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GRASPA Treatment for Patients With Acute Myeloblastic Leukemia (ENFORCE)

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ClinicalTrials.gov Identifier: NCT01810705
Recruitment Status : Completed
First Posted : March 13, 2013
Last Update Posted : March 29, 2018
Sponsor:
Information provided by (Responsible Party):
ERYtech Pharma

Brief 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.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Drug: GRASPA Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 123 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : February 2013
Actual Primary Completion Date : November 10, 2017
Actual Study Completion Date : November 10, 2017


Arm Intervention/treatment
Experimental: GRASPA
patients will receive one injection of GRASPA (100 IU/kg) after each course of low-dose cytarabine (see Arm "Control")
Drug: GRASPA
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
Other Name: L-asparaginase encapsulated in red blood cells

No Intervention: Control
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



Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. Response to treatment [ Time Frame: Each patient will be followed for a duration of 24 months. ]
    Percentage of patients with Complete remission (CR), Complete remission with incomplete recovery (neutrophil or platelet regeneration, CRi), Partial remission (PR)

  2. Progression free survival (PFS) [ Time Frame: Each patient will be followed for a duration of 24 months. ]
    Defined as the time elapsed between randomization and resistant disease or relapse or death from any cause

  3. Patient quality of life [ Time Frame: Each patient will be followed for a duration of 24 months. ]
    Collecting survey about patients quality of life

  4. Safety of GRASPA adverse events and serious adverse events [ Time Frame: Each patient will be followed for a duration of 24 months. ]
    Number of incidences, type, severity and causality of adverse events / serious adverse events

  5. Relapse free survival [ Time Frame: Each patient will be followed for a duration of 24 months. ]
    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

  6. Number of hospitalizations [ Time Frame: Each patient will be followed for a duration of 24 months. ]
    Hospitalizations (except schedule protocol visit during the study)

  7. Percentage of patients who need transfusions [ Time Frame: Until patient stops treatment (expected average of 8 months) ]
    Number of transfusions per patient (red blood cells and or platelets)

  8. Pharmacodynamic and pharmacokinetic parameters of GRASPA [ Time Frame: Until patient stops treatment (expected average of 8 months) ]
    Plasma concentrations of asparagine, aspartate, glutamine, glutamate, whole blood L- asparaginase activity

  9. Immunogenicity [ Time Frame: Until patient stops treatment (expected average of 8 months) ]
    Titer of anti L-asparaginase antibodies

  10. Asparagine synthetase (optional) [ Time Frame: Until patient stops treatment (expected average of 8 months) ]
    Asparagine synthetase and in vitro sensitivity to aspariginase on the harvested bone marrow cells

  11. Biomarker cytogenetic testing (optional) [ Time Frame: Until patient stops treatment (expected average of 8 months) ]
    Defined as cytogenetic biomarker testing



Information from the National Library of Medicine

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Ages Eligible for Study:   65 Years to 85 Years   (Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

  • 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
  • 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

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)
  • 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
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01810705


Locations
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France
Hôpital l'Archet 1
Nice, Alpes Maritimes, France, 06200
Institut Paoli Calmettes
Marseille, Bouche Du Rhone, France, 13000
Hôpital JEAN MINJOZ
Besancon, Doubs, France, 25000
Hopital Morvan
Brest, Finistere, France, 29200
Hôpital Haut-Lévèque
Pessac, Gironde, France, 33600
CHRU de Nîmes
Nimes, Guard, France, 30000
Hopital de Hautepierre
Strasbourg, Haut Rhin, France, 67000
Hopital De Purpan CHU Toulouse
Toulouse, Haute Garonne, France, 31500
Hopital Région d'Annecy
Pringy, Haute Savoie, France, 74000
Hôpital Saint Eloi
Montpellier, Hérault, France, 34295
Hôtel Dieu - CHU de NANTES
Nantes, Loire Atlantique, France, 44200
Institut de Cancérologie de la Loire
Saint-priest-en-jarez, Loire, France, 42270
Chu D'Angers
Angers, Maine Et Loire, France, 49000
Hopital de Brabois
Vandoeuvre Les Nancy, Meurthe Et Moselle, France, 54500
Hôpital Claude-Huriez
Lille, Nord, France, 59800
CHU Estaing
Clermont-ferrand, Puy De Dome, France, 63000
hopital de Perpignan
Perpignan, Pyrénées Orientales, France, 66100
Centre Léon Bérard
Lyon, Rhone Alpes, France, 69008
Centre hospitalier Lyon Sud
Pierre Benite, Rhone Alpes, France, 69310
Centre Henri Becquerel
Rouen, Seine Maritime, France, 76100
Groupe Hospitalier Sud
Amiens, Somme, France, 80090
Sponsors and Collaborators
ERYtech Pharma
Investigators
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Principal Investigator: X Thomas, Doctor

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Responsible Party: ERYtech Pharma
ClinicalTrials.gov Identifier: NCT01810705     History of Changes
Other Study ID Numbers: GRASPA-AML2012-01
First Posted: March 13, 2013    Key Record Dates
Last Update Posted: March 29, 2018
Last Verified: March 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Keywords provided by ERYtech Pharma:
myeloid
leukemia
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Cytarabine
Asparaginase
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs