The CLARA Study From the Acute Leukemia French Association (ALFA 0702 Trial)

A Randomized Phase II Study of Clofarabine / Intermediate-Dose Cytarabine (CLARA)Versus High-Dose Cytarabine (HDAC) as Consolidation in Younger Patients With Newly-Diagnosed Acute Myeloid Leukemia (AML).

This study is a phase II randomized multicenter study. Patients will be enrolled at time of diagnosis and will receive one or two cycles of induction chemotherapy. Patients, without indication of intensification by allogeneic stem cell transplantation and/or without HLA (Human Leukocyte Antigen)-compatible donor, who attain a CR after one or two cycles of induction chemotherapy, will be eligible for the study Clofarabine / Intermediate-Dose Cytarabine (CLARA)versus High-Dose Cytarabine (HDAC)and will be randomized between 3 courses of CLARA chemotherapy and 3 courses of HDAC chemotherapy as consolidation.

We will compare efficacy and toxicity among the two arms.

Because of the results of our former trial (ALFA-9802) [Thomas, 2005], chemotherapy will be combined in each arm with G-CSF (Granulocyte Colony-Stimulating Factor) given during each sequence of chemotherapy in order to increase the blast priming.

Inclusion Criteria at registration:

1. Age 18 years or more and less than 60 years

2. With:

   A morphologically proven diagnosis of AML according to the WHO classification, cytogenetically (standard karyotype, FISH-MLL) and molecularly (FLT3, CEBPA, NMP1) defined.

3. ECOG (Eastern Cooperative Oncology Group) performance status 0 to 2.

4. Have adequate renal and hepatic function as indicated by the following laboratory values:

   • Creatinine clearance (calculated by the cockcroft and Gault method) ≥ 40mL/min;
   • AST (Aspartate amino transférase) and ALT (Alanine Amino Transférase ) < or = 2.5N; total bilirubin < or = 2N (unless related to the underlying disease).

5. Cardiac function determined by radionuclide or echography within normal limits.

6. Women of child-bearing potential (i.e. women who are pre-menopausal or not surgically sterile) must use acceptable contraceptive methods, and must have a negative serum or urine pregnancy test within 2 weeks prior the beginning treatment on this trial.

7. Must be able and willing to give written informed consent.

8. The subject must be covered by a social security system.

Exclusion Criteria at registration:

1. Patients with AML with favorable risk cytogenetics: M3-AML; CBF-AML including t(8:21), inv(16), or t(16;16) AML.
2. Ph-positive AML.
3. AML following diagnosed myeloproliferation or patient with prior history of MDS known for more than 3 months
4. Prior treatment with chemotherapy or radiotherapy for another tumor.
5. Prior tumor, if not stable for at least two years, except in-situ carcinoma and skin carcinoma
6. Compromised organ function judged to be lifethreatening by the Investigator.
7. Positive serology for HIV (Human Immunodeficiency Virus), HBV (Hepatitis B Virus) and HBC (Hepatitis C Virus)(except post vaccination)
8. Uncontrolled active infection of any kind or bleeding. Patients with infections who are under active treatment with antibiotics and whose infections are controlled may be entered to the study.
9. Other active malignancy.
10. Patients concurrently receiving any other standard or investigational treatment for their leukemia, with the exception of hydroxyurea.

INCLUSION CRITERIA AT RANDOMIZATION

1. Patients with either in first CR/CRp after the first induction course or in first CR/CRp after salvage therapy.

2. ECOG performance status 0 to 2.

3. AST and ALT < or = 2.5N; total bilirubin < or = 2N.

4. Creatinine clearance ≥40mL/min (calculated by the cockcroft and Gault method or by MDRD (see http://nephron.org/cgi-bin/MDRD\_GFR/cgi)

5. Patient without HLA identical donor.

   EXCLUSION CRITERIA AT RANDOMIZATION

6. Patients belonging to the intermediate 1 risk group (CEBPA+ or NPM1+ without Flt3-ITD) in CR/CRp after the first induction course. These patients will go out of the study and receive consolidation cycles based on HD-AraC (Aracytine).

7. Known central nervous system involvement with AML.

8. Uncontrolled active infection of any kind or bleeding.

9. Compromized organ function judged to be lifethreatening by the Investigator.

10. Patient with HLA identical donor identified.