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Randomized Phase II Study Comparing Two Administration Schedules of Flavopiridol (Alvocidib, NSC 649890, IND 46,211) Given in Timed Sequential Combination With Cytosine Arabinoside (Ara-C) and Mitoxantrone Hydrochloride for Adults With Newly Diagnosed, Previously Untreated, Poor-risk Acute Myelogenous Leukemias (AML)


Phase 2
18 Years
N/A
Not Enrolling
Both
Leukemia

Thank you

Trial Information

Randomized Phase II Study Comparing Two Administration Schedules of Flavopiridol (Alvocidib, NSC 649890, IND 46,211) Given in Timed Sequential Combination With Cytosine Arabinoside (Ara-C) and Mitoxantrone Hydrochloride for Adults With Newly Diagnosed, Previously Untreated, Poor-risk Acute Myelogenous Leukemias (AML)


OBJECTIVES:

Primary

- To compare the efficacy of two different schedules (bolus vs "hybrid bolus-infusion")
of alvocidib followed by cytarabine and mitoxantrone hydrochloride in patients with
newly diagnosed acute myeloid leukemia (AML) with poor-risk features.

Secondary

- To compare the toxicities of these regimens.

- To determine the disease-free survival and overall survival of patients who demonstrate
a response to these regimens.

- To compare the pharmacokinetics of alvocidib when administered in two different
schedules (bolus vs "hybrid bolus-infusion").

- To describe alvocidib-induced alterations in AML blast cell expression of selected
target mRNA and proteins.

- To describe alvocidib-induced alterations in AML blast cell growth kinetic parameters.

OUTLINE: This is a multicenter study. Patients are stratified according to antecedent
hematologic disorder of ≥ 6 months duration prior to transformation to acute myeloid
leukemia (AML) and any prior antecedent therapy for myelodysplastic syndromes or
myeloproliferative disorder. Patients are randomized to 1 of 2 treatment arms.

- Arm I: Patients receive alvocidib IV over 1 hour on days 1-3, cytarabine IV
continuously over 72 hours on days 6-8, and mitoxantrone hydrochloride IV over 60-120
minutes on day 9.

- Arm II: Patients receive alvocidib IV over 30 minutes followed by alvocidib IV over 4
hours on days 1-3. Patients also receive cytarabine and mitoxantrone hydrochloride as
in arm I.

Patients achieving partial or complete response (CR) after the first course of treatment may
receive a second course of treatment 21-63 days following blood count recovery and/or
undergo allogeneic bone marrow transplantation. Patients ≥ 50 years of age with t (8;21),
inv (16), or t(16;16) AML who achieve CR after the first course of treatment may receive 3-4
courses of high-dose cytarabine consolidation therapy.

Bone marrow and/or blood samples are collected at baseline and periodically during study for
correlative laboratory studies, including pharmacokinetic studies by liquid chromatography
and tandem mass spectrometry, analysis of blast cell growth kinetic parameters by flow
cytometry, and blast cell expression of selected target mRNA and protein by quantitative
RT-PCR and western blotting.

After completion of study therapy, patients are followed periodically.

Inclusion Criteria


DISEASE CHARACTERISTICS:

- Pathologically confirmed newly diagnosed acute myeloid leukemia (AML) meeting the
following criteria:

- Subtypes M0, M1, M2, M4-7

- No acute promyelocytic leukemia (M3)

- At least 50 years of age OR ≥ 18 years of age with ≥ 1 of the following
poor-risk disease features:

- Antecedent hematologic disorder, including myelodysplastic syndromes
(MDS)-related AML or prior myeloproliferative disorder (MPD)

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

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

- AML with trilineage dysplasia

- AML with 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, complex
karyotypes [≥ 3 unrelated abnormalities])

- No hyperleukocytosis with ≥ 50,000 blasts/uL (leukapheresis or hydroxyurea allowed
for cytoreduction immediately prior to the first dose of alvocidib)

- No active CNS leukemia

PATIENT CHARACTERISTICS:

- ECOG performance status 0-2

- Serum creatinine ≤ 2.0 mg/dL

- ALT/AST ≤ 5 times upper limit of normal

- Bilirubin ≤ 2.0 mg/dL

- LVEF ≥ 45%

- Not pregnant or nursing

- Negative pregnancy test

- No active uncontrolled infection

- Infection that is under active treatment allowed provided it is controlled with
antibiotics

- No other life-threatening illness

- No mental deficits and/or psychiatric history that would preclude giving informed
consent or following study requirements

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

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

- Prior non-cytotoxic therapies (e.g., thalidomide or lenalidomide, interferon,
cytokines, low-dose 5-azacytidine, or low-dose cytoxan) for MDS or MPD allowed

- Prior chemotherapy or bone marrow/stem cell transplantation for non-AML malignancy
allowed

- No prior alvocidib

- No other concurrent chemotherapy, radiotherapy, or immunotherapy

- No other concurrent investigational or commercially-available antitumor therapies for
AML

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Complete response

Outcome Time Frame:

1 year

Safety Issue:

No

Principal Investigator

Judith E. Karp, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Sidney Kimmel Comprehensive Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

J0856 CDR0000625222

NCT ID:

NCT00795002

Start Date:

November 2008

Completion Date:

Related Keywords:

  • Leukemia
  • untreated adult acute myeloid leukemia
  • adult acute myeloid leukemia with 11q23 (MLL) abnormalities
  • 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 minimally differentiated myeloid leukemia (M0)
  • adult acute myeloblastic leukemia without maturation (M1)
  • adult acute myeloblastic leukemia with maturation (M2)
  • adult acute myelomonocytic leukemia (M4)
  • adult acute monoblastic leukemia (M5a)
  • adult acute monocytic leukemia (M5b)
  • adult erythroleukemia (M6a)
  • adult pure erythroid leukemia (M6b)
  • adult acute megakaryoblastic leukemia (M7)
  • acute myeloid leukemia with multilineage dysplasia following myelodysplastic syndrome
  • secondary acute myeloid leukemia
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid

Name

Location

Fred Hutchinson Cancer Research CenterSeattle, Washington  98109
Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimore, Maryland  21231-2410
Hollings Cancer Center at Medical University of South CarolinaCharleston, South Carolina  29425