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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.

Phase 2
65 Years
85 Years
Open (Enrolling)
Acute Myeloid Leukemia

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Trial Information

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.

Inclusion Criteria:

- Patient over 65 years old and less than 85 years old

- Newly diagnosed Acute Myeloid Leukemia or post myelodysplastic syndrome diagnosed in
the 6 months prior 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)

Exclusion Criteria:

- Patients with M3 AML of French American British classification ( Acute Promyelocytic

- Patients with AML involving chromosome 16 abnormalities or translocation (8:21)

- History of grade 3-4 pancreatitis or grade 3-4 thromboembolic event

- Presenting with a general or visceral contraindication (Uncontrolled or severe
cardiovascular disease ; Plasma creatinine concentration 2 times greater than the
upper limit of laboratory ranges ; Aspartate aminotransferase (AST) or alanine
aminotransferase (ALT) levels, 3.5 times greater than the upper limit of laboratory
ranges ; 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

- Has known or suspected hypersensitivity or intolerance to mannitol

- Patient presenting contra indication to cytarabine treatment

- Participation in an investigational drug study within the 30 days prior to entry

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

change from baseline blast count

Outcome Description:

Progression-free survival (PFS): Assessment of disease (Acute myeloid leukemia) progression, recording the date the event occurs

Outcome Time Frame:

once a month, until disease progression (expected average of 8 months)

Safety Issue:


Principal Investigator

X Thomas, Doctor

Investigator Role:

Principal Investigator


France: Ministry of Health

Study ID:




Start Date:

February 2013

Completion Date:

March 2017

Related Keywords:

  • Acute Myeloid Leukemia
  • myeloid
  • leukemia
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid