ALFA-0703 Study in Older Patients With Acute Myeloblastic Leukemia (AML)

Sponsor

Acute Leukemia French Association (Other)

Overall Status

Withdrawn

CT.gov ID

NCT01067274

Collaborator

Assistance Publique - Hôpitaux de Paris (Other)

Enrollment

Locations

Arms

Patients Per Site

Study Details

Study Description

Brief Summary

A Randomized Multicenter Phase III Study to Evaluate the Role of All-trans Retinoic Acid (ATRA) in Combination with Induction Chemotherapy, or Azacitidine and Idarubicin as salvage therapy and Idarubicin with Cytarabine or Azacitidine as Maintenance Therapy in Older Patients with Acute Myeloblastic Leukemia (AML).

To compare the outcome of elderly patients with newly-diagnosed AML treated with standard induction chemotherapy and post-remission therapy, in only patients in CR, with either azacitidine or cytarabine combined to idarubicin +/- ATRA and salvage therapy with azacitidine combined to idarubicin +/- ATRA.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia	Drug: Vesanoid (ATRA) Drug: AZACITIDINE (VIDAZA) Drug: CYTARABINE	Phase 3

Detailed Description

Induction therapy :

First randomization (R1) at baseline : ATRA versus no ATRA.

Salvage therapy :

No conventional salvage therapy is planned. Patients who will not achieve CR, according to IWG criteria after induction will be treated with 3 courses of azacitidine and idarubicin +/- ATRA combination, if eligible for further treatment.

Followed by 3 identical courses and 6 courses of maintenance by azacitidine alone to be delivered every 28 days, in those patients reaching CR or PR after 3 courses (evaluation of response from 28 to 56 days from course 3).

Randomization R2: type of maintenance:

Response to induction will be evaluated 2 weeks after myeloid recovery, just before first consolidation course, due use of to pegfilgrastim, lenograstim or filgrastim during induction.

Responses will be classified according to the Revised Recommendations of the IWG for AML.

Patients in CR only will be subjected to a second randomization R2 as follows 6 courses of combined chemotherapy, will be delivered as outpatients, ATRA according to R1 randomization.

Study Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Randomized Multicenter Phase III Study to Evaluate the Role of All-trans Retinoic Acid (ATRA) in Combination With Induction Chemotherapy, or Azacitidine and Idarubicin as Salvage Therapy and Idarubicin With Cytarabine or Azacitidine as Maintenance Therapy in Older Patients With Acute Myeloblastic Leukemia (AML)

Study Start Date :

Apr 1, 2010

Anticipated Primary Completion Date :

Apr 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: R1 Arm A : ATRA Idarubicin: 9 mg/m2/d D1 to D4 Cytarabine : 200 mg/m2/d Continuous IV from D1 to D7 Peg-filgrastim : 6 mg SC D9 or filgrastim 5ug/kg/d SC or lenograstim 263ug/d IV 30mn, both from D9 to myeloid recovery(PMN >1G/l over 2 days at minimum All-trans retinoic acid (ATRA): 45mg/m2/day in two divided doses from D8 to D28	Drug: Vesanoid (ATRA) 45 mg/m2/day in two divided doses from D8 to D28 Other Names: VEZANOIDE
No Intervention: R1 Arm B : no ATRA Idarubicin: 9 mg/m2/d D1 to D4 Cytarabine : 200 mg/m2/d Continuous IV from D1 to D7 Peg-filgrastim : 6 mg SC D9 or filgrastim 5ug/kg/d SC or lenograstim 263ug/d IV 30mn, both from D9 to myeloid recovery(PMN >1G/l over 2 days at minimum
Experimental: R2 Arm 1A : AZACITIDINE and ATRA Azacitidine: 75 mg/m2/12h SC from D1 to D5 Idarubicine: 9 mg/m2/d IV on D5 All-trans retinoic acid (ATRA): 45mg/m2/d in two divided doses from D8 to D21	Drug: Vesanoid (ATRA) 45 mg/m2/day in two divided doses from D8 to D28 Other Names: VEZANOIDE Drug: AZACITIDINE (VIDAZA) 75 mg/m2/12h SC from D1 to D5
Experimental: R2 Arm 1B : AZACITIDINE and No ATRA Azacitidine: 75 mg/m2/12h SC from D1 to D5 Idarubicine: 9 mg/m2/d IV on D5	Drug: AZACITIDINE (VIDAZA) 75 mg/m2/12h SC from D1 to D5
Experimental: R2 Arm 2A : ATRA Idarubicine : 9 mg/m2/d IV on D1 Cytarabine : 60 mg/m2/12h SC from D1 to D5 All-trans retinoic acid (ATRA): 45mg/ m2/d in two divided doses from D8 to D21	Drug: Vesanoid (ATRA) 45 mg/m2/day in two divided doses from D8 to D28 Other Names: VEZANOIDE Drug: CYTARABINE Cytarabine : 60 mg/m2/12h SC from D1 to D5
Experimental: R2 Arm 2B : no ATRA Idarubicine : 9 mg/m2/d IV on D1 Cytarabine : 60 mg/m2/12h SC from D1 to D5	Drug: CYTARABINE Cytarabine : 60 mg/m2/12h SC from D1 to D5

Outcome Measures

Primary Outcome Measures

For randomization R1, the primary endpoint is Event-free Survival (EFS) [2-year EFS]
For randomization R2, the primary endpoint is disease free survival (DFS) [2-year DFS]

Secondary Outcome Measures

Complete Response (CR) rate [2 years]
Overall survival [2 years]
Response rate to azacitidine idarubicin +/-ATRA combination after intensive chemotherapy failure and identification of possible predictors of response to this therapy [2 years]
Assess the safety of combination ATRA + chemotherapy or idarubicin-azacitidine courses and of maintenance with azacitidine [2 years]
Effects on relapse rates of ATRA and maintenance, with respect to cytogenetics risk groups, subtypes of AML and mutational status (FLT3, MLL), and biomarkers [2 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

65 Years to 79 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Aged of 65 to 79 years
With a morphologically proven diagnosis of AML according to WHO classification either de novo or AML with "myelodysplasia related changes"
Not previously treated for AML
Signed informed consent.

Exclusion Criteria:

APL in the WHO classification.
Ph1-positive AML or prior Ph1-positive disease
AML evolving from a prior MPN in the WHO 2008 classification.
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
Prior advanced malignant hepatic tumor
ECOG Performance Status Score > 2
Creatinine level more than 2x's the upper limit of the normal range (ULN) at the laboratory where the analysis was performed, except if AML-related.
Total serum bilirubin more than 2x's the ULN at the laboratory where the analysis was performed, except if AML-related.
AST (SGOT) or ALT (SGPT) more than 2.5x's the ULN at the laboratory where the analysis was performed, except if AML-related
LVEF less than.55 or equivalent by doppler echocardiography
Known intolerance to Azacitidine, mannitol, retinoids
Positive serum test for HIV and HTLV-1
NYHA Grade 3/4 cardiac disease .
Severe infection at inclusion time.
Psychiatric disease or an history of non-compliance to medical regimens or patients considered potentially unreliable.
Absence of health care insurance (affiliation à un régime de Sécurité Sociale)
Participation to any study requiring informed consent

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Chu Amiens Sud	Amiens	France	80054
2	CH	Argenteuil	France	95107
3	Hopital Avicenne	Bobigny	France
4	Chu Boulogne Sur Mer	Boulogne Sur Mer	France	62321
5	CH	Caen	France	14033
6	Hopital Percy	Clamart	France	92141
7	Ch Sud Francilien	Corbeil Essonnes	France	94010
8	Hopital Henri Mondor	Creteil	France
9	Ch Dunkerque	Dunkerque	France	59385
10	CH	Lens	France	62307
11	CHU	Lille	France	59037
12	CH	Limoges	France	87042
13	Hopital Edouard Herriot	Lyon	France
14	CH	Meaux	France	77104
15	Centre Antoine Lacassagne	Nice	France	06189
16	Necker Hospital	Paris 15	France	75015
17	St Antoine Hospital	Paris	France	75012
18	Hopital Pitie-Salpetriere	Paris	France	75651
19	Hopital Saint-Louis	Paris	France
20	Ch Rene Dubos	Pontoise	France	95303
21	CH	Roubaix	France	59100
22	CHU	Rouen	France	76038
23	CNLCC	Saint-Cloud	France	92210
24	CH	Valenciennes	France	59322
25	CH	Versailles	France
26	IGR	Villejuif	France