Clinical trial NCT00932412: The CLARA Study From the Acute Leukemia French Association (ALFA 0702 Trial)
Official title: 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).
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Myeloid Leukemia
Keywords: Younger Patients with Newly-Diagnosed Acute Myeloid Leukemia (AML).
Lead sponsor: Hospices Civils de Lyon
Sponsor class: OTHER
First posted: 2009-07-03
Enrollment: 735
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: 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.
timeFrame: 2 years
Secondary outcomes:
measure: • Safety profile of CLARA versus HDAC consolidation courses
timeFrame: 2 years
measure: • Possible predictors to response
timeFrame: 2 years
measure: • MRD (Minimal Residual Disease) level
timeFrame: 2 years
measure: • Overall cumulative incidence of relapse
timeFrame: 120 days
measure: • Overall survival (OS)
timeFrame: 2 years
Other outcomes:
Locations:
city: Amiens
country: France
facility: Hôpital Sud - CHU Amiens
city: Angers
country: France
facility: Centre Hospitalier Regional et Universitaire d'Angers
city: Argenteuil
country: France
facility: Hôpital Victor Dupouy
city: Bobigny
country: France
facility: Hôpital Avicenne - bobigny
city: Boulogne / Mer
country: France
facility: Centre Hospitalier Boulogne/Mer
city: Caen
country: France
facility: Hôpital Clemenceau - chu Caen
city: Cergy Pontoise
country: France
facility: Centre Hospitalier René Dubos
city: Clamart
country: France
facility: HIA Percy
city: Corbeil
country: France
facility: Hôpital de Corbeil
city: Créteil
country: France
facility: Hôpital Mondor
city: Dijon
country: France
facility: Hôpital Dubocage
city: Dunkerque
country: France
facility: Centre Hospitalier Dunkerque
city: Grenoble
country: France
facility: Hôpital Michallon
city: Le Chesnay
country: France
facility: Centre Hospitalier Versailles
city: Lens
country: France
facility: Centre Hospitalier Schaffner
city: Lille
country: France
facility: Hôpital Huriez
city: Limoges
country: France
facility: CHU Dupuytren
city: Marseille
country: France
facility: Institut Paoli-Calmette
city: Meaux
country: France
facility: Centre Hospitalier Meaux
city: Nantes
country: France
facility: CHU - Hôtel Dieu
city: Nice
country: France
facility: Centre A. Lacassagne
city: Nice
country: France
facility: Hôpital Archet 1
city: Paris
country: France
facility: Hôpital St Louis
city: Paris
country: France
facility: Pitié-Salpetrière
city: Paris
country: France
facility: Paris Necker
city: Pessac
country: France
facility: Hôpital Haut Lévêque
city: Pierre-benite
country: France
facility: Hospices Civils de Lyon - Centre Hospitalier Lyon Sud
city: Roubaix
country: France
facility: Hôpital V. Provo
city: Rouen
country: France
facility: Centre Henri Becquerel - CHRU ROUEN
city: Saint Cloud
country: France
facility: Centre Hospitalier Huguenin
city: Toulouse
country: France
facility: Hôpital Purpan
city: Valenciennes
country: France
facility: Centre Hospitalier Valenciennes
city: Vandoeuvre Les Nancy
country: France
facility: CHU de Brabois
city: Villejuif
country: France
facility: Institut Gustave Roussy
Study officials:
affiliation: Hospices Civils de Lyon
name: Xavier THOMAS, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Michallet M, Sobh M, Morisset S, Deloire A, Raffoux E, de Botton S, Caillot D, Chantepie S, Girault S, Berthon C, Bertoli S, Lepretre S, Leguay T, Castaigne S, Marolleau JP, Pautas C, Malfuson JV, Veyn N, Braun T, Gastaud L, Suarez F, Schmidt A, Gressin R, Bonmati C, Celli-Lebras K, El-Hamri M, Ribaud P, Dombret H, Thomas X, Bergeron A. Antifungal Prophylaxis in AML Patients Receiving Intensive Induction Chemotherapy: A Prospective Observational Study From the Acute Leukaemia French Association (ALFA) Group. Clin Lymphoma Myeloma Leuk. 2022 May;22(5):311-318. doi: 10.1016/j.clml.2021.10.011. Epub 2021 Oct 25.
citation: Fenwarth L, Thomas X, de Botton S, Duployez N, Bourhis JH, Lesieur A, Fortin G, Meslin PA, Yakoub-Agha I, Sujobert P, Dumas PY, Recher C, Lebon D, Berthon C, Michallet M, Pigneux A, Nguyen S, Chantepie S, Vey N, Raffoux E, Celli-Lebras K, Gardin C, Lambert J, Malfuson JV, Caillot D, Maury S, Ducourneau B, Turlure P, Lemasle E, Pautas C, Chevret S, Terre C, Boissel N, Socie G, Dombret H, Preudhomme C, Itzykson R. A personalized approach to guide allogeneic stem cell transplantation in younger adults with acute myeloid leukemia. Blood. 2021 Jan 28;137(4):524-532. doi: 10.1182/blood.2020005524.