Daratumumab for T-cell acute lymphoblastic leukemia (very high-risk)

Inclusion criteria

• {"criterion_text":"- Age 18-65 years.\n- Signed written informed consent according to ICH/E U/GCP and national local laws.\n- A diagnosis of T-ALL according to the 2022 International Consensus Classification (ICC) is required, either de novo or secondary to chemo-radiotherapy for another cancer. Pre-treatment with low-dose corticosteroids +/- cyclophosphamide in patients presenting with hyperleukocytosis is allowed.\n- Availability of fresh bone marrow (BM) (or peripheral blood (PB) in patients with hyperleukocytosis) samples to perform diagnostic procedures).\n- Bone marrow blast percentage at diagnosis ≥20%.\n- CD38 positivity on ALL blasts (any level of positivity).\n- ETP and near ETP at diagnosis according to internationally accepted criteria (appendix G) at diagnosis or other VHR T-ALL subtypes (WBC count >100 x109/L; complex karyotype with ≥5 unrelated anomalies; other CD1a-negative immunophenotypes). T-Myeloid MPAL according to the 2022 ICC of Acute Leukemias of Ambiguous Lineage (appendix H) can also be eligible and considered as VHR.\n- Availability of full cytological, cytochemical, immunophenotypic, cytogenetic and molecular disease characterization according to the EGIL and WHO classifications.\n- An ECOG performance status 0-2, unless a performance of 3 is unequivocally caused by the disease itself, (and not by pre-existing comorbidities,) and is considered and/or documented to be reversible following the application of anti-leukemic therapy and appropriate supportive measures.\n- For females of childbearing potential, a negative pregnancy test must be documented. Female and male patients who are fertile must agree to use an effective form of contraception with their sexual partners from enrollment through 12 months after the end of treatment."}

Exclusion criteria

• {"criterion_text":"- Diagnosis of B-lineage ALL, and Ph+ ALL.\n- Down’s syndrome.\n- Prior systemic chemotherapy for ALL (excluding cyclophosphamide during pre-phase).\n- Pre-existing, uncontrolled pathology such as heart failure (congestive/ischemic, acute myocardial infarction within the past 3 months, untreatable arrhythmias, NYHA classes III and IV), FE<50% (unless attributable to ALL), severe liver disease with serum direct bilirubin >3 mg/dL (unless attributable to Gilbert’ syndrome or ALL) and/or ALT >5x upper normal limit (unless attributable to ALL), kidney function impairment with serum creatinine >2 mg/dL (unless attributable to ALL), severe lung disease with FEV1<50% (unless attributable to ALL) and severe neuropsychiatric disorder that impairs the patient’s ability to understand and sign the informed consent, or to cope with the intended treatment plan. N.B. For altered liver and kidney function tests, eligibility criteria can be reassessed at 24-96 hours, following the institution of adequate supportive measures.\n- Presence of serious, active, uncontrolled infections.\n- A history of cancer that is not in a remission phase following surgery and/or radiotherapy and/or chemotherapy, with a life expectancy <2 years.\n- Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy.\n- Patients who are pregnant or breast feeding and adults of reproductive potential not employing an effective method of birth control (women of childbearing potential must have a negative serum pregnancy test within 48 hrs. prior treatment start). Postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. Male and female patients must agree to employ two effective reliable methods of birth control throughout the study and for up to 12 months following discontinuation of study drugs."}

Primary endpoints

• {"endpoint_text":"- The primary endpoint of this study is to evaluate clinical response - in terms of MRD negativity (<10^-4) after induction (TP1) - in patients with very high-risk T-ALL treated with a daratumumab plus chemotherapy approach.","definition_or_measurement_approach":"MRD negativity defined as <10^-4 measured after induction (time point 1, TP1)."}

Secondary endpoints

• {"endpoint_text":"- The rate of MRD negativity at TP2, TP3, TP4 and before allo-SCT","definition_or_measurement_approach":"MRD assessment at specified time points (TP2, TP3, TP4) and before allogeneic stem cell transplant (allo-SCT)."}
• {"endpoint_text":"- The rate of allo-SCT allocation","definition_or_measurement_approach":"Proportion of patients allocated to allogeneic stem cell transplant."}
• {"endpoint_text":"- DFS at 12 months","definition_or_measurement_approach":"Disease-free survival measured at 12 months."}
• {"endpoint_text":"- EFS at 18 months","definition_or_measurement_approach":"Event-free survival measured at 18 months."}
• {"endpoint_text":"- CIR estimation from CR achievement at 18 months","definition_or_measurement_approach":"Cumulative incidence of relapse from complete remission achievement assessed at 18 months."}
• {"endpoint_text":"- OS at 18 months","definition_or_measurement_approach":"Overall survival measured at 18 months."}
• {"endpoint_text":"- Treatment-related mortality (TRM)","definition_or_measurement_approach":"Mortality attributable to treatment."}
• {"endpoint_text":"- Rate of Adverse Events (AEs) and Serious AEs","definition_or_measurement_approach":"Frequency and severity of adverse events and serious adverse events according to standard reporting."}

Italy

Earliest CTIS Part Ii Submission Date

15-07-2024

Latest Decision Or Authorization Date

23-12-2025

Processing Time Days

526

Number Of Sites

23

Number Of Participants

31

Primary sponsor

Full Name

Fondazione Gimema Franco Mandelli Onlus

Organisation Type

Patient organisation/association

Country Of Registered Address

Italy

Contract research organisations

Name

Evidenze Health S.r.l.

Responsibilities

1

Third parties

• {"country":"Italy","full_name":"Laboratorio di Medicina Molecolare, Unità di Ematologia, Università di Perugia, CREO","duties_or_roles":"4","organisation_type":"Health care"}
• {"country":"Italy","full_name":"Laboratorio Ematologia, Azienda Policlinico \"Umberto I\", Diapartimento Medicina Traslaz. e di Precis","duties_or_roles":"4","organisation_type":"Health care"}
• {"country":"Italy","full_name":"Laboratorio di Ematologia “Paolo Belli” ASST Papa Giovanni XXIII","duties_or_roles":"4","organisation_type":"Health care"}
• {"country":"Italy","full_name":"Evidenze Health S.r.l.","duties_or_roles":"1","organisation_type":"Pharmaceutical company"}
• {"country":"Italy","full_name":"U.O.S.D. Laboratorio di Oncoematologia e Manipolazione Cellulare,Ospedali Riuniti Villa S.-Cervello","duties_or_roles":"4","organisation_type":"Health care"}