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Phase II Trial Examining Epigenetic Priming With Decitabine Followed by Idarubicin and Cytarabine for Patients With Relapsed or Refractory AML


Phase 2
18 Years
N/A
Open (Enrolling)
Both
Adult Acute Megakaryoblastic Leukemia (M7), Adult Acute Monoblastic Leukemia (M5a), Adult Acute Monocytic Leukemia (M5b), Adult Acute Myeloblastic Leukemia With Maturation (M2), Adult Acute Myeloblastic Leukemia Without Maturation (M1), Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q), Adult Acute Myeloid Leukemia With Inv(16)(p13;q22), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myeloid Leukemia With t(8;21)(q22;q22), Adult Acute Myelomonocytic Leukemia (M4), Adult Erythroleukemia (M6a), Adult Pure Erythroid Leukemia (M6b), Previously Treated Myelodysplastic Syndromes, Recurrent Adult Acute Myeloid Leukemia, Refractory Anemia With Excess Blasts

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Trial Information

Phase II Trial Examining Epigenetic Priming With Decitabine Followed by Idarubicin and Cytarabine for Patients With Relapsed or Refractory AML


PRIMARY OBJECTIVES:

I. To determine the morphologic complete remission (CR) rates using a decitabine
(DAC)-priming followed by idarubicin (IDA) and cytarabine (ARAC) in patients with relapsed
or refractory acute myeloid leukemia (AML).

SECONDARY OBJECTIVES:

I. To determine CR without minimal residual disease (CRMRD-), CR with incomplete blood count
recovery (CRi), CR with minimal residual disease (CRMRD+), and CR with incomplete blood
count recovery and with minimal residual disease (CRiMRD+) rates.

II. To estimate the frequency and severity of regimen-related toxicities.

III. To identify biomarkers (e.g., deoxyribonucleic acid [DNA] methylation and expression
changes including interferon regulatory factor [IRF]8) associated with clinical responses.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive decitabine intravenously (IV) over 1 hour on days -4 to 0,
cytarabine IV continuously over 24 hours on days 1-7, and idarubicin IV over 10-15 minutes
on days 1-3.

ARM II: Patients receive decitabine IV over 1 hour on days -9 to -5 and cytarabine and
idarubicin as in Arm I.

In both arms, treatment repeats every 28 days for up to 3 courses in the absence of disease
progression or unacceptable toxicity.

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


Inclusion Criteria:



- Written informed consent

- All patients except those with acute promyelocytic leukemia (APL) who have
morphological diagnosis of myelodysplastic syndromes (MDS) refractory anemia with
excess blasts (RAEB)-II or AML by World Health Organization (WHO) diagnostic criteria
and have either refractory or early relapsed disease; NOTE:

- Diagnosis of refractory or relapsed disease must be based on evaluation of a
bone marrow (BM) aspirate or peripheral blood (PB) flow cytometry; other
standard MDS and AML prognostic studies such as cytogenetics, flow, and
molecular testing are highly recommended prior to initiating DAC

- A previous BM evaluation or PB flow cytometry from an outside facility are
acceptable if the results have been deemed to be adequate for confirming the
diagnosis and staging by University of Washington (UW)/Seattle Cancer Care
Alliance (SSCA)/Fred Hutchinson Cancer Research Center (FHCRC) review

- A BM biopsy is not routinely required but should be obtained if the previous
evaluation is not deemed to be adequate for confirming diagnosis and staging by
UW/SCCA/FHCRC review

- Must have received at least one previous cycle of treatment for MDS or AML and be
either refractory as defined as not responded to this therapy or in early relapse as
defined as developing recurrence of the disease within 12 months of obtaining a CR

- May have previously received demethylating agents (e.g., DAC, 5-azacytidine [5AZA])
or histone deacetylases (e.g., suberoylanilide hydroxamic acid) for their MDS or AML
if these demethylating agents were not used in combination with systemic
anthracycline and ARAC chemotherapy

- May have received hematopoietic growth factors, thalidomide/lenalidomide, signal
transduction inhibitors, or low dose cytarabine (=< 20 mg/m2/day)

- May not have received any therapy for their MDS or AML other than hydroxyurea or
leukapheresis for at least 14 days prior to start of the first dose of DAC; all
non-hematologic toxicities must have resolved to < grade 2

- Must have a "simplified" treatment-related mortality (TRM) score =< 9.2

- Females of childbearing potential must have a negative pregnancy test prior to
initiation of the protocol therapy; females are considered not of child bearing
potential if they are surgically sterile (they have undergone a hysterectomy,
bilateral tubal ligation, or bilateral oophorectomy) or they are postmenopausal

- Females of childbearing potential and males must be willing to use an effective
method of contraception (hormonal or barrier method of birth control; abstinence)
from the time consent is signed until 12 weeks after treatment discontinuation

- Patients with an active or history of other malignancies are eligible, if their
projected overall survival for that malignancy is at least 6 months

- Prior hormonal therapy such as aromatase inhibitors, selective estrogen receptor
modulators, estrogen receptor down-regulators, luteinizing hormone-releasing hormone
(LHRH) agonists and antagonists, and anti-androgens, must be completed at least 30
days prior to initiation of protocol therapy and must remain off hormonal therapy
until the patient has finished chemotherapy for their MDS-RAEBII or AML

- Direct bilirubin =< 2.5 mg/dL (assessed within 14 days prior to registration) unless
elevation is thought to be due to hepatic infiltration by AML, Gilbert's syndrome, or
hemolysis

- No known hypersensitivity to DAC, ARAC, or IDA

- No clinical evidence of central nervous system (CNS) involvement with leukemia,
unless a lumbar puncture confirms the absence of leukemic blasts in the cerebrospinal
fluid (CSF)

- No prior positive test for the human immunodeficiency virus (HIV)

- No uncontrolled systemic infection

Exclusion Criteria:

- Previous therapy with demethylating agents (e.g., DAC, 5AZA, etc.) or histone
deacetylases (e.g., suberoylanilide hydroxamic acid, etc.) that was combined with
daunorubicin (DNR) or IDA and ARAC

- Patients with APL

- Known hypersensitivity to DAC, ARAC, or IDA

- Clinical evidence of CNS involvement with leukemia, unless a lumbar puncture confirms
the absence of leukemic blasts in the CSF

- Prior positive test for HIV

- Uncontrolled systemic fungal, bacterial, viral, or other infection (defined as
exhibiting ongoing signs/symptoms related to the infection and without improvement,
despite appropriate antibiotics or other treatment)

- A "simplified" TRM score > 9.2

- Bilirubin > 2.5 mg/dl (assessed within 14 days prior to registration), unless
elevation is thought to be due to hepatic infiltration by AML, Gilbert's syndrome, or
hemolysis

- Patients who have a projected overall survival < 6 months due to malignancies other
than MDS or AML

- Documented symptomatic congestive heart failure or a documented left ventricular
ejection fraction < 40% assessed by multi gated acquisition (MUGA), echocardiography,
or heart catheterization within 21 days prior to start of decitabine

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Morphologic CR rates defined as absolute neutrophil count (ANC) at least 1,000/μL, platelet count at least 100,000/μL, less than 5% BM blasts, no Auer rods, no morphologic dysplasia, and no evidence of extramedullary disease

Outcome Description:

The trial will follow an optimal two-stage Simon design. This design has an overall type 1 error rate (alpha) of 10%, and a power of 82% for a true CR rate of 30%. The probability of stopping after the first stage is 70%, if the true CR rate is 10%, and 11%, if the true CR rate is 30%.

Outcome Time Frame:

Assessed for up to 5 years

Safety Issue:

No

Principal Investigator

Derek Stirewalt

Investigator Role:

Principal Investigator

Investigator Affiliation:

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Authority:

United States: Federal Government

Study ID:

2588.00

NCT ID:

NCT01607645

Start Date:

July 2012

Completion Date:

Related Keywords:

  • Adult Acute Megakaryoblastic Leukemia (M7)
  • Adult Acute Monoblastic Leukemia (M5a)
  • Adult Acute Monocytic Leukemia (M5b)
  • Adult Acute Myeloblastic Leukemia With Maturation (M2)
  • Adult Acute Myeloblastic Leukemia Without Maturation (M1)
  • Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
  • Adult Acute Myeloid Leukemia With Del(5q)
  • Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
  • Adult Acute Myelomonocytic Leukemia (M4)
  • Adult Erythroleukemia (M6a)
  • Adult Pure Erythroid Leukemia (M6b)
  • Previously Treated Myelodysplastic Syndromes
  • Recurrent Adult Acute Myeloid Leukemia
  • Refractory Anemia With Excess Blasts
  • Congenital Abnormalities
  • Anemia
  • Anemia, Refractory
  • Anemia, Refractory, with Excess of Blasts
  • Leukemia
  • Leukemia, Erythroblastic, Acute
  • Leukemia, Megakaryoblastic, Acute
  • Leukemia, Monocytic, Acute
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myelomonocytic, Acute
  • Myelodysplastic Syndromes
  • Preleukemia
  • Leukemia, Myelomonocytic, Chronic

Name

Location

Fred Hutchinson Cancer Research Center/University of Washington Cancer ConsortiumSeattle, Washington  98109