Trial Information

Phase III Randomized Trial of Clofarabine as Induction and Post-Remission Therapy vs. Standard Daunorubicin & Cytarabine Induction and Intermediate Dose Cytarabine Post-Remission Therapy, Followed by Decitabine Maintenance vs. Observation in Newly-Diagnosed Acute Myeloid Leukemia in Older Adults (Age >/= 60 Years)

OBJECTIVES:

Primary

- To compare the overall survival of older patients with newly diagnosed acute myeloid
leukemia (AML) treated with clofarabine as induction therapy and consolidation therapy
vs standard daunorubicin hydrochloride and cytarabine.

Secondary

- To evaluate complete remission (CR) rates, duration of remission, and
toxicity/treatment-related mortality of patients treated with these regimens.

- To evaluate the feasibility of consolidation therapy with reduced-intensity
conditioning and allogeneic hematopoietic stem cell transplantation from HLA-identical
donors, in terms of the incidence of successful engraftment, acute and chronic
graft-vs-host disease, and transplant-related mortality in select patients age 60-69
years who achieve a response to induction therapy.

- To determine the impact of reduced-intensity conditioning and allogeneic stem cell
transplantation on overall survival of select patients.

- To compare the duration of remission and disease-free survival of patients in CR
following completion of consolidation therapy who are subsequently randomized to
receive decitabine as maintenance therapy vs observation.

- To perform expression and methylation profiling in patients treated with decitabine as
maintenance therapy and to correlate their integrated epigenetic signatures with
response to decitabine.

- To examine the epigenetic profiles of remission marrow in patients randomized to
receive decitabine as maintenance therapy vs observation to determine whether
epigenetic signatures of apparently morphologically normal bone marrow is predictive of
relapse or response to decitabine.

- To explore the possible association of response to clofarabine with nucleoside
transporters hENT1, hCNT3, and ABC-transporter P-glycoprotein.

- To assess the intensity of expression of CXCR4 on diagnostic leukemia cells and to
correlate this parameter with other established prognostic factors.

- To assess the entire spectrum of somatic mutations and affected pathways at diagnosis
of AML and elucidate the association between gene mutation and outcome.

Tertiary

- To compare health-related quality of life (QOL) (physical, functional,
leukemia-specific well-being) and fatigue in patients treated with clofarabine vs
standard induction therapy.

- To measure the change in health-related QOL that occurs over time.

- To comprehensively assess patient function at the time of study enrollment.

- To determine if components of a comprehensive geriatric assessment or QOL scale predict
ability to complete treatment for AML.

- To describe the impact of transplantation on QOL in patients with AML over 60 years of
age.

OUTLINE: This is a multicenter study. Patients are stratified according to age (60-69 years
vs ≥ 70 years), , disease type (secondary vs de novo), therapy-related AML (yes vs no), and
antecedent hematologic disorder (yes vs no).

- Induction therapy: Patients are randomized to 1 of 2 treatment arms.

- Arm I (standard therapy): Patients receive daunorubicin hydrochloride IV over
10-15 minutes on days 1-3 and cytarabine IV continuously on days 1-7. Patients
with residual disease or those who do not achieve an aplastic bone marrow on day
12-14 (i.e., < 5% blasts and < 20% cellularity or markedly/moderately
hypocellular) may receive a second course of induction therapy beginning no sooner
than day 14.

- Arm II: Patients receive clofarabine IV over 1 hour on days 1-5. Patients with
residual disease or those who do not achieve an aplastic bone marrow on day 12-14
(i.e., < 5% blasts and < 20% cellularity or markedly/moderately hypocellular) may
receive a second course of induction therapy beginning no sooner than day 21 and
no later than day 56.

Patients who achieve a complete remission (CR) or CR incomplete (CRi) after induction
therapy proceed to consolidation therapy. Patients who are 60-69 years of age who achieve a
"morphologic leukemia-free state" after induction therapy and who have an HLA-identical
donor proceed to allogeneic stem cell transplantation. Patients undergoing second induction
who do not achieve CR by day 56 of the start of re-induction are taken off protocol.

- Consolidation therapy: Beginning within 60 days after documentation of CR or CRi,
patients receive consolidation therapy in the same arm they were randomized to for
induction therapy.

- Arm I (standard therapy): Patients receive cytarabine IV over 1 hour once or twice
daily on days 1-6. Treatment repeats every 4-6 weeks for 2 courses.

- Arm II: Patients receive clofarabine IV over 1 hour on days 1-5. Treatment repeats
every 4-6 weeks for 2 courses.

Patients who remain in CR after completion of consolidation therapy proceed to maintenance
therapy.

- Maintenance therapy: Beginning within 60 days after completion of consolidation
therapy, patients receive maintenance therapy and are randomized to 1 of 2 arms.

- Arm I: Patients undergo observation monthly for 12 months.

- Arm II: Patients receive decitabine IV over 1 hour on days 1-3. Treatment repeats
every 4 weeks for 12 months the absence of unacceptable toxicity.

- Allogeneic stem cell transplantation with reduced-intensity conditioning regimen:
Patients begin reduced-intensity conditioning 30-90 days after the initiation of
induction therapy.

- Conditioning regimen: Patients receive fludarabine phosphate IV over 30 minutes on
days -7 to -3, busulfan IV over 2 hours every 6 hours on days -4 and -3 (for a
total of 8 doses), and anti-thymocyte globulin IV over 4-6 hours on days -4 to -2.

- Transplantation: Patients undergo allogeneic peripheral blood stem cell
transplantation on day 0.

Patients complete quality-of-life questionnaires periodically, including health-related
quality of life, physical and functional well-being, and fatigue questionnaires.

Peripheral blood, bone marrow, and karyotype samples are collected periodically for
cytogenetic analysis and other correlative laboratory studies.

After completion of study treatment, patients are followed up periodically for ≥ 5 years.