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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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).

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: CLARA
* Drug: HDAc


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria at registration: Age 18 years or more and less than 60 years With: A morphologically proven diagnosis of AML according to the WHO classification, cytogenetically (standard karyotype, FISH-MLL) and molecularly (FLT3, CEBPA, NMP1) defined. ECOG (Eastern Cooperative Oncology Group) performance status 0 to 2. 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). Cardiac function determined by radionuclide or echography within normal limits. 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. Must be able and willing to give written informed consent. The subject must be covered by a social security system. Exclusion Criteria at registration: Patients with AML with favorable risk cytogenetics: M3-AML; CBF-AML including t(8:21), inv(16), or t(16;16) AML. Ph-positive AML. AML following diagnosed myeloproliferation or patient with prior history of MDS known for more than 3 months Prior treatment with chemotherapy or radiotherapy for another tumor. Prior tumor, if not stable for at least two years, except in-situ carcinoma and skin carcinoma Compromised organ function judged to be lifethreatening by the Investigator. Positive serology for HIV (Human Immunodeficiency Virus), HBV (Hepatitis B Virus) and HBC (Hepatitis C Virus)(except post vaccination) 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. Other active malignancy. Patients concurrently receiving any other standard or investigational treatment for their leukemia, with the exception of hydroxyurea. INCLUSION CRITERIA AT RANDOMIZATION Patients with either in first CR/CRp after the first induction course or in first CR/CRp after salvage therapy. ECOG performance status 0 to 2. AST and ALT < or = 2.5N; total bilirubin < or = 2N. Creatinine clearance ≥40mL/min (calculated by the cockcroft and Gault method or by MDRD (see http://nephron.org/cgi-bin/MDRD_GFR/cgi) Patient without HLA identical donor. EXCLUSION CRITERIA AT RANDOMIZATION 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). Known central nervous system involvement with AML. Uncontrolled active infection of any kind or bleeding. Compromized organ function judged to be lifethreatening by the Investigator. Patient with HLA identical donor identified.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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: CLARA<br>Clofarabine / Intermediate-Dose Cytarabine (CLARA) with G-CSF given during each sequence of chemotherapy in order to increase the blast priming. | Drug: CLARA<br>* Clofarabine 30 mg/m2/day IV (2h) on days 2 to 6 (administered as a 2h infusion in 250 ml of 0.9% normal saline solution) Cytarabine 1 g/m2/day intravenous (2h) 4 hours later on days 1 to 5 (administered as a 2h infusion in 250 ml of 5% dextrose in water) G-CSF 5 microg/kg/day intravenous from day 1 to day 6 (administered as a 30 mn infusion in 20 ml of dextrose 5% in water)<br>|
| Active Comparator: HDAC<br>High-Dose Cytarabine (HDAC) with G-CSF given during each sequence of chemotherapy in order to increase the blast priming. | Drug: HDAc<br>* Cytarabine 3 g/m2/12h intravenous (3h) on days 1, 3, 5 (administered as a 3h infusion in 250 ml of 5% dextrose in water) G-CSF 5 microg/kg/day intravenous from day 1 to day 5 (administered as a 30 mn infusion in 20 ml of dextrose 5% in water)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DFS (disease free survival) following first remission achievement (CR : Complete Remission or CRp : Complete Remission but platelet count < 100 x109/L) in younger patients with intermediate-risk or unfavorable-risk AML. | As all these patients are eligible for allogenic stem cell transplantation in first remission if they have a donor and the comparison of interest primarily concerns non-transplanted patients, it is planned: 1) to exclude patients with an identified donor; 2) to adjust Relapse Free survival (RFS) comparison on the interaction with stem cell transplantation in first remission; and 3) to censure at transplant time the patients allografted before disease progression after randomization (late donor identification) as sensitivity analysis. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| • Safety profile of CLARA versus HDAC consolidation courses | All toxicity encountered during therapy will be evaluated according to the CTC expanded Common Toxicity Criteria and causal relationship to investigational products will be reported. Serious Adverse Events encountered 3 MONTHS after the last cycle of study chemotherapy (induction/salvage/CLARA/HDAC), whether or not ascribed to the study, will be recorded in the Serious Adverse Event form. | 2 years | 
| • Possible predictors to response | Possible predictors to response: with respect to cytogenetics risk groups and mutational status: FLT3 (Fms-like tyrosine kinase 3), MLL (myeloid/ lymphoid or mixed-lineage leukemia), CEBPA (CCAAT / enhancer binding protein α) and NPM(Nucleophosmin)) | 2 years | 
| • MRD (Minimal Residual Disease) level | Evaluation of MRD in patients with AML in clinical remission is a potentially useful tool for assessing the risk of relapse and guiding further therapeutic decisions. Once an aberrant pattern is identified at diagnosis, it will serve as a patient-specific probe to be used, with standard triple/quadruple labelling, to track residual disease longitudinally. Bone marrow and peripheral blood samples for MRD evaluation will be collected at fixed time points: End of induction in patients achieving CR/CRp. End of consolidation 3. Every 6 months during follow-up for 2 years. | 2 years | 
| • Overall cumulative incidence of relapse |  | 120 days | 
| • Overall survival (OS) | OS will be defined as the time from diagnosis to death or last contact with the patient | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Younger Patients with Newly-Diagnosed Acute Myeloid Leukemia (AML).