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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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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

Intervention / Treatment
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* Drug: alvocidib
* Drug: daunorubicin hydrochloride
* Drug: mitoxantrone hydrochloride
* Drug: cytarabine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (alvocidib, cytarabine, mitoxantrone hydrochloride)<br>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. | Drug: alvocidib<br>* Given IV<br>* Other names: L-868275;Drug: mitoxantrone hydrochloride<br>* Given IV<br>* Other names: DHAQ;Drug: cytarabine<br>* Given IV<br>* Other names: cytosine arabinoside;|
| Active Comparator: Arm II (cytarabine, daunorubicin hydrochloride)<br>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. | Drug: daunorubicin hydrochloride<br>* Given IV<br>* Other names: RP-13057;Drug: cytarabine<br>* Given IV<br>* Other names: cytosine arabinoside;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response Rate | Bone marrow showing less than 5% myeloblasts with normal maturation of all cell lines, an ANC of at least 1000/cu mm and a platelet count of 100,000/cu mm, absence of blast in peripheral blood, absence of identifiable leukemic cells in the bone marrow, clearance of disease-associated cytogenetic abnormalities, and clearance of any previously existing extramedullary disease. These criteria are taken from Dohner H, Estey EH, Amadori S, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 2010;115:453-474 | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Toxicities, Characterized by Number of Events 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 | 
| Disease-free Survival | Probabilities will be estimated with the Kaplan-Meier estimate. Survival estimates at two years will be estimated. Disease-free survival Overall survival was defined from date of randomization to death or last known follow-up. Event free survival was defined as date of randomization to the first occurrence of persistent AML after 1 cycle of induction, relapse or death. Patients were censored for event free survival if they had received non-protocol therapy or a stem cell transplant. | Time from randomization until death from any cause or relapse or recurrence, assessed up to 2 years | 
| Overall Survival | Probabilities will be estimated with the Kaplan-Meier estimate. Survival estimates at two years will be estimated. | 4 years | 
| Number of Patients With Minimal Residual Disease | Comparisons of the treatments with respect to MRD will be based on the number of patients with MRD at day 14 after the start of treatment. | From study start to 14 days after the start of treatment | 
| Progression-free Survival | Probabilities will be estimated with the Kaplan-Meier estimate. Survival estimates at two years will be estimated. | 4 years |