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Randomized Phase II Trial of Timed Sequential Therapy (TST) With Alvocidib (Flavopiridol), Ara-C and Mitoxantrone (FLAM) vs. "7+3" for Adults Age 70 and Under With Newly Diagnosed Acute Myelogenous Leukemia (AML)


Phase 2
18 Years
70 Years
Open (Enrolling)
Both
Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome, Adult Acute Minimally Differentiated Myeloid Leukemia (M0), 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), Secondary Acute Myeloid Leukemia, Untreated Adult Acute Myeloid Leukemia

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Trial Information

Randomized Phase II Trial of Timed Sequential Therapy (TST) With Alvocidib (Flavopiridol), Ara-C and Mitoxantrone (FLAM) vs. "7+3" for Adults Age 70 and Under With Newly Diagnosed Acute Myelogenous Leukemia (AML)


PRIMARY OBJECTIVES:

I. To compare the rate of complete remission (CR) after 1 course of induction therapy with
the timed-sequential combination of alvocidib (flavopiridol), cytarabine (cytosine
arabinoside [ara-C]), and mitoxantrone hydrochloride (FLAM) vs traditional "7+3" cytarabine
and daunorubicin hydrochloride (ara-C + Daunorubicin) for adults (age 18 to 70) with newly
diagnosed, previously untreated, intermediate-risk or poor-risk acute myelogenous leukemia
(AML).

SECONDARY OBJECTIVES:

I. To evaluate and compare the toxicities of FLAM vs 7+3.To compare the 2-year disease-free
survival (DFS) and overall survival (OS) in response to FLAM vs 7+3.

II. To detect and compare the presence of minimal-residual disease (MRD) remaining after
FLAM vs 7+3.

III. To determine the expression of ABC transport proteins multidrug resistance 1 (MDR1,
ABCB1) and breast cancer resistance protein (BCRP, ABCG2) on AML blasts pretreatment and
correlate the expressions of one or both proteins with CR and DFS in response to FLAM vs
7+3.

OUTLINE: This is a multicenter study. Patients are stratified according to risk features:
age (< 50 vs ≥ 50), secondary AML (pre-existing MDS, MPD, t-AML, or severe multi-lineage
dysplasia) and/or known adverse cytogenetics, and hyperleukocytosis (WBC ≥ 50,000/mm³).
Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive alvocidib IV over 1 hour on days 1-3, cytarabine IV over 72 hours on
days 6-8, and mitoxantrone hydrochloride IV over 1-2 hours on day 9. Patients who achieve
complete or partial response to the first course (completion of all doses) may receive a
second course of treatment or high-dose cytarabine after 21-63 days following blood count
recovery, and/or undergo allogeneic bone marrow transplant.

ARM II: Patients receive cytarabine IV continuously on days 1-7 and daunorubicin
hydrochloride IV on days 1-3. Patients who have residual disease on day 14 may receive
additional cytarabine for 5 days and daunorubicin hydrochloride for 2 days. Patients may
undergo blood and bone marrow collection for correlative studies.

After completion of study therapy, patients are followed up every 3 months for 2 years,
every 6 months for 5 years, and then annually thereafter.


Inclusion Criteria:



- All adults with established, pathologically confirmed newly diagnosed acute myeloid
leukemia (AML)

- Adults (≥ 18 years and ≤ 70 years of age) with newly diagnosed AML

- Excluding newly diagnosed core-binding factor (CBF) AML and acute
progranulocytic leukemia (APL, M3)

- CBF AML associated with t(8;21) or M4eo subtype (inv[16] or t[16;16]), as
diagnosed by morphologic criteria, flow cytometric characteristics, and
rapid cytogenetics, fluorescence in situ hybridization (FISH), or molecular
testing

- Newly diagnosed AML, subtypes M0, 1, 2, 4-7 but excluding M3 (APL), including those
with the following poor risk features:

- Antecedent hematologic disorder including myelodysplasia (MDS)-related AML
(MDS/AML) and prior myeloproliferative disorder (MPD)

- Treatment-related myeloid neoplasms (t-AML/t-MDS)

- Myeloid sarcoma, myeloid proliferations related to Down Syndrome, and blastic
plasmacytoid dendritic cell neoplasm

- AML with multilineage dysplasia (AML-MLD)

- Adverse cytogenetics (defined as -5/-5q; -7/-7q; abnormal 3q, 9q, 11q, 20q, 21q,
or 17p; t(6;9); t(9;22); trisomy 8; trisomy 13; trisomy 21; and complex
karyotypes (≥ 3 unrelated abnormalities)

- No active CNS leukemia

- ECOG performance status (PS) 0-3

- Patients ≥ 65 years of age must have ECOG PS ≤ 2 prior to developing leukemic
symptoms

- Serum creatinine ≤ 2.0 mg/dL

- ALT/AST ≤ 5 times upper limit of normal (ULN) (unless leukemic infiltration)

- Total bilirubin ≤ 2.0 mg/dL (unless Gilbert disease, hemolysis, or leukemia)

- Left ventricular ejection fraction ≥ 45%

- No hyperleukocytosis with ≥ 50,000 blasts/μL

- No active, uncontrolled infection

- Patients with infection under active treatment and controlled with antibiotics
are eligible

- No presence of other life-threatening illness

- No patients with mental deficits and/or psychiatric history that preclude them from
giving informed consent or from following protocol

- Not pregnant or nursing

- No active uncontrolled graft-vs-host disease following allogeneic transplantation for
non-AML condition (e.g., MDS, lymphoid malignancy, or aplastic anemia); patients with
GVHD controlled on stable doses of immunosuppressants are eligible

- Patients who have received hydroxyurea alone or have received non-cytotoxic therapies
previously for myelodysplasia (MDS) or myeloproliferative disorder (MPD) (e.g.,
thalidomide or lenalidomide, interferon, cytokines, 5-azacytidine or decitabine,
histone deacetylase inhibitors, low-dose cyclophosphamide [cytoxan], tyrosine kinase
[TK] or dual TK/src inhibitors) will be eligible for this trial

- At least 24 hours since prior leukopheresis or hydroxyurea for cytoreduction

- No prior alvocidib (flavopiridol)

- No other concomitant chemotherapy, radiotherapy, or immunotherapy

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Complete response rate

Outcome Description:

The final analysis will be by Fisher's exact test.

Outcome Time Frame:

Up to 5 years

Safety Issue:

No

Principal Investigator

B. Smith

Investigator Role:

Principal Investigator

Investigator Affiliation:

Johns Hopkins University

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2011-02587

NCT ID:

NCT01349972

Start Date:

April 2011

Completion Date:

Related Keywords:

  • Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome
  • Adult Acute Minimally Differentiated Myeloid Leukemia (M0)
  • 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)
  • Secondary Acute Myeloid Leukemia
  • Untreated Adult Acute Myeloid Leukemia
  • Congenital Abnormalities
  • Leukemia
  • Leukemia, Erythroblastic, Acute
  • Leukemia, Monocytic, Acute
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myelomonocytic, Acute
  • Myelodysplastic Syndromes
  • Preleukemia
  • Leukemia, Myelomonocytic, Chronic

Name

Location

Johns Hopkins UniversityBaltimore, Maryland  21205
Mayo ClinicRochester, Minnesota  55905
H. Lee Moffitt Cancer Center and Research InstituteTampa, Florida  33612
Medical University of South CarolinaCharleston, South Carolina  29425-0721
Rush University Medical CenterChicago, Illinois  60612-3824
Vanderbilt UniversityNashville, Tennessee  37232-6305
University of North CarolinaChapel Hill, North Carolina  27599
Northwestern UniversityChicago, Illinois  60611
Blood and Marrow Transplant Group of GeorgiaAtlanta, Georgia  30342-1601
Virginia Commonwealth UniversityRichmond, Virginia  
University of Chicago Comprehensive Cancer CenterChicago, Illinois  60637-1470
Scottsdale HealthcareScottsdale, Arizona  85251
University of Maryland Greenebaum Cancer CenterBaltimore, Maryland  21201
Masonic Cancer Center, University of MinnesotaMinneapolis, Minnesota  55455