Acute Myeloid LeukemiaPhase 2ENFORCENCT01810705
GRASPA Treatment for Patients With Acute Myeloblastic Leukemia
A Phase 2 study testing GRASPA in people with Acute Myeloid Leukemia, run by ERYtech Pharma at 21 sites in France.
Trial summary
The protocol aims at adding GRASPA (L-asparaginase encapsulated in red blood cells, eryaspase) to standard chemotherapy (low-dose cytarabine) to treat patients older than 65 years diagnosed with AML and unfit for intensive chemotherapy. Read more about this study
- Who is it for?
- Ages 65 to 85 years
- Conditions the study is for
- Acute Myeloid Leukemia
- What is being tested?
- GRASPA
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 123 participants
- Where
- 21 sitesFrance
- Study dates
- Feb 2013to 10 Nov 2017
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 65 to 85 years
- All sexes
- No healthy volunteers
- Older adult
Who may be able to join
- Patient > 65 years old and < 85 years old
- Newly diagnosed Acute Myeloid Leukemia (AML) or post myelodysplastic syndrome diagnosed within 6 months prior to study enrollment
- Unfit for intensive chemotherapy (at risk to suffer treatment related pejorative toxicities /early death) due to the presence of one or more of the following criteria: Dependence in activities of daily living owing to the presence of comorbidities other than those resulting from the deterioration caused by the neoplastic disease. Presence in the patient's medical history of three or more of the following comorbidities, even if they are under control with proper treatment: Congestive heart failure, other chronic cardiovascular diseases, chronic obstructive pulmonary disease, cerebrovascular disease, peripheral neuropathy, chronic kidney failure, hypertension, diabetes mellitus, systemic vasculitis, severe arthritis
- Presence of geriatric syndromes such as fecal or urinary incontinence, spontaneous bone fractures, mild and moderate dementia, or patients who fall repeatedly, or, patient unwilling to receive intensive chemotherapy
- Eligible to receive low-dose cytarabine treatment
- ECOG performance status ≤ 2
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- Female patients of childbearing potential and males must agree to use adequate contraception (e.g., hormonal or barrier method of birth control; abstinence) for the duration of study treatment and for 6 months after the last dose of Cytarabine or 3 months after last dose of GRASPA (whichever is the longest).
- Negative serum pregnancy test at study entry for female subjects of childbearing potential
- Subscription to social security insurance (if applicable, in accordance with local regulations)
- Ability to understand, and willingness to sign, a written informed consent document and to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures
Who cannot join
- Patients with M3 AML of FAB classification (APL, acute promyelocytic leukemia)
- Patients with AML involving chromosome 16 abnormalities or translocation (8:21) (CBF-AML)
- Patient with secondary AML subsequent to prior malignant blood disorder such as: Myelodysplastic syndrome diagnosed more than 6 months before study entry or Myeloproliferative syndrome
- Prior therapy to AML (standard therapy or investigational agents)
- Inadequate organ function : 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, Serum creatinine concentration > 2 x ULN (Upper Limit of Normal), AST or ALT levels > 3.5xULN or 5xULN if related to AML, Total bilirubin > 2 x ULN, INR > 1.5, unless patient under chronic treatment with anticoagulants (in this case, INR should be within expected ranges for the specific condition), Insulin-dependent or uncontrolled diabetes mellitus
- Concurrent malignancies other than AML requiring chemotherapy
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- Severe active infection, HIV seropositivity, or known active type B or C viral hepatitis
- Known or suspected hypersensitivity or intolerance to mannitol
- Breastfeeding or lactating women
Trial locations and contacts
21 sites in 1 country.
21 sites in 1 country
France21 sites
Groupe Hospitalier Sud
Amiens, Somme, 80090
Chu D'Angers
Angers, Maine Et Loire, 49000
Hôpital JEAN MINJOZ
Besançon, Doubs, 25000
Hopital Morvan
Brest, Finistere, 29200
CHU Estaing
Clermont-Ferrand, Puy De Dome, 63000
Hôpital Claude-Huriez
Lille, Nord, 59800
Centre Léon Bérard
Lyon, Auvergne-Rhône-Alpes, 69008
Institut Paoli Calmettes
Marseille, Bouche Du Rhone, 13000
Hôpital Saint Eloi
Montpellier, Hérault, 34295
Hôtel Dieu - CHU de NANTES
Nantes, Loire Atlantique, 44200
Hôpital l'Archet 1
Nice, Alpes Maritimes, 06200
CHRU de Nîmes
Nîmes, Guard, 30000
hopital de Perpignan
Perpignan, Pyrénées Orientales, 66100
Hôpital Haut-Lévèque
Pessac, Gironde, 33600
Centre hospitalier Lyon Sud
Pierre-Bénite, Auvergne-Rhône-Alpes, 69310
Hopital Région d'Annecy
Pringy, Haute Savoie, 74000
Centre Henri Becquerel
Rouen, Seine Maritime, 76100
Institut de Cancérologie de la Loire
Saint-priest-en-jarez, Pays de la Loire Region, 42270
Hopital de Hautepierre
Strasbourg, Haut Rhin, 67000
Hopital De Purpan CHU Toulouse
Toulouse, Haute Garonne, 31500
Hopital de Brabois
Vandœuvre-lès-Nancy, Meurthe Et Moselle, 54500
About this study
Official title: A Multicenter, Open, Randomized, Controlled Phase IIb Trial Evaluating Efficacy and Tolerability of GRASPA (L-asparaginase Encapsulated in Red Blood Cells, Eryaspase) Plus Low-dose Cytarabine vs Low-dose Cytarabine Alone, in Treatment of Newly Diagnosed Acute Myeloid Leukemia (AML) Elderly Patients, Unfit for Intensive Chemotherapy
The protocol aims at adding GRASPA (L-asparaginase encapsulated in red blood cells, eryaspase) to standard chemotherapy (low-dose cytarabine) to treat patients older than 65 years diagnosed with AML and unfit for intensive chemotherapy.
Read the detailed description
L-asparaginase (ASNase) holds a key role in chemotherapy for Acute Lymphoblastic Leukemia (ALL) in children and young adults. In elderly patients, its efficacy is counterbalanced by its toxicity, which impairs its use. However, a study conducted with GRASPA (L-asparaginase encapsulated in red blood cells, eryaspase) in elderly ALL (study reference "GRASPALL-GRAAL SA2 2008") showed that efficacy/safety profile was positive, paving the way for introducing ASNase benefit into chemotherapy for elderly patients.
In adults, Capizzi (1988) reported a significant benefit of ASNase associated with high-dose cytarabine treatment (HiDAC) in Acute Myeloid Leukemia (AML). Indeed, there was an overall statistically superior complete remission rate for HiDAC/ASNase (40%) vs HiDAC (24%) and an overall survival benefit for patients treated with HiDAC/ASNase (19.6 weeks vs 15.9 weeks).
Another study in elderly patients also displayed positive results for ASNase treatment (Petti, 1989), as well as recent single case reports that point out the potential benefit of ASNase in different AML or mixed lineage leukemia (Horikoshi, 2009; Rubnitz, 2009).
Our preclinical results also showed that an AML cell line and blast cells from the bone marrow of AML patients were sensitive to ASNase in vitro.
However, up to now, the toxicity of ASNase for elderly had prevented its use in this population that represents the majority of AML patients.
Considering the promising results of ASNase for AML treatment and the better safety profile offered by GRASPA (L-aspariginase encapsulated in red blood cells, erysapase), a multicenter, randomized, controlled IIb trial is open for recruitment. Efficacy and tolerability of GRASPA plus low-dose cytarabine will be evaluated versus low-dose cytarabine alone in treatment of AML patients over 65 year-old, unfit for intensive chemotherapy.
One hundred and twenty-three patients (65-85 year-old) newly diagnosed for AML are planned for inclusion in the study.
A 2:1 randomization will be respected (82 patients treated with GRASPA® plus low-dose cytarabine and 41 patients treated with low-dose cytarabine alone). Each patient will be followed for 24 months.
- Conditions
- Acute Myeloid Leukemia
- Being tested
- GRASPA
- Keywords
- myeloid, leukemia
- Medical subject headings
- Leukemia, Myeloid, Acute, Leukemia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
GRASPADrug
Also called L-asparaginase encapsulated in red blood cells
Patients receiving Intervention (experimental group) will be treated with one injection of graspa per cycle of treatment, each cycle during 28 days, for a duration up to 24 cycles maximum
| Study group | Role | What they receive |
|---|---|---|
| GRASPA | Experimental | patients will receive one injection of GRASPA (100 IU/kg) after each course of low-dose cytarabine (see Arm "Control") Receives: Drug: GRASPA |
| Control | No intervention | patients will receive successive courses of low intensive chemotherapy, as subcutaneous low-dose cytarabine 20mg twice daily for 10 days per course (from day 1 to day 10), each course occurring every 28 days, for a duration up to 24 months |
What is being measured
The primary outcome is the main question the study is designed to answer.
Overall Survival
OS is defined as the time elapsed between randomization and death from any cause.
Measured: Each patient will be followed for a duration of 24 months.
Secondary outcomes (11)
Response to Treatment
Percentage of patients with Complete remission (CR), Complete remission with incomplete recovery (neutrophil or platelet regeneration, CRi), Partial remission (PR)
Measured: Each patient will be followed for a duration of 24 months.
Progression Free Survival (PFS)
Defined as the time elapsed between randomization and resistant disease or relapse or death from any cause
Measured: Each patient will be followed for a duration of 24 months.
Patient Quality of Life
Collecting survey about patients quality of life
Measured: Each patient will be followed for a duration of 24 months.
Safety of GRASPA Adverse Events and Serious Adverse Events
Number of incidences, type, severity and causality of adverse events / serious adverse events
Measured: Each patient will be followed for a duration of 24 months.
Relapse Free Survival
Defined only for patients who achieve CR or CRi as the time elapsed between date of CR/CRi and date of disease relapse or death from any cause
Measured: Each patient will be followed for a duration of 24 months.
Number of Hospitalizations
Hospitalizations (except schedule protocol visit during the study)
Measured: Each patient will be followed for a duration of 24 months.
Percentage of Patients Who Need Transfusions
Number of transfusions per patient (red blood cells and or platelets)
Measured: Until patient stops treatment (expected average of 8 months)
Pharmacodynamic and Pharmacokinetic Parameters of GRASPA
Plasma concentrations of asparagine, aspartate, glutamine, glutamate, whole blood L- asparaginase activity
Measured: Until patient stops treatment (expected average of 8 months)
Immunogenicity
Titer of anti L-asparaginase antibodies
Measured: Until patient stops treatment (expected average of 8 months)
Asparagine Synthetase (Optional)
Asparagine synthetase and in vitro sensitivity to aspariginase on the harvested bone marrow cells
Measured: Until patient stops treatment (expected average of 8 months)
Biomarker Cytogenetic Testing (Optional)
Defined as cytogenetic biomarker testing
Measured: Until patient stops treatment (expected average of 8 months)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Mar 2013 (estimated)
- Study startFeb 2013
- Primary completion10 Nov 2017
- Study completion10 Nov 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Acute Myeloid LeukemiaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 123 participants (actual)
Sponsor and investigators
- Lead sponsor
- ERYtech Pharma
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- X Thomas, Doctor, Principal investigator
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01810705
- Sponsor's protocol ID
- GRASPA-AML2012-01
- Acronym
- ENFORCE
- Status last verified
- Feb 2022
- First submitted
- 7 Mar 2013
- Last updated
- 21 Feb 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 21 Feb 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Multicenter, Open, Randomized, Controlled Phase IIb Trial Evaluating Efficacy and Tolerability of GRASPA (L-asparaginase Encapsulated in Red Blood Cells, Eryaspase) Plus Low-dose Cytarabine vs Low-dose Cytarabine Alone, in Treatment of Newly Diagnosed Acute Myeloid Leukemia (AML) Elderly Patients, Unfit for Intensive Chemotherapy
- ClinicalTrials.gov ID
- NCT01810705
- Acronym / sponsor ID
- ENFORCE / GRASPA-AML2012-01
- Conditions
- Acute Myeloid Leukemia
- Keywords
- myeloid, leukemia
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 123 participants (actual)
- Lead sponsor
- ERYtech PharmaIndustry (pharma, biotech, devices)
- Study start
- Feb 2013 (actual)
- Primary completion
- 10 Nov 2017 (actual)
- Study completion
- 10 Nov 2017 (actual)
- First posted
- 13 Mar 2013 (estimated)
- Results
- Posted 21 Feb 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The protocol aims at adding GRASPA (L-asparaginase encapsulated in red blood cells, eryaspase) to standard chemotherapy (low-dose cytarabine) to treat patients older than 65 years diagnosed with AML and unfit for intensive chemotherapy.
Detailed description
L-asparaginase (ASNase) holds a key role in chemotherapy for Acute Lymphoblastic Leukemia (ALL) in children and young adults. In elderly patients, its efficacy is counterbalanced by its toxicity, which impairs its use. However, a study conducted with GRASPA (L-asparaginase encapsulated in red blood cells, eryaspase) in elderly ALL (study reference "GRASPALL-GRAAL SA2 2008") showed that efficacy/safety profile was positive, paving the way for introducing ASNase benefit into chemotherapy for elderly patients.
In adults, Capizzi (1988) reported a significant benefit of ASNase associated with high-dose cytarabine treatment (HiDAC) in Acute Myeloid Leukemia (AML). Indeed, there was an overall statistically superior complete remission rate for HiDAC/ASNase (40%) vs HiDAC (24%) and an overall survival benefit for patients treated with HiDAC/ASNase (19.6 weeks vs 15.9 weeks).
Another study in elderly patients also displayed positive results for ASNase treatment (Petti, 1989), as well as recent single case reports that point out the potential benefit of ASNase in different AML or mixed lineage leukemia (Horikoshi, 2009; Rubnitz, 2009).
Our preclinical results also showed that an AML cell line and blast cells from the bone marrow of AML patients were sensitive to ASNase in vitro.
However, up to now, the toxicity of ASNase for elderly had prevented its use in this population that represents the majority of AML patients.
Considering the promising results of ASNase for AML treatment and the better safety profile offered by GRASPA (L-aspariginase encapsulated in red blood cells, erysapase), a multicenter, randomized, controlled IIb trial is open for recruitment. Efficacy and tolerability of GRASPA plus low-dose cytarabine will be evaluated versus low-dose cytarabine alone in treatment of AML patients over 65 year-old, unfit for intensive chemotherapy.
One hundred and twenty-three patients (65-85 year-old) newly diagnosed for AML are planned for inclusion in the study.
A 2:1 randomization will be respected (82 patients treated with GRASPA® plus low-dose cytarabine and 41 patients treated with low-dose cytarabine alone). Each patient will be followed for 24 months.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| GRASPA | Experimental | Drug: GRASPApatients will receive one injection of GRASPA (100 IU/kg) after each course of low-dose cytarabine (see Arm "Control") |
| Control | No intervention | –patients will receive successive courses of low intensive chemotherapy, as subcutaneous low-dose cytarabine 20mg twice daily for 10 days per course (from day 1 to day 10), each course occurring every 28 days, for a duration up to 24 months |
Who may qualify
- Ages
- 65 to 85 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Older adult
Key inclusion criteria (10 listed)
- Patient > 65 years old and < 85 years old
- Newly diagnosed Acute Myeloid Leukemia (AML) or post myelodysplastic syndrome diagnosed within 6 months prior to study enrollment
- Unfit for intensive chemotherapy (at risk to suffer treatment related pejorative toxicities /early death) due to the presence of one or more of the following criteria: Dependence in activities of daily living owing to the presence of comorbidities other than those resulting from the deterioration caused by the neoplastic disease. Presence in the patient's medical history of three or more of the following comorbidities, even if they are under control with proper treatment: Congestive heart failure, other chronic cardiovascular diseases, chronic obstructive pulmonary disease, cerebrovascular disease, peripheral neuropathy, chronic kidney failure, hypertension, diabetes mellitus, systemic vasculitis, severe arthritis
- Presence of geriatric syndromes such as fecal or urinary incontinence, spontaneous bone fractures, mild and moderate dementia, or patients who fall repeatedly, or, patient unwilling to receive intensive chemotherapy
- Eligible to receive low-dose cytarabine treatment
Key exclusion criteria (9 listed)
- Patients with M3 AML of FAB classification (APL, acute promyelocytic leukemia)
- Patients with AML involving chromosome 16 abnormalities or translocation (8:21) (CBF-AML)
- Patient with secondary AML subsequent to prior malignant blood disorder such as: Myelodysplastic syndrome diagnosed more than 6 months before study entry or Myeloproliferative syndrome
- Prior therapy to AML (standard therapy or investigational agents)
- Inadequate organ function : 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, Serum creatinine concentration > 2 x ULN (Upper Limit of Normal), AST or ALT levels > 3.5xULN or 5xULN if related to AML, Total bilirubin > 2 x ULN, INR > 1.5, unless patient under chronic treatment with anticoagulants (in this case, INR should be within expected ranges for the specific condition), Insulin-dependent or uncontrolled diabetes mellitus
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| GRASPAAlso: L-asparaginase encapsulated in red blood cellsPatients receiving Intervention (experimental group) will be treated with one injection of graspa per cycle of treatment, each cycle during 28 days, for a duration up to 24 cycles maximum | Drug | GRASPA |
Primary outcome
Overall Survival
Time frame: Each patient will be followed for a duration of 24 months.
OS is defined as the time elapsed between randomization and death from any cause.
11 secondary outcomes
Response to Treatment
Time frame: Each patient will be followed for a duration of 24 months.
Progression Free Survival (PFS)
Time frame: Each patient will be followed for a duration of 24 months.
Patient Quality of Life
Time frame: Each patient will be followed for a duration of 24 months.
Safety of GRASPA Adverse Events and Serious Adverse Events
Time frame: Each patient will be followed for a duration of 24 months.
Relapse Free Survival
Time frame: Each patient will be followed for a duration of 24 months.
Number of Hospitalizations
Time frame: Each patient will be followed for a duration of 24 months.
Percentage of Patients Who Need Transfusions
Time frame: Until patient stops treatment (expected average of 8 months)
Pharmacodynamic and Pharmacokinetic Parameters of GRASPA
Time frame: Until patient stops treatment (expected average of 8 months)
Immunogenicity
Time frame: Until patient stops treatment (expected average of 8 months)
Asparagine Synthetase (Optional)
Time frame: Until patient stops treatment (expected average of 8 months)
Biomarker Cytogenetic Testing (Optional)
Time frame: Until patient stops treatment (expected average of 8 months)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Feb 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
X Thomas, Doctor principal investigator
21 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing GRASPA in people with Acute Myeloid Leukemia, run by ERYtech Pharma at 21 sites in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 21 Feb 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 21 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 21 Feb 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Overall Survival (time frame: Each patient will be followed for a duration of 24 months.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Feb 2022.