ISATUXIMAB for T-cell acute lymphoblastic leukemia | Relapsed/refractory T-cell acute lymphoblastic leukemia | CD38-positive T-cell acute lymphoblastic leukemia

Inclusion criteria

• {"criterion_text":"- Patients with CD38 positive T-ALL fitting either to the definitions for cohort 1 or cohort 2:\n- Adequate renal function defined as follows: - Serum creatinine ≤ 2 x ULN; - Any serum creatinine level associated with a calculated creatinine clearance >= 40 mL/min\n- Negative pregnancy test in women of childbearing potential (WOCBP)\n- WOCBP must commit to either abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously\n- Men who are sexually active with a WOCBP must agree to use a barrier method of contraception\n- Participation in the registry of the German Multicenter Study Group for Adult ALL (GMALL)\n- Cohort 1: In relapse or with primary refractory disease defined as ≥5% blasts in bone marrow after at least three chemotherapy cycles (induction I-II, consolidation I) with the following additional specifications: •\tearly relapse within 12 months from first achievement of CR or •\tlate relapse later than 12 months from first achievement of CR or •\tprimary refractory disease without any CR or •\tany relapse after stem cell transplantation or •\tany refractory relapse, defined as no response to at least one salvage therapy or •\tany second or later relapse and •\tAvailability of patient material with blast cells (bone marrow or peripheral blood) for central MRD assessment.\n- Cohort 2: In complete hematological remission (defined as less than 5% blasts in bone marrow and no evidence of extramedullary disease) after at least three chemotherapy cycles (induction I-II, consolidation I) •\tDetection of quantifiable MRD at a level of ≥10-4, either as molecular failure without prior achievement of molecular remission or molecular relapse after prior achievement of molecular remission •\tMRD assay at the central reference lab with at least one marker a minimum sensitivity of 10-4 •\tMRD detection for study inclusion after an interval of at least 2 weeks from last systemic chemotherapy including antibody therapy •\t(in patients without clonal molecular MRD marker, MRD testing can be based on flow-cytometry established in reference laboratory)\n- ECOG status: •\tCohort 1: 0-2 •\tCohort 2: 0-1\n- Age at least 18 years or older\n- Evidence of a personally signed and dated informed consent indication that the patient has been informed of all pertinent aspects of the study\n- Patient must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures\n- Regeneration from last chemotherapy defined as follows: •\tCohort 1: -Platelets >=10.000/µL (platelet transfusion allowed); - Hemoglobin >=7.5 g/dL (red blood cell transfusion allowed) •\tCohort 2: -Neutrophils >=1.000/µL; -Platelets >=50.000/µL; - Hemoglobin >=9 g/dL\n- Adequate liver function defined as follows: - Bilirubin ≤ 1.5 ULN (unless Gilbert Meulengracht disease or classified as result of liver infiltration by investigator); - AST and ALT ≤ 2.5 x ULN (unless classified as result of liver infiltration by investigator)"}

Exclusion criteria

• {"criterion_text":"- Extramedullary involvement except for non-bulky (<7.5 cm) lymph node involvement, splenomegaly, or hepatomegaly\n- Treatment with an investigational agent within 4 weeks from start of study treatment (safety follow-up period of respective study)\n- Concurrent active malignancy other than non-melanoma skin cancer, carcinoma in situ of the cervix, or localized prostate cancer that has been treated with radiation or surgery; patients with previous malignancies are eligible if they have been disease free for >= 2 years and do not require any antitumor therapy\n- Evidence of uncontrolled current serious active infection or recent history (within 4 months) of deep tissue infections such as fasciitis or osteomyelitis\n- Known allergies, hypersensitivity, or intolerance to Boron or Mannitol, corticosteroids, mAb (including Isatuximab) or human proteins, or their excipients (refer to respective Summary of Product Characteristics), or known sensitivity to mammalian-derived products\n- Active infection, any other concurrent disease or medical condition that are deemed to interfere with the conduct of the study as judged by the investigator\n- Pregnant or breastfeeding females\n- Vaccination with live attenuated vaccines within 4 weeks of first study agent administration\n- Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgement of the investigator, would make the patient inappropriate for entry into this study\n- Patients who have received prior antileukemic immunotherapy within 2 weeks prior to start of Isatuximab treatment\n- Patients who have received treatment for leukemia with chemotherapy as follows: • Cohort 1: Patients who have received treatment for leukemia with chemotherapy within 2 weeks prior to start of Isatuximab treatment (exception: pre-phase therapy with 5-7 days of Dexamethasone, 3 days of Cyclophosphamide; intrathecal prophylaxis); • Cohort 2: Any chemotherapy or antibody therapy after the MRD assay leading to study inclusion (exception: intrathecal prophylaxis)\n- Patients must have recovered from acute non-hematologic toxicity form previous therapies to ≤ grade I unless signs or symptoms are correlated to leukaemia involvement\n- Prior SCT ≤ 3 months from start of study treatment\n- Acute GvHD >= grade II or active chronic GvHD requiring systemic treatment\n- Any systemic GvHD prophylaxis or treatment within 2 weeks from start of study treatment\n- Known HIV positivity, known hepatitis B surface antigen positivity or known history of hepatitis C\n- Unstable or severe uncontrolled medical condition e.g. unstable cardiac function or unstable pulmonary condition"}

Primary endpoints

• {"endpoint_text":"- Cohort 1: Proportion of patients with complete hematologic response (ORR= CR and CRi) after 2 cycles of induction therapy including Isatuximab (refer to Section 12 for definitions of CR and CRi).","definition_or_measurement_approach":"Proportion of patients achieving complete hematologic response (ORR = CR and CRi) measured after 2 cycles of induction therapy including Isatuximab; refer to Section 12 of protocol for definitions of CR and CRi."}

Secondary endpoints

• {"endpoint_text":"- Cohort 2: Proportion of patients with molecular response (MolCR) after one cycle of Isatuximab (refer to Section 12 for definitions of molecular response). (Key secondary end point)","definition_or_measurement_approach":"Proportion with molecular response (MolCR) after 1 cycle; refer to Section 12 for molecular response definitions and MRD assay methodology."}
• {"endpoint_text":"- Proportion of patients with CR and CRi, MolCR and cMolCR in R/R (cohort 1) after 1 or 2 cycles of induction (best response)","definition_or_measurement_approach":"Proportion achieving CR, CRi, MolCR, cMolCR as best response assessed after 1 or 2 cycles."}
• {"endpoint_text":"- Probability of continuous complete remission (remission duration) at 18 months","definition_or_measurement_approach":"Probability estimate of continuous complete remission at 18 months (time-to-event analysis)."}
• {"endpoint_text":"- Probability of overall survival at 18 months","definition_or_measurement_approach":"Overall survival probability at 18 months measured from treatment start."}
• {"endpoint_text":"- Probability of relapse-free survival at 18 months","definition_or_measurement_approach":"Relapse-free survival probability at 18 months measured from treatment start."}
• {"endpoint_text":"- Probability of event-free survival at 18 months","definition_or_measurement_approach":"Event-free survival probability at 18 months."}
• {"endpoint_text":"- Incidence of relapses and proportion of relapse localisations","definition_or_measurement_approach":"Incidence counts of relapse events and descriptive localisation analysis."}
• {"endpoint_text":"- Overall incidence and severity of adverse events (CTCAE 5.0) including incidence of GvHD in patients with prior SCT","definition_or_measurement_approach":"Adverse events graded by CTCAE v5.0; incidence and severity summarized; GvHD incidence specifically tracked in patients with prior SCT."}
• {"endpoint_text":"- Evaluation of overall survival, relapse-free survival, remission duration and treatment related mortality in patients with and without SCT in complete remission after therapy","definition_or_measurement_approach":"Comparative time-to-event analyses (OS, RFS, remission duration, treatment-related mortality) stratified by SCT status."}
• {"endpoint_text":"- Duration of molecular remission","definition_or_measurement_approach":"Time from achievement of MolCR to molecular relapse or last follow-up."}
• {"endpoint_text":"- Treatment realization for Isatuximab","definition_or_measurement_approach":"Measures of treatment implementation/completion rates for Isatuximab."}
• {"endpoint_text":"- Probability of continuous MolCR and cMolCR and duration of MolCR and cMolCR","definition_or_measurement_approach":"Time-to-event analyses for continuous molecular remission and complete molecular remission and their durations."}
• {"endpoint_text":"- Time to MolCR and cMolCR measured by time-point of first achievement","definition_or_measurement_approach":"Time from treatment start to first documented MolCR or cMolCR."}
• {"endpoint_text":"- Realization of SCT in patients with CR (ORR), MolCR, cMolCR, SCT parameters and outcome","definition_or_measurement_approach":"Documentation of subsequent SCT procedures, parameters, and outcomes in patients achieving CR/MolCR/cMolCR."}
• {"endpoint_text":"- Evaluation of all endpoints by T-ALL subgroups","definition_or_measurement_approach":"Subgroup analyses by predefined T-ALL subgroups."}
• {"endpoint_text":"- Measurement of Quality of Life with EORTC instruments (e.g. EORTC QLQ-C30) at different time-points during treatment","definition_or_measurement_approach":"QoL measured using EORTC instruments (e.g., QLQ-C30) at specified time-points; scores summarized over time."}
• {"endpoint_text":"- Hospitalisation days","definition_or_measurement_approach":"Number of hospitalization days per participant during study period."}

Methods

• Recruitment via participation in the registry of the German Multicenter Study Group for Adult ALL (GMALL) targeting adult ALL patients in Germany
• Site-based recruitment at participating university hospitals and clinics across Germany (listed trial sites)

Germany

Earliest CTIS Part Ii Submission Date

26-03-2024

Latest Decision Or Authorization Date

08-12-2025

Processing Time Days

622

Number Of Sites

18

Number Of Participants

40

Primary sponsor

Full Name

Goethe University Frankfurt

Organisation Type

Educational Institution

Country Of Registered Address

Germany