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

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)

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.

Study Overview

• Status: Withdrawn
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: Vesanoid (ATRA); Drug: AZACITIDINE (VIDAZA); Drug: CYTARABINE

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 Type: Interventional
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Amiens, France, 80054
    • CHU Amiens Sud
  • Argenteuil, France, 95107
    • CH
  • Bobigny, France
    • Hôpital Avicenne
  • Boulogne Sur Mer, France, 62321
    • CHU Boulogne sur Mer
  • Caen, France, 14033
    • CH
  • Clamart, France, 92141
    • Hôpital Percy
  • Corbeil Essonnes, France, 94010
    • CH Sud Francilien
  • Creteil, France
    • Hôpital Henri Mondor
  • Dunkerque, France, 59385
    • Ch Dunkerque
  • Lens, France, 62307
    • CH
  • Lille, France, 59037
    • CHU
  • Limoges, France, 87042
    • CH
  • Lyon, France
    • Hôpital Edouard Herriot
  • Meaux, France, 77104
    • CH
  • Nice, France, 06189
    • Centre Antoine Lacassagne
  • Paris, France
    • Hopital Saint-Louis
  • Paris, France, 75651
    • Hôpital Pitié-Salpétrière
  • Paris, France, 75012
    • St Antoine Hospital
  • Paris 15, France, 75015
    • Necker Hospital
  • Pontoise, France, 95303
    • CH René Dubos
  • Roubaix, France, 59100
    • CH
  • Rouen, France, 76038
    • CHU
  • Saint-Cloud, France, 92210
    • CNLCC
  • Valenciennes, France, 59322
    • CH
  • Versailles, France
    • CH
  • Villejuif, France
    • IGR

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 65 years to 79 years (Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

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

Exclusion Criteria:

1. APL in the WHO classification.
2. Ph1-positive AML or prior Ph1-positive disease
3. AML evolving from a prior MPN in the WHO 2008 classification.
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. Prior advanced malignant hepatic tumor
7. ECOG Performance Status Score > 2
8. 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.
9. Total serum bilirubin more than 2x's the ULN at the laboratory where the analysis was performed, except if AML-related.
10. AST (SGOT) or ALT (SGPT) more than 2.5x's the ULN at the laboratory where the analysis was performed, except if AML-related
11. LVEF less than.55 or equivalent by doppler echocardiography
12. Known intolerance to Azacitidine, mannitol, retinoids
13. Positive serum test for HIV and HTLV-1
14. NYHA Grade 3/4 cardiac disease .
15. Severe infection at inclusion time.
16. Psychiatric disease or an history of non-compliance to medical regimens or patients considered potentially unreliable.
17. Absence of health care insurance (affiliation à un régime de Sécurité Sociale)
18. Participation to any study requiring informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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

Outcome Measure	Time Frame
Overall survival	2 years
Complete Response (CR) rate	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

Collaborators and Investigators

• Sponsor: Acute Leukemia French Association
• Collaborators: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: GARDIN CLAUDE, MD, Acute Leukemia French Association

Study record dates

Study Major Dates

• Study Start: April 1, 2010
• Primary Completion (Anticipated): April 1, 2016

Study Registration Dates

• First Submitted: February 10, 2010
• First Submitted That Met QC Criteria: February 10, 2010
• First Posted (Estimate): February 11, 2010

Study Record Updates

• Last Update Posted (Estimate): December 30, 2015
• Last Update Submitted That Met QC Criteria: December 29, 2015
• Last Verified: February 1, 2010

More Information

Terms related to this study

• Keywords: Acute Myeloid Leukemia; Aged of 65 to 79 years; Older Patients with Acute Myeloblastic Leukemia
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Keratolytic Agents; Azacitidine; Cytarabine; Tretinoin
• Other Study ID Numbers: ALFA-0703 Study - P060205