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GRASPA-AML 2012-01 study (NCT01810705): A multicenter, open, randomized phase 2b trial
evaluating GRASPA (L-asparaginase encapsulated in red blood cells) plus low-dose cytarabine vs
low-dose cytarabine alone, in treatment of newly diagnosed Acute Myeloid Leukemia (AML) elderly
patients, unfit for intensive chemotherapy.
Xavier THOMAS1, Emmanuelle TAVERNIER TARDY2, Romain GUIEZE3, Patrice CHEVALLIER4, Jean Pierre MAROLLEAU5,
Frédérique ORSINI6,Elena Carmen RADU7, Ian HITCHCOCK8
(1) Centre Hospitalier Lyon Sud, France, (2) Institut de Cancérologie Lucien Neuwirth, Saint-Priest-En-Jarez, France, (3) Centre Hospitalier Universitaire (CHU) Estaing, Clermont-Ferrand,
France, (4) Hôtel Dieu, Nantes, France,(5) Groupe Hospitalier Sud, Amiens, France, (6) CH de la Région d’Annecy, France, (7) Erytech Pharma, France (8) Orphan-Europe, Puteaux, France,
•Acute myeloid leukemia (AML) is a heterogeneous clonal disorder of hematopoietic
progenitor cells and the most common malignant myeloid disorder in adults, with
a median age of 65 years at diagnosis.
•There is unmet medical need for the treatment of elderly patients with AML unfit
for intensive chemotherapy.
•L-asparaginase (L-ASP) plays a key role in all treatment phases for Acute Lymphoblastic Leukemia (ALL). Most leukemic cells in ALL are asparagine synthetase
(ASNS) deficient requiring endogenous plasma asparagine for protein synthesis
and survival. L-ASP hydrolyses L-asparagine depleting this essential amino acid
and causing tumor cell starvation. Normal cells are resistant to L-ASP as they can
synthesize asparagine using ASNS.
•Several clinical studies and case reports have shown a potential benefit of L-ASP
in certain AML cell lines or mixed lineage leukemia.
•GRASPA is a novel platform of RBC encapsulation of L-ASP
RATIONALE FOR GRASPA IN AML
•GRASPA has demonstrated clinical activity and a favorable toxicity profile in a
Phase III trial in pediatric and adult patients aged from 1-55 years with relapsed
ALL, in combination with multi-agent chemotherapy and in combination in a Phase
II study of newly diagnosed patients >55 years with ALL.
•Poor tolerability of currently available asparaginases limits their utility in elderly
and poor performance status patients
•GRASPA has been shown to deplete serum asparagine, which is well established
surrogate marker for survival in ALL.
•High-dose cytarabine and asparaginase intensification improved 5-year survival
rate: 36% vs 29% (p < 0.02) in children with AML1. Evidence of clinical activity
has been demonstrated in adult patients with AML2,3
GRASPA – MECHANISM OF ACTION
• prolongs enzymatic
activity
• limits the off-target
toxicity
GRASPA- entrapped
asparaginase in
erythrocyte
Y
Y
Y
Y
•This is an open, randomized, multicenter, European Phase IIb study, comparing
the clinical activity and tolerability of GRASPA in combination with low-dose cytarabine (LDAC) compared to LDAC alone, for the treatment of newly diagnosed patients with AML.
•123 patients are planned for enrollment
OBJECTIVES
Primary
Asparagine
•To evaluate progression free survival (PFS) in AML patients older than 65 years and
unfit for intensive chemotherapy
Asparaginase
Y Antibodies
»»Temporary interruption or permanent withdrawn of LDAC therapy: GRASPA may be
continued as per treatment schedule
•Identify AML subtypes with high sensitivity to asparaginase
STUDY DESIGN
Newly diagnosed AML or MDS
Elderly patients (65 – 85 years)
Unfit for intensive
chemotherapy treatment
ECOG ≤ 2
•GRASPA
»»If injection is delayed > 1 week from scheduled day (D11), omit dose and resume
injection at the next scheduled cycle
»»LDAC may be continued if GRASPA therapy is terminated
GRASPA*
+ Low-dose ARA-C**
Low-dose ARA-C**
* GRASPA is administered at a dose of 100 IU/kg IV on Day 11.
** LDAC: 40 mg daily subcutaneously for 10 consecutive days (D1 to D10),
repeated every 4 weeks for up to 24 months
KEY PATIENT POPULATION
Inclusion Criteria:
•Patient ≥65 and ≤ 85 years old
•Newly diagnosed AML or post myelodysplastic syndrome diagnosed within 6
months prior of study enrollment
•Provision of written Informed Consent
Exclusion Criteria:
•Chromosome 16 abnormalities or translocation (8:21) (CBF-AML)
•Secondary AML: myelodysplastic syndrome diagnosed more than 6 months before
study entry, or myeloproliferative syndrome
TPS7099
•LDAC
•Response to treatment, overall survival, quality of life assessment, safety assessment, pharmacokinetic and pharmacodynamic parameters, and Immunogenicity of
GRASPA
•M3 AML of FAB classification (APL, Acute Promyelocytic Leukemia)
2015 ASCO Annual Meeting May 31, 2015 Chicago, Ill
Dosage adaptation
»»May be adjusted to 20 mg daily for toxicity
Y
Macrophages
•10 consecutive days (from D1 to D10) per course repeated every 28 days
Secondary
•Adequate organ function
Encapsulated
asparaginase
hy dro ly s e s a s pa ra g ine
•40 mg daily / subcutaneous injections (one or two injections per day)
•GRASPA at a dose of 100 UI/kg at D11 and LDAC (D1 – D10).
Y
Y
Y
Y
Y
Control arm: patients treated with LDAC
Experimental arm: patients treated with LDAC + GRASPA.
•ECOG performance status ≤2 and estimated life expectancy ≥ 3 months
Y
TREATMENT PLAN
•Treatment duration for up to 24 months
•Unfit for intensive chemotherapy (at risk to suffer treatment related pejorative toxicities or early death) or patient unwilling to receive intensive chemotherapy
Y
Y
The circulating
asparagine is
transported into
the erythrocyte
METHODS
RANDOMIZE 2:1
BACKGROUND
•History of Grade 3-4 pancreatitis or Grade 3-4 thromboembolic event (according
NCI-CTCAE Version 4.0)
STATUS UPDATE
•A data safety monitoring committee regularly reviewed patient safety when:
»»30 patients were included
»»60 patients were included
»»5 patients with Diabetes were included and followed up for one month
--All meetings to date concluded to continue the study
CONCLUSION
•This study is ongoing and a total of 20 European centers are currently enrolling
patients
• GRASPA can be administered and is tolerable in this elderly group of patients
(maximum number of cycles administered to one patient to date is twenty-two)
REFERENCES
1.Impact of high-dose cytarabine and asparaginase intensification on childhood acute myeloid
leukemia: a report from the Childrens Cancer Group. Wells RJ, Woods WG, Lampkin BC, Nesbit
ME, Lee JW, Buckley JD, Versteeg C, Hammond GD, JCO MAR 1, 1993:538-45
2.The pharmacologic basis for the efficacy of high-dose Ara-C and sequential asparaginase in
adult acute myelogenous leukemia. R. L. Capizzi and C. White, Yale J Biol Med. 1988 Jan-Feb;
61(1): 11–22
3.High-dose Ara-C (HiDAC) plus asparaginase in elderly patients with acute non-lymphocytic
leukemia: a pilot multicentric study by the Italian Cooperative Group GIMEMA. Petti MC1,
Mandelli F, Avvisati G, Covelli A, Amadori S, Liso V, Leone G, De Laurenzi A, Leoni P, Neri A, et al.,
Eur J Haematol. 1989 Jan;42(1):24-31.
ACKNOWLEDGEMENT
The study is sponsored by ERYTECH pharma and done in partnership with Orphan
Europe Recordati
The authors would like to express their sincere thanks to the patients and their
families for participating in this study.
DISCLOSURE: Dr. Xavier Thomas is consultant for ERYTECH Pharma