TDT-3 for Acute lymphoblastic leukemia|Lymphoblastic lymphoma

Inclusion criteria

• {"criterion_text":"- Age ≥1 year at screening"}
• {"criterion_text":"- Evidence of T-cell recovery from previous therapy defined as ≥100 CD4+ T cells/µL in peripheral blood."}
• {"criterion_text":"- For the first 3 patients, and for all patients <6 years: an allogeneic hematopoietic stem cell donor must have been identified."}
• {"criterion_text":"- Patients must meet criteria for a non-mobilized Leukapheresis procedure, taking wash-out periods for lymphotoxic drugs (see Medication restrictions prior to leukapheresis) into account. Patients should have at least 150 CD3+ T cells/µl peripheral blood prior to the start of the leukapheresis procedure. CD3 counts below this threshold should be evaluated on a case-by-case basis and discussed with the study lead. An autologous leukapheresis product cryopreserved prior study entry may be accepted if it fulfils the protocol criteria, is accepted by the manufacturing facility, and upon individual approval by the study lead."}
• {"criterion_text":"- For patients with a history of allogeneic stem cell transplantation (SCT), at least 100 days elapsed from most recent SCT, at least 30 days from last donor lymphocyte infusion, and no longer taking immunosuppressive agents for at least 30 days prior to enrollment."}
• {"criterion_text":"- For patients with a history of Chimeric Antigen Receptor (CAR) T-cell therapy, at least 30 days elapsed from most recent CAR T-cell infusion."}
• {"criterion_text":"- Women of child-bearing potential must have a negative pregnancy test within 24 hours prior to leukapheresis."}
• {"criterion_text":"- Life expectancy of at least 3 months, as judged by the investigator."}
• {"criterion_text":"- Once all other eligibility criteria are confirmed, must have a leukapheresis product of non-mobilized cells accepted by the cell manufacturing facility."}
• {"criterion_text":"- Relapsed and/or refractory B-/T-ALL or B-/T-LBL in which standard curative treatment options have either failed or are unavailable: a) all standard curative treatment options in both the newly diagnosed and relapsed/refractory disease stage must have failed, or b) the patient is deemed ineligible for any remaining treatment options in the relapsed/refractory stage based on the investigator's assessment"}
• {"criterion_text":"- Malignant cells must express TdT (assessed by immunohistochemistry and/or flow cytometry)."}
• {"criterion_text":"- Patients must have HLA-A*02:01 genotype, and tumor cells must express HLA-A2."}
• {"criterion_text":"- Evaluable disease at study screening: in ALL patients: the presence of leukemic cells in the bone marrow (BM) detected either by flow cytometry or leukemia-specific PCR with Minimal Residual Disease (MRD) ≥1% in LBL patients: measurable disease by radiological criteria. Lymphoma lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy."}
• {"criterion_text":"- Written informed consent from patients, or from parents/legal representative in addition to age-appropriate assent for minors, according to local regulations, before any study specific screening procedures are conducted."}
• {"criterion_text":"- Adequate performance score: - Children <16 years: Lansky performance status ≥50, - Children age ≥16 and adults: Karnofsky performance status ≥50"}
• {"criterion_text":"- Adequate organ function: - Renal function: for adults ≥18 years: estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m2, For children (<18 years): serum creatinine ≤1.5x upper limit of normal (ULN) for age (institutional normal). - Liver function: Serum ALT/AST ≤3xULN (institutional normal), and total bilirubin ≤1.5 mg/dL (26 μmol/L), except in participants with Gilbert’s disease. Elevations related to leukemia or lymphoma involvement of the liver will not disqualify a participant, but patient needs to be discussed with the sponsor to confirm the eligibility. - Adequate pulmonary function defined as Oxygen saturation of >90% on room air for adults: Forced Expiratory Volume in 1 s (FEV1) >50% and Diffusion Capacity of the Lung for Carbon Monoxide corrected for hemoglobin by the Dinakara equation (DLCOcorr)>50%. - Adequate cardiac function defined as Shortening Fraction (SF) ≥28% (>35% for children <3 years) or Left Ventricular Ejection Fraction (LVEF) ≥45% evaluated by echocardiography (ECHO) at screening."}
• {"criterion_text":"- Absence of QTc prolongation (QTc prolongation defined as >500 msec using the Fridericia correction), or other clinically significant ventricular or atrial arrhythmia."}

Exclusion criteria

• {"criterion_text":"- Treatment with any experimental or non-commercial substance within 4 weeks of screening and during trial participation."}
• {"criterion_text":"- Uncontrolled active bacterial, fungal or viral infection evidenced by clinical symptoms, imaging, or positive laboratory tests (e.g., blood cultures, PCR for DNA/RNA)."}
• {"criterion_text":"- Active HIV, HBV or HCV infection. History of HBV or HCV infection is permitted if viral load is undetectable by qPCR and/or nucleic acid testing."}
• {"criterion_text":"- Concomitant and uncontrolled medical conditions, including cardiac, renal, liver, gastrointestinal, endocrine, pulmonary, neurologic or psychiatric diseases that, in the investigator’s opinion does not allow treatment according to the protocol."}
• {"criterion_text":"- History of other malignancies, apart from non-melanoma skin cancer or carcinoma in situ, unless disease free for at least 3 years, or in remission 1-2 years and investigator assesses other malignancy as unlikely to return within 1 year."}
• {"criterion_text":"- Active CNS disorder, or autoimmune disease with CNS involvement such as multiple sclerosis, optic neuritis, or other immunologic or inflammatory disease that in investigator’s judgement impair ability to evaluate neurotoxicity."}
• {"criterion_text":"- History of autoimmune disease (e.g. Crohn’s disease, rheumatoid arthritis, systemic lupus) requiring systemic immunosuppression/ systemic disease modifying agents within the last 2 years."}
• {"criterion_text":"- Primary immunodeficiency."}
• {"criterion_text":"- Any known hypersensitivity to any of the active substances or to any of the excipients of the Investigational Medicinal Product (IMP) or any of the Auxiliary medicinal products (AxMPs) used for LDC"}
• {"criterion_text":"- Active acute GvHD of any grade or chronic GvHD of more than mild grade."}
• {"criterion_text":"- Any medical condition requiring chronic corticosteroids at a dose higher than 10 mg/day (or 0.2 mg/kg/d in patients less than 18 years) of prednisolone (or equivalent) or any other chronic immunosuppressant."}
• {"criterion_text":"- Unresolved toxicity after previous anti-cancer therapy greater than CTCAE version 5.0 grade 1, including major surgery, except: - hematological toxicity for which exclusion criteria are absolute neutrophil count <0.5x109/L unless caused by underlying disease. platelet count <25x109/L unless caused by underlying disease. - Peripheral neuropathy related to vinca alkaloid based chemotherapy, - other toxicity that in the opinion of the investigator is not clinically relevant given the expected safety/toxicity profile of the study treatment (e.g., alopecia)."}
• {"criterion_text":"- Any medical condition that, in investigator’s judgement, is likely to interfere with assessment of safety or efficacy or the participants ability to complete all protocol-required visits and procedures."}
• {"criterion_text":"- Pregnant or nursing (lactating) women."}
• {"criterion_text":"- Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they agree to use highly effective methods (see Chapter 13.2) of contraception from enrollment until the end of the study"}
• {"criterion_text":"- Men who cannot or do not wish to use highly effective contraceptive measures (see Chapter 13.2) from enrollment until the end of the study"}
• {"criterion_text":"- Active Central Nervous System (CNS) involvement of ALL or LBL at screening. Patients with a history of CNS involvement, but who are CNS1 at screening are eligible in the absence of neurologic symptoms that may mask or interfere with neurological assessment of toxicity, as judged by the investigator."}

Primary endpoints

• {"endpoint_text":"- Safety: Type, incidence and severity of Dose Limiting Toxicities (DLTs) from infusion until day +28.","definition_or_measurement_approach":"DLTs assessed from infusion until day +28; type, incidence and severity recorded and graded (CTCAE v5.0 where applicable) within the DLT observation window."}
• {"endpoint_text":"- Incidence and severity of adverse events, serious adverse events, laboratory abnormalities, changes in vital signs, and changes in physical examination following infusion of TdT-3, recorded, and graded according to CTCAE version 5.0 at fractionated dose levels","definition_or_measurement_approach":"AE/SAE monitoring with grading according to CTCAE v5.0 at fractionated dose levels; includes lab abnormalities, vitals and physical exam changes."}
• {"endpoint_text":"- Maximum Tolerated Dose (MTD), defined as the dose level with an estimated DLT probability closest to the target DLT probability of 25%, or the highest administered dose if the MTD is not achieved","definition_or_measurement_approach":"MTD determined using observed DLT rates; target DLT probability = 25%; MTD = dose with estimated DLT probability closest to 25% or highest administered dose if MTD not reached."}
• {"endpoint_text":"- Feasibility: Rate of successful provision (i.e., manufacture, release and shipment) of TdT-3 within a clinically relevant time frame (intent-to-treat)","definition_or_measurement_approach":"Feasibility measured as proportion of participants for whom TdT-3 is successfully manufactured, released and shipped within predefined clinically relevant time frame (intent-to-treat population)."}

Secondary endpoints

• {"endpoint_text":"- Quantification of TdT-3 in Peripheral Blood (PB), BM, Cerebrospinal Fluid (CSF) in vivo using TdT-3 specific immunoassays and transgene detection","definition_or_measurement_approach":"Measurement via TdT-3 specific immunoassays and transgene detection in PB, BM, CSF."}
• {"endpoint_text":"- Changes in levels of soluble immune mediators in PB, BM and CSF from baseline until day +28 after TdT-3 treatment","definition_or_measurement_approach":"Measurement of soluble immune mediator levels in PB, BM and CSF baseline to day +28; assays per protocol."}
• {"endpoint_text":"- Identification of cellular composition, T cell phenotype distribution and functionality of the TdT-3 infusion product","definition_or_measurement_approach":"Characterisation of infusion product cellular composition, T-cell phenotype and functional assays per laboratory methods in protocol."}
• {"endpoint_text":"- Rate of successful manufacturing of TdT 3 of at least 80% of the intended dose level","definition_or_measurement_approach":"Proportion of manufactured products achieving ≥80% of intended dose level."}
• {"endpoint_text":"- Preliminary efficacy of TdT-3 in B-/T-ALL patients: •\tProportion of participants achieving a response at 1- or 3-months post infusion defined as - Complete Remission (CR) or CR with incomplete blood count recovery (CRi) (only participants with >5% BM blasts prior to TdT-3 infusion are evaluable) and - MRD negativity in the bone marrow (defined as MRD<0.01% by flowcytometry or leukemia-specific PCR) (only participants with >0.01% BM blasts prior to TdT-3 infusion are evaluable)","definition_or_measurement_approach":"Response assessed at 1 and 3 months post infusion: CR/CRi (for those with >5% BM blasts pre-infusion) and MRD negativity (MRD<0.01% by flow cytometry or leukemia-specific PCR for those with >0.01% BM blasts pre-infusion)."}
• {"endpoint_text":"- Duration of Response (DOR)","definition_or_measurement_approach":"Time from first documented response to progression or relapse as defined in protocol."}
• {"endpoint_text":"- Disease-free Survival (DFS), event-free survival (EFS) and Overall Survival (OS) at 6 months, 1- and 2-years post TdT 3 infusion","definition_or_measurement_approach":"DFS, EFS, OS measured at specified timepoints (6 months, 1 year, 2 years) after infusion per survival analysis definitions in protocol."}
• {"endpoint_text":"- Proportion of participants proceeding to SCT for any reason, including for recurrence of disease, consolidation of response or immunological rescue","definition_or_measurement_approach":"Proportion proceeding to stem cell transplantation for any listed reasons, captured during follow-up."}
• {"endpoint_text":"- Preliminary efficacy of TdT-3 in B-/T-LBL: •\tOverall response rate (ORR) (CR and PR) within 3 months of infusion •\tDOR, DFS, EFS and OS at 1- and 2-years post TdT-3 infusion","definition_or_measurement_approach":"ORR within 3 months (CR+PR) and DOR/DFS/EFS/OS at 1 and 2 years per protocol-defined radiological and clinical response criteria."}
• {"endpoint_text":"- Change of the Patient-reported Outcomes (PRO) and Health-related Quality of life (HRQoL) from baseline to day 28, and 3-, 6-, 9- and 12- and 24-months post infusion for the group and the individual patient","definition_or_measurement_approach":"PRO/HRQoL assessed using specified instruments (e.g., EQ-5D variants) at baseline and scheduled post-infusion timepoints up to 24 months."}
• {"endpoint_text":"- Exploratory endpoint: Correlation between TdT and HLA-A*02:01 expression and/or tumor burden and TdT-3 efficacy, persistence, and toxicity","definition_or_measurement_approach":"Exploratory analyses correlating tumor TdT and HLA-A*02:01 expression and tumor burden with efficacy, persistence and toxicity measures."}
• {"endpoint_text":"- Exploratory endpoint: Rate of relapses after TdT-3 treatment • with or without loss of TdT and/or HLA-A*02:01 expression","definition_or_measurement_approach":"Rate of relapse post-treatment and characterization of relapse regarding TdT and HLA-A*02:01 expression."}
• {"endpoint_text":"- Exploratory endpoint: Quantification of thymic output and circulating immune cell subsets after TdT 3 infusion to assess B- and T-cell maturation, phenotype and T-cell receptor diversity","definition_or_measurement_approach":"Quantification of thymic output and immune cell subsets, including TCR diversity analyses as specified in lab procedures."}
• {"endpoint_text":"- Exploratory enpoint: Determine the presence of anti-TdT-3 antibodies before and after TdT-3 treatment","definition_or_measurement_approach":"Assessment of anti-TdT-3 antibodies pre- and post-treatment using immunoassays per protocol."}
• {"endpoint_text":"- Exploratory endpoint: Evaluate dose-exposure-response relationships","definition_or_measurement_approach":"Analyses of relationships between dose, exposure (e.g., cell counts/transgene levels) and response/toxicity."}
• {"endpoint_text":"- Exploratory endpoint: Explore associations between PK, PD, toxicity and efficacy of TdT-3","definition_or_measurement_approach":"Exploratory PK/PD analyses correlating exposure and pharmacodynamic markers with toxicity and efficacy."}
• {"endpoint_text":"- Exploratory endpoint: Explore associations between participants’ baseline disease characteristics including tumor genetics/genomic profiles, toxicity and efficacy outcomes","definition_or_measurement_approach":"Exploratory correlation analyses between baseline disease/genomic characteristics and safety/efficacy outcomes."}

Other endpoints

• {"endpoint_text":"- Exploratory endpoint: Correlation between TdT and HLA-A*02:01 expression and/or tumor burden and TdT-3 efficacy, persistence, and toxicity","definition_or_measurement_approach":"Correlation analyses of TdT and HLA-A*02:01 expression and tumor burden with efficacy, persistence and toxicity."}
• {"endpoint_text":"- Exploratory endpoint: Rate of relapses after TdT-3 treatment • with or without loss of TdT and/or HLA-A*02:01 expression","definition_or_measurement_approach":"Assessment of relapse rates and characterization with respect to TdT and HLA-A*02:01 expression changes."}
• {"endpoint_text":"- Exploratory endpoint: Quantification of thymic output and circulating immune cell subsets after TdT 3 infusion to assess B- and T-cell maturation, phenotype and T-cell receptor diversity","definition_or_measurement_approach":"Immune phenotyping and TCR diversity assessments per protocol laboratory methods."}
• {"endpoint_text":"- Exploratory enpoint: Determine the presence of anti-TdT-3 antibodies before and after TdT-3 treatment","definition_or_measurement_approach":"Anti-drug antibody assays before and after treatment."}
• {"endpoint_text":"- Exploratory endpoint: Evaluate dose-exposure-response relationships","definition_or_measurement_approach":"Analyses of dose, exposure metrics and response relationships."}
• {"endpoint_text":"- Exploratory endpoint: Explore associations between PK, PD, toxicity and efficacy of TdT-3","definition_or_measurement_approach":"Exploratory PK/PD correlation analyses."}
• {"endpoint_text":"- Exploratory endpoint: Explore associations between participants’ baseline disease characteristics including tumor genetics/genomic profiles, toxicity and efficacy outcomes","definition_or_measurement_approach":"Exploratory analyses linking baseline genomic/disease features to outcomes."}

Norway

Earliest CTIS Part Ii Submission Date

30-05-2025

Latest Decision Or Authorization Date

19-12-2025

Processing Time Days

203

Number Of Sites

1

Number Of Participants

15

Primary sponsor

Full Name

Oslo University Hospital HF

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Norway