E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
minimal residual disease (MRD) of B-precursor ALL |
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E.1.1.1 | Medical condition in easily understood language |
very small numbers of blood cancer cells remaining in the bone marrow after chemotherapy |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
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 | 10000845 |
E.1.2 | Term | Acute lymphoblastic leukemia |
E.1.2 | System Organ Class | 100000012958 |
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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 efficacy of blinatumomab to induce complete MRD response
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E.2.2 | Secondary objectives of the trial |
Key secondary objective for patients with Ph-negative ALL
• To evaluate the effect of blinatumomab on hematological relapse
Other Secondary objectives
• To evaluate overall survival in patients with ALL treated with blinatumomab
• To evaluate the effect of blinatumomab on the 100d mortality rate associated with allogeneic HSCT
• To evaluate the safety and tolerability of blinatumomab
• To evaluate the effect of blinatumomab on duration of MRD negativity
• To evaluate the effect of blinatumomab on the kinetics of MRD
• To evaluate patient’s quality of life during and after therapy
• To evaluate resource utilization
Exploratory objectives
• To assess potential biologic predictors of response to blinatumomab |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patients with B–precursor ALL in complete hematological remission defined as less than 5% blasts in bone marrow after at least three intense chemotherapy blocks (e.g., GMALL induction I-II/consolidation I, induction/intensification/ consolidation or three blocks of Hyper CVAD)
2. Presence of minimal residual disease at a level of ≥10-3 (molecular failure or molecular relapse) in an assay with a minimum sensitivity of 10-4 documented after an interval of at least 2 weeks from last systemic chemotherapy
3. For evaluation of minimal residual disease, patients must have at least one molecular marker based on individual rearrangements of immunoglobulin or TCR-genes or a flow cytometric marker profile, evaluated by a national or local reference lab approved by the Sponsor
4. Bone marrow or peripheral blood specimen from primary ALL diagnosis /diagnosis of ALL relapse (a sufficient amount of DNA or a respective amount of cell material) for clone-specific MRD assessment must be received by central MRD lab and lab must confirm that the sample is available
5. Bone marrow function as defined in the protocol
-ANC (Neutrophile) ≥ 1 000/µL
-Thrombozyten ≥ 50,000/µL (transfusion permitted)
-HB Level ≥ 9g/dl (transfusion permitted)
6. Renal and hepatic function as defined in the protocol
-AST (GOT), ALT (GPT), und AP < 2 x upper limit of normal (ULN)
-Total bilirubin < 1.5 x ULN
-Creatinin-Clearance ≥ 50 mL/min (e.g. calculated according Cockroft & Gault)
7. Negative HIV test, negative hepatitis B (HbsAg) and hepatitis C virus (anti-HCV) test
8. Negative pregnancy test in women of childbearing potential
9. ECOG Performance Status 0 or 1
10. Age ≥18 years
11. Ability to understand and willingness to sign a written informed consent
12. Signed and dated written informed consent is available
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E.4 | Principal exclusion criteria |
1. Presence of circulating blasts or current extramedullary involvement by ALL
2. History of relevant CNS pathology or current relevant CNS pathology (e.g. seizure, paresis, aphasia, cerebrovascular ischemia/hemorrhage, severe brain injuries, dementia, Parkinson’s disease, cerebellar disease, organic brain syndrome, psychosis, coordination or movement disorder)
3. Current infiltration of cerebrospinal fluid by ALL
4. History of or active relevant autoimmune disease
5. Prior allogeneic HSCT
6. Eligibility for treatment with TKIs (i.e., Philadelphia chromosome-positive (Ph) patients with no documented treatment failure of or intolerance/contraindication to at least 2 TKIs)
7. Systemic cancer chemotherapy within 2 weeks prior to study treatment, (except for intrathecal prophylaxis)
8. Radiotherapy within 4 weeks prior to study treatment
9. Autologous hematopoietic stem cell transplantation (HSCT) within six weeks prior to study treatment
10. Therapy with monoclonal antibodies (rituximab, alemtuzumab) within 4 weeks prior to study treatment
11. Treatment with any investigational product within four weeks prior to study treatment
12. Previous treatment with blinatumomab
13. Known hypersensitivity to immunoglobulins or to any other component of the study drug formulation
14. Active malignancy other than ALL with the exception of basal cell or
squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix
15. 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
16. Nursing women or women of childbearing potential not willing to use an effective form of contraception during participation in the study and at least 3 months thereafter or male patients not willing to ensure effective contraception during participation in the study and at least three months thereafter. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Endpoint:
Proportion of patients who achieve complete MRD response defined by absence of MRD after one cycle of treatment with blinatumomab |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary efficacy assessment will be analyzed at the completion of the first cycle of treatment. |
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E.5.2 | Secondary end point(s) |
Key secondary endpoint in patients with Ph-negative ALL
• Hematological relapse-free survival rate at 18 months following initiation of blinatumomab
Secondary endpoints
• Overall Survival
• Mortality rate within 100 days after allogeneic HSCT
• Time to hematological relapse
• Duration of complete MRD response
• Effect on MRD level
• Overall incidence and severity of adverse events
• Patient’s quality of life during and after therapy
• Resource utilization |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The key secondary endpoint will be assessed at 18 months following initiation of blinatumomab infusion.
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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 | Yes |
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 | No |
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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 65 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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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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Last subject last visit after approximately 4 years
6 monthly phone contacts for overall survival for 3 addtional years.
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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 | 8 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 8 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |