Brief Title
Alvocidib, Cytarabine, and Mitoxantrone Hydrochloride or Cytarabine and Daunorubicin Hydrochloride in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia
Official Title
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)
Brief Summary
This randomized phase II trial is studying how alvocidib, cytarabine, and mitoxantrone
hydrochloride work compared to cytarabine and daunorubicin hydrochloride in treating patients
with newly diagnosed acute myeloid leukemia. Alvocidib may stop the growth of cancer cells by
blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as
cytarabine, mitoxantrone hydrochloride, and daunorubicin hydrochloride work in different ways
to stop the growth of cancer cells, either by killing the cells or by stopping them from
dividing. It is not yet known whether giving alvocidib, cytarabine, and mitoxantrone
hydrochloride is more effective than giving cytarabine and daunorubicin hydrochloride in
treating patients with acute myeloid leukemia.
Detailed Description
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. II. To compare the 2-year
disease-free survival (DFS) and overall survival (OS) in response to FLAM vs 7+3.
III. To detect and compare the presence of minimal-residual disease (MRD) remaining after
FLAM vs 7+3.
IV. 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 myelodysplatic syndrome [MDS],
myeloproliferative diseases [MPD], treatment-related [t]-AML, or severe multi-lineage
dysplasia) and/or known adverse cytogenetics, and hyperleukocytosis (white blood cells [WBC]
>= 50,000/mm^3). Patients are randomized to 1 of 2 treatment arms.
ARM I: Patients receive alvocidib intravenously (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.
Study Phase
Phase 2
Study Type
Interventional
Primary Outcome
Complete Response Rate
Secondary Outcome
Incidence of Toxicities, Characterized by Number of Events by Treatment and Grade
Condition
Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome
Intervention
alvocidib
Study Arms / Comparison Groups
Arm I (alvocidib, cytarabine, mitoxantrone hydrochloride)
Description: 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.
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
172
Start Date
April 2011
Completion Date
May 2014
Primary Completion Date
May 2014
Eligibility Criteria
Inclusion Criteria:
- All adults with established, pathologically confirmed diagnoses of newly diagnosed AML
and adults with newly diagnosed AML, excluding newly diagnosed core-binding factor
(CBF) AMLs and acute progranulocytic leukemia (APL, M3), will be considered eligible
for study
- Eastern Cooperative Oncology Group (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
- Alanine aminotransferase (ALT)/aspartate aminotransferase (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%
- 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)
- 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
Exclusion Criteria:
- Any previous treatment with flavopiridol
- Concomitant chemotherapy, radiation therapy, or immunotherapy
- Hyperleukocytosis with >= 50,000 blasts/uL; leukopheresis or hydroxyurea may be used
immediately prior to study drug administration for cytoreduction; must be stopped 24
hours before first dose of study chemotherapy
- CBF AMLs 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 or
FISH or molecular testing
- Acute Progranulocytic Leukemia (APL, M3)
- Active central nervous system (CNS) leukemia
- Active, uncontrolled infection; patients with infection under active treatment and
controlled with antibiotics are eligible
- Active, uncontrolled graft vs. host disease (GVHD) following allogeneic transplant for
non-AML condition (e.g. MDS, lymphoid malignancy, aplastic anemia); patients with GVHD
controlled on stable doses of immunosuppressants are eligible
- Presence of other life-threatening illness
- Patients with mental deficits and/or psychiatric history that preclude them form
giving informed consent or from following protocol
- Pregnant and nursing patients are excluded
Gender
All
Ages
18 Years - 70 Years
Accepts Healthy Volunteers
No
Contacts
B. Smith, ,
Location Countries
United States
Location Countries
United States
Administrative Informations
NCT ID
NCT01349972
Organization ID
NCI-2011-02587
Secondary IDs
NCI-2011-02587
Responsible Party
Sponsor
Study Sponsor
National Cancer Institute (NCI)
Study Sponsor
B. Smith, Principal Investigator, Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center
Verification Date
July 2017