E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
E.1.1.1 | Medical condition in easily understood language |
|
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 | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000886 |
E.1.2 | Term | Acute myeloid leukemia |
E.1.2 | System Organ Class | 100000004864 |
|
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 Progression Free Survival (PFS) in AML patients older than 65 unfit for intensive chemotherapy, when treated with GRASPA (L-asparaginase encapsulated in erythrocytes) plus low-dose cytarabine compared to low-dose cytarabine alone. |
|
E.2.2 | Secondary objectives of the trial |
To evaluate
- Response to treatment
- Event Free Survival
- Overall survival
- Patient transfusion needs
- Patients Quality of life evolution
- Number of hospitalization
- Global safety of GRASPA in combination with cytarabine
- Pharmacokinetic and pharmacodynamic parameters of GRASPA
- Immunogenicity of GRASPA
Exploratory: Asparagine Synthetase exploration (in bone marrow cells) |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Patient over 65 years old and less than 85 years old
- Newly diagnosed Acute Myeloid Leukemia (AML) or post myelodysplastic syndrome diagnosed in the 6 months prior to study enrollment
- Unfit for intensive chemotherapy (at risk to suffer treatment related pejorative toxicities /early death) or patient unwilling to receive intensive chemotherapy
- WHO performance status ≤2 and estimated life expectancy ≥ 3 months
- Eligible to receive low-dose cytarabine treatment
- Evidence of post-menopausal status for female (absence of menstruation for 12 months)
- Subscription to social security insurance
- Provision of written Informed Consent |
|
E.4 | Principal exclusion criteria |
- Patients with M3 AML of FAB classification (APL, acute promyelocytic leukemia)
- Patients with AML involving chromosome 16 abnormalities or translocation (8:21) (CBF-AML)
- History of grade 3-4 pancreatitis or grade 3-4 thromboembolic event (according NCI-CTCAE Version 4.0)
- Presenting with a general or visceral contraindication including :
* Uncontrolled or severe cardiovascular disease including myocardial infarction within 6 months of enrollment, New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, clinically significant pericardial disease, or cardiac amyloidosis. Cardiac insufficiency defined as Left Ventricular Ejection Fraction < 50% of the theoretical value
* Plasma creatinine concentration, 2 times greater than the upper limit of laboratory ranges, except if related to AML
* AST or ALT levels, 3.5 times greater than the upper limit of laboratory ranges, except if related to AML
* Patient presenting evolutive cancer other than AML, except in situ basal-cell carcinoma or in situ cervix cancer
* Severe evolutive infection, or, HIV seropositive or, active hepatitis related to B or C viral infection
- History of Grade 3 Transfusional incident (life threatening)
- Has known or suspected hypersensitivity or intolerance to mannitol, or heparin
- Patient presenting contra indication to cytarabine treatment (hypersensitivity to cytarabine, antimitotic treatment, preexisting medullary aplasia, toxic degenerative encephalopathy - especially after methotrexate treatment or ioniding radiations-, yellow fever vaccination)
- Participation in an investigational drug study within the 30 days prior to entry |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Progression free survival (PFS) defined as the time elapsed between treatment initiation and disease progression or death related to disease (AML or study treatment) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Timepoint(s) of evaluation of Primary end points are described in E.5.1 |
|
E.5.2 | Secondary end point(s) |
- Percentage of patients with Complete remission (CR), Complete remission with incomplete recovery (neutrophile or platelet regeneration, CRi), Partial remission (PR)
- Event Free Survival defined as the time elapsed between treatment initiation and treatment failure, or treatment stop/delayed from toxicity reason, or disease progression, or death from any cause
- Overall survival defined as the time elapsed between treatment initiation and death from any cause
- Percentage of patients who need transfusions (red cells and/or platelets), number of transfusion by patient
- Patient quality of life (patient survey)
- Number of hospitalization (except scheduled protocol visit)
- General safety of GRASPA® in combination with low-dose cytarabine, specific attention to :
* Grade 3 to 4 of Pancreatic toxicity
* Grade 3 or 4 of hepatic toxicity, allergic reaction or thromboembolic event
* All other non hematologic grade 4 toxicities
(NB grading reference used : NCI CTCAE version 4.0)
- Pharmacodynamic and pharmacokinetic parameters of GRASPA:
* Plasmatic concentrations of asparagine, aspartate, glutamine, glutamate
* Total L-asparaginase activity
* Immunogenicity : titer of anti-L-asparaginase antibodies
Exploratory endpoints :
- Asparagine synthetase, Asparagine synthetase mRNA expression and in vitro sensitivity to asparaginase on the tumoral bone marrow cells harvested before treatment |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Timepoint(s) of evaluation of Secondary end points are described in E.5.2 |
|
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) | No |
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 | 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 | Yes |
E.8.2.3.1 | Comparator description |
standard polychemotherapy with low dose cytarabine |
|
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 5 |
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
|
Definition is provided in the protocol and is defined as last patient / last visit |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
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 | 4 |
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 |