A Phase IIb Trial Evaluating Efficacy and Tolerability of GRASPA Plus Low-dose Cytarabine vs Low-dose Cytarabine Alone, in Treatment of Newly Diagnosed Acute Myeloid Leukemia (AML) Patients, Over 65 Years, Unfit for Intensive Chemotherapy.
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 current study with Red Blood Cells (RBC)
encapsulating ASNase (GRASPA®) 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.
Aim Considering the promising results of ASNase for AML treatment and the better safety
profile offered by RBC encapsulating ASNase (GRASPA®), 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.
Progression-free survival (time elapsed between treatment initiation and disease
progression/death) will be evaluated as a primary endpoint. A 75% improvement in the median
progression-free survival is assumed in the experimental group vs control group.
Percentages of remission (complete and partial), survival (event-free and overall), patient
quality of life, general safety, pharmacodynamic/pharmacokinetic and immunogenicity of
GRASPA® will be also evaluated.
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
change from baseline blast count
Progression-free survival (PFS): Assessment of disease (Acute myeloid leukemia) progression, recording the date the event occurs
once a month, until disease progression (expected average of 8 months)
X Thomas, Doctor
France: Ministry of Health