Clinical trial NCT01349972: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: 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
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2011-05-09
Enrollment: 172
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Complete Response Rate
timeFrame: 3 years
Secondary outcomes:
measure: Incidence of Toxicities, Characterized by Number of Events by Treatment and Grade
timeFrame: Up to 14 days after completion of study treatment
measure: Disease-free Survival
timeFrame: Time from randomization until death from any cause or relapse or recurrence, assessed up to 2 years
measure: Overall Survival
timeFrame: 4 years
measure: Number of Patients With Minimal Residual Disease
timeFrame: From study start to 14 days after the start of treatment
measure: Progression-free Survival
timeFrame: 4 years
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic Scottsdale-Phoenix
state: Arizona
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Blood and Marrow Transplant Group of Georgia
state: Georgia
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Baltimore
country: United States
facility: University of Maryland/Greenebaum Cancer Center
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center
state: Maryland
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
city: Dallas
country: United States
facility: Baylor University Medical Center
state: Texas
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
Study officials:
affiliation: Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center
name: B. Smith
role: PRINCIPAL_INVESTIGATOR
References:
citation: Zeidner JF, Foster MC, Blackford AL, Litzow MR, Morris LE, Strickland SA, Lancet JE, Bose P, Levy MY, Tibes R, Gojo I, Gocke CD, Rosner GL, Little RF, Wright JJ, Doyle LA, Smith BD, Karp JE. Randomized multicenter phase II study of flavopiridol (alvocidib), cytarabine, and mitoxantrone (FLAM) versus cytarabine/daunorubicin (7+3) in newly diagnosed acute myeloid leukemia. Haematologica. 2015 Sep;100(9):1172-9. doi: 10.3324/haematol.2015.125849. Epub 2015 May 28.
citation: Gerber JM, Zeidner JF, Morse S, Blackford AL, Perkins B, Yanagisawa B, Zhang H, Morsberger L, Karp J, Ning Y, Gocke CD, Rosner GL, Smith BD, Jones RJ. Association of acute myeloid leukemia's most immature phenotype with risk groups and outcomes. Haematologica. 2016 May;101(5):607-16. doi: 10.3324/haematol.2015.135194. Epub 2016 Jan 27.