Phase I clinical trial on the use of fresh, allogeneic, second-generation CD19-CAR T cells for treatment of children and young adult with relapsed/refractory B-cell Acute Lymphoblastic Leukemia

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

23 Apr 2024 → ongoing

Decision date (initial)

2024-04-17

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Dose response, Safety

The primary objective of the study is to evaluate the safety and to establish the recommended dose (RD) of donor-derived, CD19-directed second-generation CAR T cells (CD19-CAR_Lenti_ALLO ) in pediatric patients and young adults affected by relapsed/refractory B-cell precursor Acute Lymphoblastic Leukemia (BCP-ALL) occurring either after allogeneic hematopoietic stem cell transplantation (alloHSCT) or before alloHSCT, the latter in case of extremely refractory disease and availability of a familiar HLA-fully matched donor.

Secondary objectives 1

1. Incidence of grade II-IV acute and chronic graft-versus-host disease (GvHD) Determination of the rate of bone marrow (BM) complete remission (CR) with minimal residual disease (MRD) negativity at day +28 Improvement of 1-year event-free and overall survival (EFS and OS) rates, in comparison to historical controls, represented by patients relapsing after allo-HSCT Cumulative incidence of both molecular and morphological relapse, defined as an MRD >10-4 and a BM blast percentage > 5% Toxicity of treatment with CD19-CAR_Lenti_ALLO in comparison to data of historical control given chemotherapy, donor-derived lymphocytes infusion (DLIs) or autologous CAR T cells Incidence of CRS and neurotoxicity Assessment of CD19-CAR_Lenti_ALLO expansion and persistence Duration of B-cell aplasia, where the event is defined as >50 B cells/mcl or >3% of the lymphocytes represented in the peripheral blood, whichever occurs first Evaluation of disease response in patients with previous CD19-directed immunotherapy, including autologous CD19-directed CAR T cell therapy

Conditions and MedDRA coding

Relapsed/refractory B-cell Acute Lymphoblastic Leukemia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. Patients must meet the following eligibility inclusion criteria at the time of treatment. 1. Diagnosis of CD19 expressing B Acute Lymphoblastic leukemia (B-ALL) relapse and one of the following a. Relapse after alloHSCT b. Relapsed/refractory disease, with failure of frontline therapy and at least 2 rescue strategies, including CD19/CD22-directed monoclonal antibody AND availability of a fully matched related donor. OR 2. Age: 1 year – 35 years. 3. CD19+ count > 50 cells/mcl and/or MRD > 10-4 4. Patients that received previously a CD19-directed therapy are eligible provided that all the following 4 criteria are present: i) the disease is still CD19-positive; ii) the inclusion criteria #3 is fulfilled; iii) at least 1 month has elapsed between the previous therapy and CD19-CAR_Lenti_ALLO infusion; iv) the previous therapy was associated with grade <3 CRS and/or ICANS, both resolved without sequelae. 5. Patients must be ineligible for the commercially available autologous CD19-directed CAR T cell product OR have relapsed <6 months after allogeneic HSCT OR be unable to undergo an autologous CAR T cell production [peripheral CD3+ cell count < 300/mcl; relapse after treatment with an autologous CD19-CAR T cell product; >50% of circulating blasts]. 6. 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. 7. 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%. 8. Women of childbearing potential must have a negative serum or urine pregnancy test at the time of screening and within the week preceding starting lymphodepletion. 9. Female subjects of childbearing potential must agree to use acceptable method(s) of contraception from consent through at least 12 months after the CD19-CAR_Lenti_ALLO drug product infusion and, in any case, until viable positive CAR T cells are no longer detected, whichever are longer. Male subjects of reproductive capacity must agree to use effective contraception from consent through at least 12 months after the CD19-CAR_Lenti_ALLO drug product infusion and, in any case, until viable positive CAR T cells are no longer detected, whichever are longer.

Exclusion criteria 1

1. 1. Pregnant or lactating women. 2. Burkitt acute lymphoblastic leukemia and blast crisis of chronic myeloid leukemia 3. Severe, uncontrolled active intercurrent infections. 4. HIV or active HCV (<12 weeks between achievement of a sustained virological response to the specific treatment and apheresis) and/or HBV infection (either positive for Hepatitis B core antibody [HBcAb] or positive hepatitis B surface antigen [HBsAg] AND NAT tests), defined according to the American Association for the Study of Liver Diseases guidelines. 5. Life-expectancy < 6 weeks or rapidly progressive disease that in the evaluation of the investigator would compromise ability to complete study therapy. 6. Hepatic function: Inadequate liver function defined as total bilirubin > 3x upper limit of normal (ULN) or transaminase (ALT and AST) > 5 x ULN. 7. Renal function: Creatinine clearance calculated using the Schwartz formula1, or radioisotope glomerular filtration rate (GFR) <70 mL/min/1.73 m2 8. Blood oxygen saturation < 90%. 9. Cardiac function: Left ventricular ejection fraction lower than 45% by ECHO. 10. 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. 11. Presence of active, grade 2-4 acute or chronic GvHD requiring steroid therapy or other immune-suppressive treatment. 12. Relapse occurring before 60 days after alloHSCT. 13. Concurrent or recent prior therapies, before infusion: i. Systemic steroids (at a dose > 2 mg/kg prednisone) in the 2 weeks before infusion of CD19-CAR_Lenti_ALLO. Recent or current use of inhaled/topical/non-absorbable steroids is not exclusionary. ii. Systemic chemotherapy in the 2 weeks preceding infusion of CD19-CAR_Lenti_ALLO. iii. Anti-thymocyte globulin (ATG) or Alemtuzumab (Campath®) in the 8 weeks preceding infusion of CD19-CAR_Lenti_ALLO. iv. Immunosuppressive agents in the 2 weeks preceding infusion of CD19-CAR_Lenti_ALLO. v. Radiation therapy must have been completed at least 2 weeks before infusion of CD19-CAR_Lenti_ALLO. vi. Donor lymphocytes infusion in the 4 weeks preceding infusion vii. Other anti-neoplastic investigational agents currently administered or within 30 days prior to infusion of CD19-CAR_Lenti_ALLO (i.e., start of protocol therapy); viii. Exceptions: 1. There is no time restriction in regards to prior intrathecal chemotherapy, but there must be a complete recovery from any acute toxic effects from such treatment; 2. Subjects receiving steroid therapy at physiologic replacement doses only are allowed provided that there has been no increase in dose for at least 2 weeks prior to starting apheresis.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. To evaluate the safety of the infusion of CD19-CAR_Lenti_ALLO evaluating 2 dose levels (DLs) for each cohort of patients, depending on the donor HLA-matching (for fully matched, familial or unrelated donor, DL1: 3.0 x 106; DL2: 5.0 x 106 cells/kg recipient total body weight of CAR+ T cells; for haploidentical donor, DL1: 1.0 x 106; DL2: 3.0 x 106 cells/kg recipient total body weight of CAR+ T cells) and establish the dose-limiting toxicity (DLT) of the cellular product. DLT will be defined as an

Secondary endpoints 1

1. 1. To estimate the rate of occurrence and the severity of acute and/or chronic GvHD 2. To evaluate the proportion of patients achieving either CR or CR with incomplete blood count recovery (CRi) and MRD negativity by either flow-cytometry or qPCR at day 28 (defined as a value < 1x10-4 ). 3. To estimate the probability of obtaining CR with MRD negativity stratified according to the disease burden at time of enrollment

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 Sant'onofrio 4

City

Rome

Postcode

00165

Country

Italy

Scientific contact point

Organisation

Ospedale Pediatrico Bambino Gesu'

Contact name

Franco Locatelli

Public contact point

Organisation

Ospedale Pediatrico Bambino Gesu'

Contact name

Francesca Del Bufalo

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

Application history

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