E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Subjects with treatment-resistant mixed chimerism or MRD of CD19+ B-precursor ALL after allogeneic SCT |
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E.1.1.1 | Medical condition in easily understood language |
Subjects after allogeneic stem cell transplantation who have achieved a complete morphologic remission but are in very high risk for relapse because of mixed chimerim or MRD. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10063621 |
E.1.2 | Term | Acute lymphoblastic leukaemia recurrent |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10063625 |
E.1.2 | Term | Acute lymphoblastic leukemia recurrent |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the safety and tolerability of combined DLI and blinatumomab treatment in subjects with treatment-resistant MC or MRD of CD19+ B-precursor ALL after allogeneic SCT. |
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E.2.2 | Secondary objectives of the trial |
1) To evaluate the efficacy of a combined treatment of DLI and blinatumomab to induce a complete MRD/chimerism response. 2) To evaluate the duration of the response and survival
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Patients with CD19+ B–precursor ALL (as determined by immunophenotyping) in hCR (defined as having less than 5% blasts in bone marrow) after allogeneic SCT. 2) One, or a combination of the following documented after an interval of at least 2 weeks since cessation of the most recent leukemia-targeting therapy (i.e. chemotherapy, immunotherapy or cellular therapy, except for intrathecal prophylaxis): - Positivity for CD19+ MRD (molecular failure or molecular relapse), defined as presence of MRD at a level of ≥10-4 according to an assay with a minimum sensitivity of 10-4. - Donor chimerism <90%, as determined by analysis of host and donor STRs in bone marrow sample engraftment analysis. 3) At least one previous line of treatment for MRD-positivity and/or reduced donor chimerism (i.e. blinatumomab, DLI, TKI or other agents) after allogeneic SCT. 4) For those with BCR/ABL-positive B-precursor ALL only: persistence of MRD and/or MC following at least one ≥ second generation TKI (dasatinib, nilotinib, bosutinib, ponatinib) OR intolerance to second generation TKI and intolerance to or persistence of MRD and/or MC following imatinib mesylate. 5) Availability of allogeneic donor lymphocytes from the subject’s donor (at least 2 x 108 T cells/kg). 6) Subject (or subject's legally acceptable representative when the subject is legally too young to provide informed consent) has provided written informed consent prior to initiation of any study-specific activities/procedures. 7) Subject (or Subject’s legally acceptable representative when the subject is legally too young to provide informed consent) has provided informed consent to be followed up in the GMALL-Registry. 8) Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2. 9) Renal function as follows: serum creatinine < 2.0 mg/dL and estimated glomerular filtration rate > 30 mL/min. 10) Hepatic function as follows: - Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 3.0 x upper limit of normal (ULN) - Alkaline phosphatase (ALP) < 3.0 x ULN - Bilirubin ≤ 2.0 x ULN (unless considered due to Gilbert's syndrome or hemolysis) |
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E.4 | Principal exclusion criteria |
1) Eligibility for treatment with blinatumomab ALONE or other antibody-based treatment approaches (e.g. inotuzumab ozogamicin), as considered by the treating physician. 2) Eligibility for standard chemotherapy, as considered by the treating physician. 3) Antitumor therapy (chemotherapy, antibody therapy, molecular-targeted therapy, retinoid therapy, or investigational agent) within 14 days or 5 half-lives (whichever is longer) prior to baseline MRD and/or chimerism assessment. 4) Treatment with systemic immune modulators including, but not limited to, non-topical systemic corticosteroids, cyclosporine, and tacrolimus within 2 weeks before enrollment. 5) Any grade of GvHD currently requiring treatment. 6) Clinically relevant central nervous system (CNS) pathology requiring treatment (e.g., unstable epilepsy). 7) Evidence of current CNS involvement by ALL. Subjects with CNS relapse at the time of relapse are eligible if CNS is successfully controlled prior to enrollment. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Subject incidence and grade of AEs including GvHD |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety in terms of AE incidence will be evaluated after the first patient received at least one dose with blinatumomab until LVLS. |
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E.5.2 | Secondary end point(s) |
1) For MRD-positive patients: MRD response. Efficacy parameters: complete MRD response rate (patients achieving MolCR, defined as MRD which is not detectable by molecular probes with a sensitivity of ≥10−4), duration of complete MRD response, and time to complete MRD response. 2) For patients with MC: chimerism response. Efficacy parameters: CC/low-level MC response rate (defined as patients with ≥90% donor STRs present in bone marrow DNA sample at engraftment analysis), duration of CC/low-level MC response, and time to CC/low-level MC response. 3) Progression-free survival and overall survival.
Exploratory Endpoints: 1) Expansion of Donor Lymphocytes as measured by T cell chimerism. 2) Lymphocyte counts as well as T cell activation (including T cell subsets). Other immune subsets may also be examined. 3) Changes in serum cytokine levels. 4) CD19 expression levels on the ALL cell surface. 5) Number of blood products transfused during the study period. 6) Days of antibiotic treatment for infection during the study period |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy analysis will be performed on all subjects who received a minimum of 4 days blinatumomab. Endpoints will be analysed by use of appropriate descriptive techniques after the EOCS visit has been completed by all subjects. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |