T-ALL
Conditions
Keywords
R/R or MRD CD38-positive T-ALL
Brief summary
The planned trial offers treatment cohorts for patients with full cytologic relapse (R/R ALL - Cohort 1), as well as for patients with molecular failure/relapse (MRD+ ALL - Cohort 2). Basically, the study aims to develop data for optimization of first-line therapy of T-ALL, either by modification of standard induction with Isatuximab or by establishing a post-induction therapy for eradication of MRD and thereby evaluates in parallel two different strategies.
Interventions
DRUGIsatuximab
Cohort 1: All patients will receive two cycles of induction therapy with standard chemotherapy, Bortezomib and Isatuximab. Isatuximab maintenance may be administered in patients with CR until SCT, progression/relapse, unacceptable toxicity, physicians' decision to change treatment or withdrawal of consent.
Sponsors
Goethe University
Sanofi
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Cohort 1: * Patients with CD38 positive T-ALL/T-LBL * Either: In relapse or with primary refractory disease defined as ≥5% blasts in bone marrow cytology or ≥1% minimal residual disease (MRD) * Or: Extramedullary relapse or primary refractory disease confirmed by standard imaging with measurable target leasions * 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 (not required in patients with extramedullary disease only). * ECOG status: 0-2 * 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: * Platelets ≥10.000/uL (platelet transfusion allowed) * Hemoglobin ≥ 7.5 g/dl (red blood cell transfusion allowed) * 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) * Adequate renal function defined as follows: * Serum creatinine ≤ 2 x ULN * Any serum creatinine level associated with a calculated creatinine clearance ≥ 40 mL/min * Negative pregnancy test in women of childbearing potential (WOCBP) * WOCBP must commit to either abstain continuously from heterosexual sexual intercourse 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 of contraception * Participation in the registry of the German Multicenter Study Group for Adult ALL (GMALL) Cohort 2: • terminated with protocol version 3.2.
Exclusion criteria
Cohort 1: * Patients with CNS-only relapse * Patients who have received prior antileukemic immunotherapy within 2 weeks prior to start of Isatuximab treatment * Patients who have received treatment for leukemia with chemotherapy as follows: * Patients who have received treatment for leukemia with chemotherapy within 2 weeks prior to start of Isatuximab treatment (exception: documented disease progression under chemotherapy and pre-phase therapy with 5-7 days of Dexamethasone, 3 days of Cyclophosphamide; intrathecal prophylaxis) * Patients who are candidates for a treatment with Nelarabine (eligibility to be assessed particularly in patients with extramedullary involvement and/or early/mature T-ALL/T-LBL, due to limited efficacy) * Patients must have recovered from acute non-hematologic toxicity form previous therapies to ≤ grade I unless signs or symptoms are correlated to leukaemia involvement * 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 study treatment * Known HIV positivity, known hepatitis B surface antigen positivity or known history of hepatitis C * Unstable or severe uncontrolled medical condition e.g. unstable cardiac function or unstable 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 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 * 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 to mammalian-derived products * 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 * Pregnant or breastfeeding females * Vaccination with live attenuated vaccines within 4 weeks of first study agent administration * 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 Cohort 2: • terminated with protocol version 3.2.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall incidence and severity of adverse events | Day 22, Week 9, month 3, month 6 (depends on duration of therapy which is variable) | Cohort 1: Overall incidence and severity of adverse events (CTCAE 5.0). |
| Proportion of patients with molecular response (MolCR) | Day 22, Week 9, per SoC | Cohort 2: Proportion of patients with molecular response (MolCR) after one cycle of Isatuximab. |
| Proportion of patients with complete hematologic response (ORR= CR and CRi) | Day 22, Week 9, per SoC | Cohort 1: Proportion of patients with complete hematologic response (ORR= CR and CRi) after 2 cycles of induction therapy including Isatuximab. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Conduct of SCT in patients with CR (ORR), MolCR, cMolCR | Through completion of the trial, average 18 months | The conduct of SCT will be assessed in patients with CR (ORR), MolCR, cMolCR, SCT parameters and outcome |
| Measurement of Quality of Life | Day 22, Week 9 | Measurement of Quality of Life with EORTC instruments (e.g. EORTC QLQ-C30) at different time-points during treatment |
| Hospitalisation days | Day 22, Week 9, month 3 and 6 (depending on treatment duration which is individual) | Hospitalisation days |
| Probability of event-free survival | at 18 months | Probability of event-free survival at 18 months |
| Duration of molecular remission (mimimal residual disease by PCR) | Day 22, Week 9, per SoC | — |
| Incidence of relapses and proportion of relapse localisations | Day 22, Week 9, per SoC | Incidence of relapses and proportion of relapse localisations |
| Incidence of GvHD in patients with prior SCT | until end of trial | Incidence of GvHD in patients with prior SCT |
| Proportion of patients with CR and CRi, MolCR and cMolCR in R/R | Day 22, Week 9, per SoC | Cohort 1: Proportion of patients with CR and CRi, MolCR and cMolCR in R/R (cohort 1) after 1 or 2 cycles of induction (best response) |
| Probability of continuous complete remission | at 18 months | Probability of continuous complete remission (remission duration) at 18 months |
| Probability of overall survival | at 18 Months | Probability of overall survival at 18 months |
| Treatment realization for Isatuximab | d22, week 9, per maintenance cycle, end of treatment at month 6 | Dosing of Isatuximab as scheduled per protocol |
| Probability of relapse-free survival | at 18 months | Probability of relapse-free survival at 18 months |
| Probability of continuous MolCR and cMolCR and duration of MolCR and cMolCR | Day 22, Week 9, per SoC | Probability of continuous MolCR and cMolCR and duration of MolCR and cMolCR |
| Time to MolCR and cMolCR | Day 22, Week 9, per SoC | Time to MolCR and cMolCR measured by time-point of first achievement. |
Countries
Germany
Contacts
CONTACTNicola Goekbuget, MD
STUDY_DIRECTORNicola Goekbuget, MD
Department of Medicine, Hematology and Oncology, Goethe University Frankfurt, Frankfurt, Germany
PRINCIPAL_INVESTIGATORAnjali Cremer, MD
Department of Medicine, Hematology and Oncology, Goethe University Frankfurt, Frankfurt, Germany
Outcome results
None listed