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

Acute Myeloid Leukemia Clinical Trial

— CLARA  

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).

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00932412
• Other study ID #: 2006.456/50
• Status: Completed
• Phase: Phase 2
• First received: July 2, 2009
• Last updated: September 20, 2016
• Start date: March 2009
• Est. completion date: April 2016

Study information

• Verified date: September 2016
• Source: Hospices Civils de Lyon
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 735
• Est. completion date: April 2016
• Est. primary completion date: April 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 60 Years

Eligibility

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.

Study Design

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

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• CLARA
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)
• HDAc
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)

Locations

Country	Name	City	State
France	Hôpital Sud - CHU Amiens	Amiens
France	Centre Hospitalier Regional et Universitaire d'Angers	Angers
France	Hôpital Victor Dupouy	Argenteuil
France	Hôpital Avicenne - bobigny	Bobigny
France	Centre Hospitalier Boulogne/Mer	Boulogne / Mer
France	Hôpital Clemenceau - chu Caen	Caen
France	Centre Hospitalier René Dubos	Cergy Pontoise
France	HIA Percy	Clamart
France	Hôpital de Corbeil	Corbeil
France	Hôpital Mondor	Créteil
France	Hôpital Dubocage	Dijon
France	Centre Hospitalier Dunkerque	Dunkerque
France	Hôpital Michallon	Grenoble
France	Centre Hospitalier Versailles	Le Chesnay
France	Centre Hospitalier Schaffner	Lens
France	Hôpital Huriez	Lille
France	CHU Dupuytren	Limoges
France	Institut Paoli-Calmette	Marseille
France	Centre Hospitalier Meaux	Meaux
France	CHU - Hôtel Dieu	Nantes
France	Centre A. Lacassagne	Nice
France	Hôpital Archet 1	Nice
France	Hôpital St Louis	Paris
France	Paris Necker	Paris
France	Pitié-Salpetrière	Paris
France	Hôpital Haut Lévêque	Pessac
France	Hospices Civils de Lyon - Centre Hospitalier Lyon Sud	Pierre-benite
France	Hôpital V. Provo	Roubaix
France	Centre Henri Becquerel - CHRU ROUEN	Rouen
France	Centre Hospitalier Huguenin	Saint Cloud
France	Hôpital Purpan	Toulouse
France	Centre Hospitalier Valenciennes	Valenciennes
France	CHU de Brabois	Vandoeuvre Les Nancy
France	Institut Gustave Roussy	Villejuif

Sponsors (1)

Lead Sponsor	Collaborator
Hospices Civils de Lyon

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	• 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	Yes
Secondary	• 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 a) and NPM(Nucleophosmin))	2 years	No
Secondary	• 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	No
Secondary	• Overall cumulative incidence of relapse		120 days	No
Secondary	• Overall survival (OS)	OS will be defined as the time from diagnosis to death or last contact with the patient	2 years	No