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Randomized Phase II Study of Epigenetic Priming Using Decitabine With Induction Chemotherapy in Patients With Acute Myelogenous Leukemia (AML)


Phase 2
18 Years
65 Years
Open (Enrolling)
Both
Leukemia

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Trial Information

Randomized Phase II Study of Epigenetic Priming Using Decitabine With Induction Chemotherapy in Patients With Acute Myelogenous Leukemia (AML)


OBJECTIVES:

Primary

- To "Pick a Winner" by deciding whether further development of epigenetic priming with
decitabine prior to standard "7+3" induction chemotherapy should be pursued.

Secondary

- To determine whether epigenetic priming with decitabine prior to standard cytarabine
and daunorubicin hydrochloride "7+3" induction chemotherapy has sufficient efficacy to
warrant further development as assessed by an overall CR1 rate ≥ 50%.

- To establish the safety and expected toxicities of decitabine when used as priming for
cytarabine and daunorubicin hydrochloride "7+3" induction chemotherapy in acute myeloid
leukemia (AML).

- To assess the pharmacodynamics of DNA hypomethylation when decitabine is administered
as a short infusion.

- To investigate, in selected cases, the molecular and cellular consequences of
decitabine-induced hypomethylation by assessing the effects of decitabine-mediated
hypomethylation on transcriptional patterns in AML cells, and by determining the effect
of hypomethylation on the differentiation and/or apoptosis of leukemic blasts.
(exploratory)

- To identify biomolecular correlates of treatment response (biomarkers) to induction
chemotherapy in AML based upon the epigenetic pattern of DNA methylation in AML
specimens obtained prior to treatment. (exploratory)

OUTLINE: This is a multicenter study. Patients are stratified according to age (< 50 years
vs 50-65 years), white blood cell count (≤ 30 K/mL vs > 30 K/mL), cytogenetic risk group
(intermediate vs adverse risk), and antecedent hematological condition preceding the
diagnosis of acute myeloid leukemia (yes vs no). Patients are randomized to 1 of 2 treatment
arms.

- Arm I: Patients receive induction chemotherapy comprising daunorubicin hydrochloride IV
daily on days 1-3 and cytarabine IV continuously on days 1-7 in the absence of disease
progression or unacceptable toxicity. Patients who do not achieve a complete remission
(CR) after the first induction-chemotherapy course receive a second identical induction
course.

- Arm II: Patients receive decitabine IV over 24 hours on days -5 to -1. Patients then
receive induction chemotherapy as in arm I in the absence of disease progression or
unacceptable toxicity. Patients who do not achieve a CR after the first
induction-chemotherapy course receive a second identical induction course.

Patients undergo blood, bone marrow, and oral mucosa cells sample collection at baseline,
prior to induction therapy, and after treatment for DNA methylation studies and
pharmacodynamic studies.

After completion of study treatment, patients are followed up for up to 10 years.

Inclusion Criteria


DISEASE CHARACTERISTICS:

- Diagnosis of acute myeloid leukemia (AML) as defined by the World Health Organization

- Molecular AML-risk group is less-than-favorable as defined by any of the following
criteria:

- The absence of good-risk karyotype t(8;21), inv(16), t(16;16), or t(15;17)
identified by metaphase karyotype

- The absence of t(8;21), inv(16), t(16;16), or t(15;17) identified by fluorescent
in situ hybridization (FISH)

- The absence of the corresponding fusion transcripts, AML1-ETO, CBFβ- SMMHC, or
PML-RARα, identified by reverse transcriptase-polymerase chain reaction (RT-PCR)

- Patient does not have acute promyelocytic leukemia (APL, FAB M3)

- Patients with central nervous system (CNS) (or leptomeningeal) infiltration by AML
may be considered for treatment at the Investigator's discretion and following
discussion with the Principle Investigator

PATIENT CHARACTERISTICS:

- ECOG performance status ≤ 2 (Karnofsky ≥ 60%)

- Adequate cardiac function as defined by either of the following:

- An echocardiogram demonstrating an ejection fraction within normal limits

- A MUGA scan demonstrating an ejection fraction within normal limits

- AST(SGOT)/ALT(SGPT) ≤ 2.5 times institutional upper limit of normal (ULN)

- Creatinine ≤ 2 mg/dL OR creatinine clearance ≥ 50 mL/min

- Total bilirubin ≤ 2 times ULN

- Patients with documented diagnosis of Gilbert syndrome resulting in elevated
total bilirubin levels will be eligible, provided all other eligibility criteria
are met

- Patients with a total bilirubin of 2-3 mg/dL and direct (conjugated) bilirubin
in the normal range will be eligible, provided all other eligibility criteria
are met

- No patient with circulating blast count (CBC) > 50,000/μL (subjects may be enrolled
if CBC is controlled by hydroxyurea and/or, if clinically indicated, by
leukophoresis)

- Not pregnant or nursing

- Negative pregnancy test

- Women and men of childbearing potential must use two acceptable methods of birth
control—one highly effective method (e.g., IUD, oral or non-oral hormonal
contraceptive, tubal ligation, or partner's vasectomy) and one additional effective
method (e.g., latex condom, diaphragm or cervical cap) at the same time from the time
of screening through final Treatment Response Assessment

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition of decitabine, cytarabine, or daunorubicin hydrochloride

- No uncontrolled intercurrent illness considered by the investigator to constitute an
unwarranted high risk for investigational drug treatment; examples include, but are
not limited to, the following:

- Uncontrolled serious infection

- Unstable angina pectoris

- Uncontrolled cardiac arrhythmia

- Active second malignancy requiring treatment

- Symptomatic congestive heart failure

- No HIV-positive patients with a CD4 count < 200 cells/μL

- Patients with HIV infection and a CD4 count ≥ 200 cells/μL are eligible but
combination antiretroviral therapy should be held during administration of
chemotherapy

- No patient with a psychiatric disorder, altered mental status, or social situation
that would preclude understanding of the informed consent process and/or limit
compliance with study requirements

- No patients with inability or unwillingness, in the opinion of the investigator, to
comply with the protocol requirements

PRIOR CONCURRENT THERAPY:

- No prior chemotherapy for acute myeloid leukemia (AML) other than hydroxyurea

- No chemotherapy (other than hydroxyurea) or radiation within the 2 weeks prior to
planned therapy on this study or ongoing adverse events due to agents administered
more than 2 weeks earlier

- No concurrent treatment with other investigational agents

- No cumulative lifetime dose of anthracycline chemotherapeutic > 80 mg/m^2

- No other concurrent antineoplastic medications

- No concurrent herbal medications and supplements

- No concurrent erythroid-stimulating agents (e.g., erythropoietin, Aranesp)

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Complete remission rate after one course of induction chemotherapy

Safety Issue:

No

Principal Investigator

Joseph M. Scandura, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Weill Medical College of Cornell University

Authority:

Unspecified

Study ID:

CDR0000712322

NCT ID:

NCT01627041

Start Date:

September 2011

Completion Date:

Related Keywords:

  • Leukemia
  • adult acute basophilic leukemia
  • adult acute eosinophilic leukemia
  • 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)
  • untreated adult acute myeloid leukemia
  • secondary acute myeloid leukemia
  • adult acute myelomonocytic leukemia (M4)
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid

Name

Location

Roswell Park Cancer InstituteBuffalo, New York  14263
Memorial Sloan-Kettering Cancer CenterNew York, New York  10021
Montefiore Medical CenterBronx, New York  10467-2490
New York Weill Cornell Cancer Center at Cornell UniversityNew York, New York  10021