E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute Lymphoblastic Leukemia |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000845 |
E.1.2 | Term | Acute lymphoblastic leukemia |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the safety of 1 course of blinatumomab added to the Interfant-06 backbone in infants with newly diagnosed ALL. |
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E.2.2 | Secondary objectives of the trial |
- to assess the feasibility of adding 1 course of blinatumomab to the Interfant-06 backbone - to define the preliminary response rate of this regimen - to assess pharmacokinetics of blinatumomab in infants |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patients must be treated according to Interfant-06 backbone 2. Patients must have newly diagnosed, CD19 positive, B-precursor acute lymphoblastic leukemia 3. Morphological verification of the diagnosis, confirmed with immunophenotyping 4. < 365 days of age at time of diagnosis of ALL 5. > 28 days of age at start of blinatumomab administration 6. MR and HR patients according to risk stratification of the Interfant-06 protocol (see table 1), thus including all MLL-rearranged and MLL not-evaluable patients (these latter are stratified and treated according to MR). 7. M1 or M2 bone marrow after induction (~day 33). If the peripheral blood shows pancytopenia at day 33 it is justified to postpone the bone marrow puncture according to the Interfant-06 protocol. If the bone marrow at day 33 is hypocellular and one is therefore unable to determine M1 or M2 status, then the bone marrow puncture should be repeated. 8. Written informed consent from parents or guardians
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E.4 | Principal exclusion criteria |
1. Biphenotypic ALL 2. Mature B-ALL 3. Presence of t(9;22) (q34;q11) or BCR-ABL fusion transcript 4. M3 marrow after induction 5. Patients with Down syndrome (because of increased toxicity of conventional chemotherapy) 6. Clinically relevant CNS pathology requiring treatment (eg unstable epilepsy) 7. Evidence of CNS involvement of ALL (CNS2 or CNS3) at the end of induction. Subjects with CNS disease at the time of diagnosis are eligible if a CNS1 status is obtained prior to enrolment (lumbar puncture at ~day 29 of induction, see definitions CNS status in Appendix D) 8. Known infection with human immunodeficiency virus (HIV) 9. Known hypersensitivity to immunoglobulins or any of the products or components to be administered during dosing
Exclusion criteria before start (-d3) of blinatumomab: 1. Peripheral neutrophils <0.5 x 109/l and WBC < 2 x 109/l (for M1 marrow only, with a maximum delay of 2 weeks. Patients with M2 bone marrow will not recover their blood counts and can start as soon as the other inclusion criteria are met) 2. Peripheral platelets < 50 x 109/L (for M1 marrow only with a maximum delay of 2 weeks. Patients with M2 bone marrow will not recover their blood counts and can start as soon as the other inclusion criteria are met) 3. Creatinine > 1.5 X ULN, based on the normal ranges for age and gender of the local laboratories 4. Total bilirubin > 3 x ULN unless the patient has documented Gilbert Syndrome 5. Chemotherapy related toxicities that have not resolved to < grade 2 6. Symptoms and/or clinical signs and/or radiological and/or sonographic signs that indicate an acute or uncontrolled chronic infection, any other concurrent disease or medical condition that could be exacerbated by the treatment or would seriously complicate compliance with the protocol
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E.5 End points |
E.5.1 | Primary end point(s) |
Incidence of clinically relevant toxicities defined as any toxicity that is possibly or definitely attributable to blinatumomab AND results in permanent discontinuation of blinatumomab OR death. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Continuously through treatment and safety follow-up |
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E.5.2 | Secondary end point(s) |
Toxicity/feasibility: 1. Incidence and severity of (serious) adverse events, independently to relationship with blinatumomab 2. Number of treatment interruptions due to toxicity occurring during blinatumomab 3. Proportion of patients that receive a full course (4 weeks) of blinatumomab 4. Incidence and severity of key safety parameters till start of maintenance and during long-term follow-up Activity/Efficacy: 5. MRD response at the following time-points: TP2 d33 (end of induction), TPblina1 d15 (after initial 15 days of blinatumomab) and TPblina2 d29 (after the complete course of blinatumomab) 6. MRD response at the following time-points: TP2 d33 (end of induction) and TP4 (end of Protocol IB) 7. Proportion of MR patients with MRD > 5x10-4 before OCTADAD (indication for SCT) 8. cCR/CR and 6 months post-induction EFS and the long-term EFS and OS Pharmacokinetics: 9. Steady state concentration of blinatumomab (Css)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Continuously through treatment and safety follow-up |
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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 | Yes |
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 | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 17 |
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 |
Australia |
Austria |
Belgium |
Czech Republic |
Denmark |
France |
Germany |
Italy |
Netherlands |
United Kingdom |
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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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
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 | 5 |
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 |