Safety and Efficacy Study of Ara-c at 18 gm/m2 Versus 12 gm/m2 for 3 Cycles Each in AML Consolidation

Sponsor

All India Institute of Medical Sciences, New Delhi (Other)

Overall Status

Unknown status

CT.gov ID

NCT01615757

Collaborator

(none)

180

Enrollment

Location

Arms

Duration (Months)

7.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The study will be conducted in the Department of Medical Oncology and Department of Haematology , AIIMS, Delhi. A total of 180 patients of Acute Myeloid Leukemia who are in complete remission after induction chemotherapy will be enrolled into the study and will be further randomized to the two study arms . ARM- A will receive Ara-c at 18 gm /m2 for 3 cycles and ARM -B will receive Ara-c at 12 gm/m2 for 3 cycles according to the study protocol. Aim of the study will be to compare the efficacy of the two doses in terms of the relapse free survival and overall survival as well as time to relapse and toxicity /treatment related morbidity.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia	Drug: Ara-c Drug: Ara-c	Phase 3

Detailed Description

Objectives

To compare the efficacy of two different doses of Cytarabine during consolidation therapy for newly diagnosed patients of Non APML - Acute Myeloid Leukemia who are in CR post induction
To compare the toxicity of the two different Cytarabine doses

Primary end point

Relapse free survival at 1 yr from randomization
Relapse will be defined as >5 % leukemic blasts in the marrow aspirate or new extramedullary disease anytime after randomization

Secondary end points

Overall survival
Median time to relapse
Toxicity- Haematological and Non -Haematological

Inclusion criteria

Confirmation of Acute Myeloid Leukemia by morphologic, immunophenotypic analysis
Suitable for HIDAC as consolidation
AML with underlying MDS will be included

Exclusion criteria

Previous AML chemotherapy [Hydroxyurea - not an exclusion.]
CML-BC
Concurrent active malignancy
HIV infection, Uncontrolled Hepatitis B/C
Patients being considered for upfront PBSCT (before completion of CONSOLIDATION)
Serum Bilirubin > 2
APML
Delayed recovery of blood counts /persistent active infection > 45 days from start of induction
Patients receiving reinduction with HIDAC
Therapy related AML Methodology
The period of enrollment will be from July 1, 2012 to September 30 ,2013
Baseline information will be recorded in a preformulated proforma designed for analysis at a later date

Treatment

Standard 3 + 7 INDUCTION with Daunomycin and Cytarabine with DNR at 60- 90 mg/m2 as per the PS and comorbidities/active infections at presentation
Bone marrow examination - D+ 28 of induction or earlier if needed . Patients not in CR - reinduction regimen as per discretion of treating physician
Patients in complete morphological remission ( after 1 or 2 inductions) : will receive consolidation with HIDAC and will be randomized into the two study arms after written Informed Consent: Arm A and B with 90 patients in each arm Arm A will receive HIDAC at 18 gm/m2/cycle for 3 cycles , i.e. 3 gm/m2 BD , Day 1,3,5 Arm B will receive HIDAC at 12 gm/m2/cycle for 3 cycles , i.e. 2 gm/m2 BD , Day 1,3,5

sample size

Assuming a RFS of 60 % at 1 yr in each arm and keeping a non-inferiority margin of 20 % , Alpha at 5 % ,75 patients are required in each arm on the basis of statistical calculation.
15 patients added in each arm to account for losses
Total required in each arm = 90
ANC> 1000 , Platelet count > 1 lac required to start HIDAC
Detailed information of the course of all the chemotherapy cycles will be recorded including-

toxicity
details of antimicrobials
supportive care ( including transfusions)
Use of growth factors

Cytogenetic analysis using standard technique of chromosomal banding
Molecular analysis for mutation of FLT3-ITD will be performed
Risk stratification will be done as per guidelines
Patients in both arms will be kept under close follow up and will be assessed with blood counts /PS , 2 monthly / or earlier as clinically indicated

Statistical Analysis

Qualitative data will be analyzed using the Chi-square test
Quantitative data will be compared by using t-test /Mann Whitney test
Besides this survival analysis will be carried out.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

180 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Comparison of Ara-c 12 gm/m2 vs 18 gm/m2 Per Cycle for 3 Cycles Each as Consolidation in AML ; An Open Label Randomized Non-inferiority Study

Study Start Date :

Aug 1, 2012

Anticipated Primary Completion Date :

Sep 1, 2014

Anticipated Study Completion Date :

Sep 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm B, Ara-c - 12 gm/m2 Arm B will receive HIDAC at 12 gm/m2/cycle for 3 cycles , i.e. 2 gm/m2 BD , Day 1,3,5	Drug: Ara-c IV formulation, administered as a 2 hr infusion in 1 pint of normal saline, BD on D1,3,5 at 2 gm/m2 /dose Other Names: Cytosar, Cytarabine
Active Comparator: Arm A. Ara-c 18 gm/m2 Arm A will receive HIDAC at 18 gm/m2/cycle for 3 cycles , i.e. 3 gm/m2 BD , Day 1,3,5	Drug: Ara-c IV formulation, administered as a 2 hr infusion in 1 pint of normal saline, BD on D1,3,5 at 3 gm/m2 /dose Other Names: Cytosar, Cytarabine

Arm

Intervention/Treatment

Experimental: Arm B, Ara-c - 12 gm/m2

Arm B will receive HIDAC at 12 gm/m2/cycle for 3 cycles , i.e. 2 gm/m2 BD , Day 1,3,5

Drug: Ara-c

IV formulation, administered as a 2 hr infusion in 1 pint of normal saline, BD on D1,3,5 at 2 gm/m2 /dose

Other Names:

Cytosar, Cytarabine

Active Comparator: Arm A. Ara-c 18 gm/m2

Arm A will receive HIDAC at 18 gm/m2/cycle for 3 cycles , i.e. 3 gm/m2 BD , Day 1,3,5

Drug: Ara-c

IV formulation, administered as a 2 hr infusion in 1 pint of normal saline, BD on D1,3,5 at 3 gm/m2 /dose

Other Names:

Cytosar, Cytarabine

Outcome Measures

Primary Outcome Measures

Relapse free survival at 1 yr of follow up [1 year]

Secondary Outcome Measures

Toxicity- Haematological and Non -Haematological [at 1 yr]
The following variables will be compared in the two arms to - -Nadir blood counts,Ara c related fever ,Allergic or skin reactions,Alopecia,Diarrhea ,Stomatitis,Bleeding ,Febrile neutropenia,Infection(fungal /bacterial/viral),Liver related event,ocular toxicity,Neurologic event,Peripheral neuropathy,Cerebral/Cerebellar toxicity,Transfusions,Time to recovery of platelets,Time to recovery of neutrophils,Duration of Hospital stay,Emergency visits,Deaths,Use of growth factors

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Confirmation of Acute Myeloid Leukemia by morphologic, immunophenotypic analysis
Suitable for HIDAC as consolidation
AML with underlying MDS will be included

Exclusion Criteria:

Previous AML chemotherapy [Hydroxyurea - not an exclusion.]
CML-BC
Concurrent active malignancy
HIV infection, Uncontrolled Hepatitis B/C
Patients being considered for upfront PBSCT (before completion of CONSOLIDATION)
Serum Bilirubin > 2
APML
Delayed recovery of blood counts /persistent active infection > 45 days from start of induction
Patients receiving reinduction with HIDAC
Therapy related AML