Alvocidib, Cytarabine, and Mitoxantrone Hydrochloride or Cytarabine and Daunorubicin Hydrochloride in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01349972
• Other study ID #: NCI-2011-02587
• Secondary ID: NCI-2011-02587JH
• Status: Completed
• Phase: Phase 2
• First received: May 6, 2011
• Last updated: October 10, 2014
• Start date: April 2011
• Est. completion date: May 2014

Study information

• Verified date: January 2014
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 167
• Est. completion date: May 2014
• Est. primary completion date: May 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• 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)
• Leukemia
• Leukemia, Erythroblastic, Acute
• Leukemia, Monocytic, Acute
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Leukemia, Myelomonocytic, Acute
• Leukemia, Myelomonocytic, Chronic
• Myelodysplastic Syndromes
• Preleukemia
• Secondary Acute Myeloid Leukemia
• Untreated Adult Acute Myeloid Leukemia

Intervention

Drug:
• alvocidib
Given IV
• daunorubicin hydrochloride
Given IV
• mitoxantrone hydrochloride
Given IV
• cytarabine
Given IV

Locations

Country	Name	City	State
United States	Blood and Marrow Transplant Group of Georgia	Atlanta	Georgia
United States	Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center	Baltimore	Maryland
United States	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland
United States	University of North Carolina	Chapel Hill	North Carolina
United States	Medical University of South Carolina	Charleston	South Carolina
United States	University of Chicago	Chicago	Illinois
United States	Baylor University Medical Center	Dallas	Texas
United States	Baylor All Saints Medical Center at Fort Worth	Fort Worth	Texas
United States	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee
United States	Virginia Commonwealth University	Richmond	Virginia
United States	Mayo Clinic	Rochester	Minnesota
United States	Mayo Clinic in Arizona	Scottsdale	Arizona
United States	Mayo Clinic Scottsdale-Phoenix	Scottsdale	Arizona
United States	Moffitt Cancer Center	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Complete response rate	The final analysis will be by Fisher's exact test.	Up to 5 years	No
Secondary	Incidence of toxicities, characterized as percentages by treatment and grade	The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting.	Up to 14 days after completion of study treatment	Yes
Secondary	Disease-free survival	Probabilities will be estimated with the Kaplan-Meier estimate. Survival estimates at two years will be estimated.	Time from randomization until death from any cause or relapse or recurrence, assessed up to 5 years	No
Secondary	Overall survival	Probabilities will be estimated with the Kaplan-Meier estimate. Survival estimates at two years will be estimated.	From time of enrollment until time of death, assessed up to 5 years	No
Secondary	Progression-free survival	Probabilities will be estimated with the Kaplan-Meier estimate. Survival estimates at two years will be estimated.	Time from study entry to the first date that recurrent or progressive disease is objectively documented, or death from any cause occurs, assessed up to 5 years	No
Secondary	Proportion of patients with minimal residual disease	Comparisons of the treatments with respect to MRD will be based on the proportion of patients with MRD at each time point (e.g., day 14, recovery from induction but before beginning course 2, etc.).	Up to 5 years	No