenti in pediatric patients affected by relapsed/refractory B-ALL or aggressive B-NHL

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Ospedale Pediatrico Bambino Gesu

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

15 Feb 2021 → ongoing

Decision date (initial)

2025-01-14

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Miltenyi Biotec GmbH, Germany

External identifiers

EU CT number

2024-519174-39-00

EudraCT number

2020-003452-32

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

The primary objective of the phase I portion of the study is to evaluate the safety and to establish the recommended dose of CD19-CAR_Lenti infused in pediatric patients affected by relapsed/refractory B-ALL or aggressive B-NHL, starting from a minimum target dose of 1.0 x 106 cells/kilogram recipient total body weight, using the Miltenyi CliniMACS Prodigy® automated system. The primary objective of the phase II extension is to test the efficacy of the treatment at the optimal dose defined in the phase I, by determining BM morphological complete remission (CR) and minimal residual disease (MRD), at day 28, in patients with CD19-positive ALL. In patients with B-cell aggressive lymphoma, we will evaluate the Overall Response Rate (ORR), which includes Complete Remission (CR), CR with incomplete blood count recovery (CRi), Partial Response (PR) and Stable Disease (SD), at day 28, day 90 and 180 after CD19-CAR_Lenti
infusion.

Secondary objectives 1

1. To assess long-term response variables, including relapse rate (RR), overall survival (OS), and disease-free survival (DFS) at 1 and 2 years. To describe the in vivo expansion and persistence of CD19-CAR_Lenti, in blood and BM, measured by flow cytometry and qPCR. To characterize the T-cell subpopulations of the CD19-CAR_Lenti cells before and after infusion, including the exhaustion profile, and to describe the changes in CD19-CAR_Lenti cells after infusion and their correlation with disease response and adverse events. To characterize the cytokine profile after infusion and its correlation with cytokine release syndrome (CRS) in order to define a possible predictive profile.

Conditions and MedDRA coding

Relapsed/refractory CD19+ Acute Lymphoblastic Leukemia and Diffuse Large B Cell Lymphoma or Primary Mediastinal B Cell Lymphoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. Procurement eligibility 1. Diagnosis of CD19 expressing B acute lymphoblastic leukemia (ALL) or diffuse large Bcell lymphoma (DLBCL) or primary mediastinal lymphoma (PML) and one of the following: a. Patients in 1st relapse, with High-Risk (HR) features including: MLLrearrangements, E2A/TCF3-PBX1 [t(1;19)], TCF3-HLF [t(17;19)], hypodiploidy (i.e., <44 chromosomes), TP53 alterations, early (i.e., <30 months from diagnosis)/very early (i.e., <18 months from diagnosis) isolated or combined bone marrow relapse b. MRD > 0.1% after either reinduction therapy or any course of consolidation for relapsed ALL c. Patients with DLBCL or PML in 1st or subsequent relapse, after at least one standard frontline chemotherapy 2. Age: 1 year – 25 years for BCP-ALL and 1-35 years for B-NHL. 3. Adequate venous access for apheresis or eligible for appropriate catheter placement, and no other contraindications for leukapheresis 4. Voluntary informed consent is given. For subjects < 18 year-old their legal guardian must give informed consent. Pediatric subjects will be included in age-appropriate discussion and verbal assent will be obtained for those greater than or equal to 12 years of age, when appropriate. 5. Clinical performance status: Patients > 16 years of age: Karnofsky greater than or equal to 60%; Patients < 16 years of age: Lansky scale greater than or equal to 60%. Treatment eligibility (i.e., eligibility to drug product infusion) 1. Diagnosis of CD19 expressing B-ALL or DLBCL or PML and one of the following: a. Patients in 1st relapse, with High-Risk (HR) features including: MLLrearrangements, E2A/TCF3-PBX1, TCF3-HLF [t(17;19)], hypodiploidy (i.e., <44 chromosomes), TP53 alterations, early (i.e., <30 months from diagnosis)/very early (i.e., <18 months from diagnosis) isolated or combined bone marrow relapse b. MRD > 0.1% after either reinduction therapy or any course of consolidation for relapsed c. Patients with DLBCL or PML in 1st or subsequent relapse, after at least one standard frontline chemotherapy 2. Age: 1 year – 25 years for Bcp-ALL and 1-35 years for B-NHL. 3. Voluntary informed consent is given. For subjects < 18 year-old their legal guardian must give informed consent. Pediatric subjects will be included in age-appropriate discussion and verbal assent will be obtained for those greater than or equal to 12 years of age, when appropriate. 4. Clinical performance status: Patients > 16 years of age: Karnofsky greater than or equal to 60%; Patients < 16 years of age: Lansky scale greater than or equal to 60%. 5. Patients of child-bearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study and for four months after receiving the preparative regimen. 6. Females of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects on the fetus.

Exclusion criteria 1

1. Procurement eligibility 1. Severe, uncontrolled active infections 2. HIV, or active HCV and/or HBV infection (detection of viral RNA/DNA in blood) 3. Previous allogeneic HSCT in the preceding 100 days before apheresis 4. Concurrent or recent prior therapies, before apheresis: a) Systemic steroids (at a dose equivalent to or greater 2 mg/kg prednisone) in the 2 weeks before apheresis collection. Recent or current use of inhaled/topical/nonabsorbable steroids is not exclusionary. b) Systemic chemotherapy in the 2 weeks preceding apheresis collection. c) Anti-thymocyte globulin (ATG) in the 4 weeks preceding apheresis collection. d) Immunosuppressive agents in the 2 weeks preceding apheresis collection. e) Radiation therapy must have been completed at least 1 week prior to apheresis. f) Other anti-neoplastic investigational agents currently administered or within 30 days prior to apheresis (i.e., start of protocol therapy); Treatment eligibility 1. Pregnant or lactating women 2. Severe, uncontrolled active infections 3. HIV, or active HCV and/or HBV infection (detection of viral RNA/DNA in blood) 4. Life-expectancy < 6 weeks 5. Hepatic function: Inadequate liver function defined as total bilirubin > 4x upper limit of normal (ULN) or transaminase (ALT and AST) > 6 x ULN 6. Renal function: serum creatinine > 3x ULN for age. 7. Blood oxygen saturation < 90%. 8. Cardiac function: Left ventricular ejection fraction lower than 45% by ECHO. 9. Congestive heart failure, cardiac arrhythmia, psychiatric illness, or social situations that would limit compliance with study requirements or in the opinion of the PI would pose an unacceptable risk to the subject. 10. BM blasts > 50% pre-infusion. 11. Hyperleukocytosis (greater than or equal to 20,000 blasts/microliter) or rapidly progressive disease that in the evaluation of the investigator would compromise ability to complete study therapy 12. Presence of active, grade 2-4 acute or moderate-severe chronic GvHD 13. Recurrent or refractory ALL with testicular involvement 14. Concurrent or recent prior therapies, before infusion: a) Systemic steroids (at a dose > 2 mg/kg prednisone) in the 2 weeks before infusion. Recent or current use of inhaled/topical/non-absorbable steroids is not exclusionary. b) Systemic chemotherapy in the week preceding infusion. c) Anti-thymocyte globulin (ATG) in the 4 weeks preceding infusion. d) Immunosuppressive agents in the 1 week preceding infusion. e) Radiation therapy must have been completed at least 3 weeks prior to enrollment. f) Other anti-neoplastic investigational agents currently administered or within 30 days prior to infusion (i.e. start of protocol therapy); 15. Patient-derived CD19-CAR_Lenti production failure: vitality of the fresh product <80%, CD3+ cells <80%, CD3+ CAR+ cells <10%, non-sterility in IPC at day 5, endotoxin contamination (> 5 EU/ml) in IPC at day 5, mycoplasma contamination in IPC at day 5, failure of the visual inspection.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. PHASE I The safety and tolerability of CD19-CAR_Lenti will be assessed by: - Suspected adverse events, and - Suspected serious adverse events As evidenced by clinically relevant: - Changes in clinical laboratory tests (clinical chemistry, hematology, etc). - Changes in vital signs (blood pressure, pulse, respiratory rate and body temperature). - Changes in physical examination. Signs and symptoms assessed may require additional testing as clinically indicated such as ECG, PFT, radiographic studi

Secondary endpoints 1

1. Secondary Endpoints phase I and II Relapse rate (RR), overall survival (OS), and disease-free survival (DFS) will be evaluated at 1 and 2 years. - The expansion and persistence of CD19-CAR_Lenti will be measured by flow cytometry and qPCR. - The T cell subpopulations of the CD19-CAR_Lenti cells before and after infusion and the exhaustion profile will be measured by flow cytometry - Disease outcome will be correlated with: a) use of either steroids and/or tocilizumab for CRS/Neurotoxicity; b) pr

Investigational products

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

Test 1

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Ospedale Pediatrico Bambino Gesu

Sponsor organisation

Ospedale Pediatrico Bambino Gesu

Address

Piazza Di Sant'onofrio 4

City

Rome

Postcode

00165

Country

Italy

Scientific contact point

Organisation

Ospedale Pediatrico Bambino Gesu

Contact name

Locatelli Franco

Public contact point

Organisation

Ospedale Pediatrico Bambino Gesu

Contact name

Locatelli Franco

Locations

1 EU/EEA country · 1 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 9 files

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

Application history

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