A Phase I/IIa study to assess the safety and biological activity of TdT-3, an autologous TCR T-cell therapy targeting TdT, in HLA-A*02:01+ patients aged ≥1 year with relapsed or refractory TdT+ acute leukemia or lymphoblastic lymphoma.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Oslo University Hospital HF

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

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

Decision date (initial)

2025-06-26

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Dose response, Safety, Efficacy, Pharmacodynamic

Safety:
- Assess the safety of administering escalating fractionated doses of TdT-3 following a Fludarabine and Cyclophosphamide conditioning regimen.
- Determine a preliminary Recommended Phase 2 Dose (RP2D)

Feasibility:
- Determine the feasibility of manufacturing TdT-3 that meets established release criteria defined in the IMPD within a clinically relevant time frame.

Secondary objectives 5

1. Evaluate the pharmacokinetics (PK), pharmacodynamics (PD) and biodistribution of TdT-3
2. Determine the feasibility of manufacturing TdT-3 at the intended dose level
3. Evaluate the preliminary efficacy of TdT-3
4. Describe the Patient-reported Outcomes (PRO) and Health-related Quality of life (HRQoL) after TdT-3 therapy
5. Exploratory objective: Explore biomarkers of TdT-3 efficacy and toxicity

Conditions and MedDRA coding

Acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL)

Regulatory references

Scientific advice from competent authorities

Norwegian Medical Products Agency, Paul-Ehrlich-Institut, Norwegian Medical Products Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 17

1. Age ≥1 year at screening
2. 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
3. Malignant cells must express TdT (assessed by immunohistochemistry and/or flow cytometry).
4. Patients must have HLA-A*02:01 genotype, and tumor cells must express HLA-A2.
5. 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.
6. 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.
7. Adequate performance score: - Children <16 years: Lansky performance status ≥50, - Children age ≥16 and adults: Karnofsky performance status ≥50
8. 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.
9. Absence of QTc prolongation (QTc prolongation defined as >500 msec using the Fridericia correction), or other clinically significant ventricular or atrial arrhythmia.
10. Evidence of T-cell recovery from previous therapy defined as ≥100 CD4+ T cells/µL in peripheral blood.
11. For the first 3 patients, and for all patients <6 years: an allogeneic hematopoietic stem cell donor must have been identified.
12. 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.
13. 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.
14. 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.
15. Women of child-bearing potential must have a negative pregnancy test within 24 hours prior to leukapheresis.
16. Life expectancy of at least 3 months, as judged by the investigator.
17. Once all other eligibility criteria are confirmed, must have a leukapheresis product of non-mobilized cells accepted by the cell manufacturing facility.

Exclusion criteria 17

1. Treatment with any experimental or non-commercial substance within 4 weeks of screening and during trial participation.
2. Active acute GvHD of any grade or chronic GvHD of more than mild grade.
3. 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.
4. 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).
5. 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.
6. Pregnant or nursing (lactating) women.
7. 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
8. 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
9. 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.
10. Uncontrolled active bacterial, fungal or viral infection evidenced by clinical symptoms, imaging, or positive laboratory tests (e.g., blood cultures, PCR for DNA/RNA).
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. Primary immunodeficiency.
17. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 4

1. Safety: Type, incidence and severity of Dose Limiting Toxicities (DLTs) from infusion until day +28.
2. 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
3. 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
4. Feasibility: Rate of successful provision (i.e., manufacture, release and shipment) of TdT-3 within a clinically relevant time frame (intent-to-treat)

Secondary endpoints 17

1. Quantification of TdT-3 in Peripheral Blood (PB), BM, Cerebrospinal Fluid (CSF) in vivo using TdT-3 specific immunoassays and transgene detection
2. Changes in levels of soluble immune mediators in PB, BM and CSF from baseline until day +28 after TdT-3 treatment
3. Identification of cellular composition, T cell phenotype distribution and functionality of the TdT-3 infusion product
4. Rate of successful manufacturing of TdT 3 of at least 80% of the intended dose level
5. Preliminary efficacy of TdT-3 in B-/T-ALL patients: • Proportion 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)
6. Duration of Response (DOR)
7. Disease-free Survival (DFS), event-free survival (EFS) and Overall Survival (OS) at 6 months, 1- and 2-years post TdT 3 infusion
8. Proportion of participants proceeding to SCT for any reason, including for recurrence of disease, consolidation of response or immunological rescue
9. Preliminary efficacy of TdT-3 in B-/T-LBL: • Overall response rate (ORR) (CR and PR) within 3 months of infusion • DOR, DFS, EFS and OS at 1- and 2-years post TdT-3 infusion
10. 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
11. Exploratory endpoint: Correlation between TdT and HLA-A*02:01 expression and/or tumor burden and TdT-3 efficacy, persistence, and toxicity
12. Exploratory endpoint: Rate of relapses after TdT-3 treatment • with or without loss of TdT and/or HLA-A*02:01 expression
13. 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
14. Exploratory enpoint: Determine the presence of anti-TdT-3 antibodies before and after TdT-3 treatment
15. Exploratory endpoint: Evaluate dose-exposure-response relationships
16. Exploratory endpoint: Explore associations between PK, PD, toxicity and efficacy of TdT-3
17. Exploratory endpoint: Explore associations between participants’ baseline disease characteristics including tumor genetics/genomic profiles, toxicity and efficacy outcomes

Investigational products

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

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Oslo University Hospital HF

Sponsor organisation

Oslo University Hospital HF

Address

Taarnbygget, Kirkeveien 166 Kirkeveien 166

City

Oslo

Postcode

0450

Country

Norway

Scientific contact point

Organisation

Oslo University Hospital HF

Contact name

Jochen Büchner

Public contact point

Organisation

Oslo University Hospital HF

Contact name

Jochen Büchner

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Results and documents

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

Documents 17 files

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

Application history

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