Isatuximab in Adult Patients With Cytologic or Molecular Relapsed/Refractory CD38 Positive T-cell Acute Lymphoblastic Leukemia

Inclusion Criteria:

• Patients with CD38 positive T-ALL fitting either to the definitions for cohort 1 orcohort 2:

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:

• early relapse within 12 months from first achievement of CR or

• late relapse later than 12 months from first achievement of CR or

• primary refractory disease without any CR or

• any relapse after stem cell transplantation or

• any refractory relapse, defined as no response to at least one salvage therapy or

• any second or later relapse and

• Availability of patient material with blast cells (bone marrow or peripheral blood)for central MRD assessment or availability of respective predefined marker.

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)

• Detection of quantifiable MRD at a level of ≥10-4, either as molecular failurewithout prior achievement of molecular remission or molecular relapse after priorachievement of molecular remission

• MRD assay at the central reference lab with at least one marker a minimumsensitivity of 10-4

• MRD detection for study inclusion after an interval of at least 2 weeks from lastsystemic chemotherapy including antibody therapy

• (in patients without clonal molecular MRD marker, MRD testing can be based onflow-cytometry established in reference laboratory)

ECOG status:

• Cohort 1: 0-2

• Cohort 2: 0-1

Age ≥ 18 years Evidence of a personally signed and dated informed consent indicating that the patient has been informed of all pertinent aspects of the study Patient must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures

Regeneration from last chemotherapy defined as follows:

Cohort 1:

• Platelets ≥10.000/uL (platelet transfusion allowed)

• Hemoglobin ≥ 7.5 g/dl (red blood cell transfusion allowed)

Cohort 2:

• Neutrophils ≥1.000/uL

• Platelets ≥50.000/uL

• Hemoglobin ≥9 g/dl

Adequate liver function defined as follows:

• Bilirubin ≤ 1.5 ULN (unless Gilbert Meulengracht disease or classified as result ofliver infiltration by investigator)

• AST and ALT ≤ 2.5 x ULN (unless classified as result of liver infiltration byinvestigator)

Adequate renal function defined as follows:

• Serum creatinine ≤ 2 x ULN

• Any serum creatinine level associated with a calculated creatinine clearance ≤ 40mL/min

• Negative pregnancy test in women of childbearing potential (WOCBP)

• WOCBP must commit to either abstain continuously from heterosexual sexualintercourse or to use 2 methods of reliable birth control simultaneously.

• Men who are sexually active with a WOCBP must agree to use a barrier method ofcontraception

• Participation in the registry of the German Multicenter Study Group for Adult ALL (GMALL)

Exclusion Criteria:

• Extramedullary involvement except for non-bulky (<7.5 cm) lymph node involvement,splenomegaly, or hepatomegaly

• Patients who have received prior antileukemic immunotherapy within 2 weeks prior tostart of Isatuximab treatment

• Patients who have received treatment for leukemia with chemotherapy as follows:

Cohort 1:

• Patients who have received treatment for leukemia with chemotherapy within 2 weeksprior to start of Isatuximab treatment (exception: pre-phase therapy with 5-7 daysof Dexamethasone, 3 days of Cyclophosphamide; intrathecal prophylaxis)

• Patients who are candidates for a treatment with Nelarabine

Cohort 2:

• Any chemotherapy or antibody therapy after the MRD assay leading to study inclusion (exception: intrathecal prophylaxis)

• Patients must have recovered from acute non-hematologic toxicity from previoustherapies to ≤ grade I unless signs or symptoms are correlated to leukemiainvolvement

• Prior SCT ≤ 3 months from start of study treatment

• Acute GvHD ≥ grade II or active chronic GvHD requiring systemic treatment

• Any systemic GvHD prophylaxis or treatment within 2 weeks from start of studytreatment

• Known HIV positivity, known hepatitis B surface antigen positivity or known historyof hepatitis C

• Unstable or severe uncontrolled medical condition e.g. unstable cardiac function orunstable pulmonary condition

• Treatment with an investigational agent within 4 weeks from start of study treatment (safety follow-up period of respective study)

• Concurrent active malignancy other than non-melanoma skin cancer, carcinoma in situof the cervix, or localized prostate cancer that has been treated with radiation orsurgery; patients with previous malignancies are eligible if they have been diseasefree for ≥ 2 years and do not require any antitumor therapy.

• Evidence of uncontrolled current serious active infection or recent history (within 4 months) of deep tissue infections such as fasciitis or osteomyelitis

• 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 tomammalian-derived products.

• Active infection, any other concurrent disease or medical condition that are deemedto interfere with the conduct of the study as judged by the investigator

• Pregnant or breastfeeding females

• Vaccination with live attenuated vaccines within 4 weeks of first study agentadministration.

• Other severe acute or chronic medical or psychiatric condition or laboratoryabnormality that may increase the risk associated with study participation orinvestigational product administration or may interfere with the interpretation ofstudy results and, in the judgement of the investigator, would make the patientinappropriate for entry into this study