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.

Prior treatment

• Treatment with any experimental or non-commercial substance within 4 weeks of screening and during trial participation.
• 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.

Other illness

• 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.
• 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.
• 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.
• 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.
• 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
• 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.
• 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.
• 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.

Lab values

• Uncontrolled active bacterial, fungal or viral infection evidenced by clinical symptoms, imaging, or positive laboratory tests (e.g., blood cultures, PCR for DNA/RNA).
• 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).

Other

• Primary immunodeficiency.
• Active acute GvHD of any grade or chronic GvHD of more than mild grade.
• Pregnant or nursing (lactating) women.
• 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
• 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

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