E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute Lymphoblastic Leukaemia |
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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 | 17.1 |
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 | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Determine the efficacy and safety of GRASPA® at a dose equivalent to 150 IU/kg of L-asparaginase combined with standard polychemotherapy in several populations of patients with first recurrence of ALL Ph-, i.e. children from 1 to 17 years old, adults from 18 to 55 years old, with or without known hypersensitivity to L-asparaginase. |
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E.2.2 | Secondary objectives of the trial |
to evaluate
- the molecular and clinical response rate: minimal residual disease, (MRD) and complete remission (CR),
- the safety of GRASPA® compared to the reference L-asparaginase treatment,
- the biological efficacy of GRASPA® compared to the reference L-asparaginase treatment by measurement of the total mean duration of plasmatic asparagine depletion in days,
- the number of patients with adequate asparagine depletion (i.e. ≤ 2 µM) and without allergic reaction during the induction phase
- number of patients with asparaginase activity >100IU/L and without allergic reaction during the induction phase.
- the immunogenicity of GRASPA® compared to reference L-asparaginase treatment by the assessment of specific antibodies,
- and compare the treatment adherence of GRASPA® and the reference L-asparaginase treatment,
- the event-free survival (EFS), the relapse-free survival (RFS) and the overall survival (OS) at 6, 12, 24 and 36 months after inclusion. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Patient from 1 to 55 years old
- Children and adolescents from 1 up to 17 years
- Adults over 18 up to 55 years
- Patients with
- Patients with 1st ALL relapse, which could be either isolated bone marrow relapse, or combined (medullary and extra-medullary) relapse, or extra-medullary isolated relapse; or lymphoblastic lymphoma (excepted Burkitt lymphoma)
OR
- Failure to ALL first line treatment (no complete remission obtained).
- Patient previously treated with free E.Coli L-asparaginase form or pegylated one.
- Performance Status ≤ 2 (WHO score).
- Patient informed and consent provided (the 2 parents need to consent when children below 18) |
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E.4 | Principal exclusion criteria |
- ALL t(9;22) and/or BCR-ABL positive (Philadelphia chromosome positive).
- Patient with 2nd relapse and over.
- Women of childbearing potential without effective contraception as well as pregnant or breast feeding women.
- Patient unable to receive treatments used in global chemotherapy protocols, due to general or visceral conditions such as:
- Severe cardiac impairment (NYHA grade 3 or 4 cardiomyopathy)
- Serum creatinine 2 x ULN unless related to ALL
- ALT or AST 5 x ULN unless related to ALL
- Pancreatitis history
- Other malignancy that ALL
- Severe Infection, HIV positive, active hepatitis related to B or C virus infection
- Trisomy 21
- Other serious conditions according to investigator's opinion.
- Known grade 4 allergic reaction to E.Coli L-asparaginase (according NCI-CTCAE, Version 3.0).
- History of grade 3 transfusionnal incident.
- Presence of specific anti-erythrocyte antibodies preventing from getting a compatible erythrocyte concentrate for the patient.
- Patient under concomitant treatment likely to cause hemolysis.
- Patient undergoing yellow fever vaccination.
- Patient under phenytoine treatment.
- Patient included in previous clinical study less than 6 weeks |
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E.5 End points |
E.5.1 | Primary end point(s) |
EXPLORATORY PHASE II AND CONFIRMATORY PHASE III:
There are 2 primary endpoints in the study: one regarding Efficacy and one regarding Safety. The study will be declared positive if the 2 primary endpoints are met.
Primary endpoint of efficacy
The initially specified endpoint for efficacy was :
- Efficacy endpoint at end of F2 block (or VANDA) (i.e. Day 28):
• Mean duration of asparagine depletion in days throughout F1-F2 blocks.
Asparagine depletion will be defined as plasmatic asparagine concentration ≤ 2µM.
According to the CHMP advice, this efficacy endpoint was revised to :
- Efficacy endpoint at end of induction phase (i.e. day 28):
• Duration in days of asparaginase activity >100 IU/L.
Primary endpoint of safety
• Toxicity endpoint at end of F2 block (or VANDA) : Incidence of allergic reaction, whatever the grade. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Timepoint(s) of evaluation of Primary end points described in E.5.1 |
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E.5.2 | Secondary end point(s) |
EXPLORATORY PHASE II
• Molecular response rate (MRD).
• Percentage of CR patients at F2 block ending.
• Biological and clinical toxicity according to NCI-CTCAE (version 3.0) grading, in particular pancreatic, hepatic toxicity, deep vein thrombosis and other coagulation disorders, which are well known adverse events related to L-asparaginase.
• Plasma concentrations of asparagine, aspartate, glutamine, glutamate and asparaginase.
• Percentage of patient presenting with asparagine depletion (i.e. ≤ 2µM) at different time points.
CONFIRMATORY PHASE III:
Secondary endpoints listed above are still used and the following are added:
• Number of patients with adequate asparagine depletion (i.e. ≤ 2 µM) and without allergic reaction during the induction phase.
• Number of patients with asparaginase activity >100 IU/L and without allergic reaction during the induction phase.
• Specific anti-L-asparaginase antibodies level.
• Ratio of performed / planned injections regarding GRASPA® and reference asparaginase treatment over the total mean duration of study treatment.
• At 6, 12, 24, 36 months:
o Event free survival rate
o Relapse free survival rate
o Overall survival rate. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Timepoint(s) of evaluation of Secondary end points described in E.5.2 |
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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 | Yes |
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) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
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 | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
The allergic patients will all be treated with GRASPA® |
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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 | Yes |
E.8.2.3.1 | Comparator description |
standard polychemotherapy |
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E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 60 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 100 |
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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The definition is defined as :
The final analysis will be performed in Q3 2014 when all patients have been follow-up for one year.
In addition all patients will be followed up for two additional years (Q3 2016 =last patient last visit) |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |