GRASPA Treatment for Patients With Acute Myeloblastic Leukemia

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: GRASPA


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 65 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GRASPA<br>patients will receive one injection of GRASPA (100 IU/kg) after each course of low-dose cytarabine (see Arm Control) | Drug: GRASPA<br>* 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<br>* Other names: L-asparaginase encapsulated in red blood cells;|
| No Intervention: Control<br>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 the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | OS is defined as the time elapsed between randomization and death from any cause. | Each patient will be followed for a duration of 24 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response to Treatment | Percentage of patients with Complete remission (CR), Complete remission with incomplete recovery (neutrophil or platelet regeneration, CRi), Partial remission (PR) | 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 | Each patient will be followed for a duration of 24 months. | 
| Patient Quality of Life | Collecting survey about patients quality of life | 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 | 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 | Each patient will be followed for a duration of 24 months. | 
| Number of Hospitalizations | Hospitalizations (except schedule protocol visit during the study) | 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) | 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 | Until patient stops treatment (expected average of 8 months) | 
| Immunogenicity | Titer of anti L-asparaginase antibodies | 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 | Until patient stops treatment (expected average of 8 months) | 
| Biomarker Cytogenetic Testing (Optional) | Defined as cytogenetic biomarker testing | Until patient stops treatment (expected average of 8 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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myeloid, leukemia