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

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT01349972
• Collaborator: (none)
• Enrollment: 172
• Locations: 11
• Arms: 2
• Duration (Months): 37
• Patients Per Site: 15.6
• Patients Per Site Per Month: 0.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
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	Drug: alvocidib; Drug: daunorubicin hydrochloride; Drug: mitoxantrone hydrochloride; Drug: cytarabine	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. 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:

1. 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.

2. To detect and compare the presence of minimal-residual disease (MRD) remaining after FLAM vs 7+3.

3. 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 Design

• Study Type: Interventional
• Actual Enrollment: 172 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: Apr 1, 2011
• Actual Primary Completion Date: May 1, 2014
• Actual Study Completion Date: May 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (alvocidib, cytarabine, mitoxantrone hydrochloride) 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; Given IV; Other Names: FLAVO flavopiridol HMR 1275 L-868275 ; Drug: mitoxantrone hydrochloride; Given IV; Other Names: CL 232315 DHAD DHAQ ; Drug: cytarabine; Given IV; Other Names: ARA-C arabinofuranosylcytosine arabinosylcytosine Cytosar-U cytosine arabinoside
Active Comparator: Arm II (cytarabine, daunorubicin hydrochloride) 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; Given IV; Other Names: Cerubidin Cerubidine daunomycin hydrochloride daunorubicin RP-13057 ; Drug: cytarabine; Given IV; Other Names: ARA-C arabinofuranosylcytosine arabinosylcytosine Cytosar-U cytosine arabinoside

Outcome Measures

Primary Outcome Measures

1. Complete Response Rate [3 years]

   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

Secondary Outcome Measures

1. Incidence of Toxicities, Characterized by Number of Events by Treatment and Grade [Up to 14 days after completion of study treatment]

   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.

2. Disease-free Survival [Time from randomization until death from any cause or relapse or recurrence, assessed up to 2 years]

   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.

3. Overall Survival [4 years]

   Probabilities will be estimated with the Kaplan-Meier estimate. Survival estimates at two years will be estimated.

4. Number of Patients With Minimal Residual Disease [From study start to 14 days after the start of treatment]

   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.

5. Progression-free Survival [4 years]

   Probabilities will be estimated with the Kaplan-Meier estimate. Survival estimates at two years will be estimated.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic Scottsdale-Phoenix	Scottsdale	Arizona	United States	85259
2	Moffitt Cancer Center	Tampa	Florida	United States	33612
3	Blood and Marrow Transplant Group of Georgia	Atlanta	Georgia	United States	30342
4	University of Chicago	Chicago	Illinois	United States	60637
5	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland	United States	21201
6	Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center	Baltimore	Maryland	United States	21287
7	Mayo Clinic	Rochester	Minnesota	United States	55905
8	University of North Carolina	Chapel Hill	North Carolina	United States	27599
9	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee	United States	37232
10	Baylor University Medical Center	Dallas	Texas	United States	75246
11	Virginia Commonwealth University	Richmond	Virginia	United States	23298

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: B. Smith, Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Pubmed

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01349972
• Other Study ID Numbers: NCI-2011-02587; NCI-2011-02587; JHOC-J1101; CDR0000699421; J1101; 8972; U01CA070095; N01CM00100; P30CA006973; NCT01413880
• First Posted: May 9, 2011
• Last Update Posted: Jul 31, 2017
• Last Verified: Jul 1, 2017

• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukemia, Monocytic, Acute; Leukemia, Myelomonocytic, Acute; Leukemia, Erythroblastic, Acute; Myelodysplastic Syndromes; Cytarabine; Daunorubicin; Mitoxantrone; Alvocidib

Study Results

Participant Flow

Arm/Group Title	Arm I (Alvocidib, Cytarabine, Mitoxantrone Hydrochloride)	Arm II (Cytarabine, Daunorubicin Hydrochloride)
Arm/Group 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. alvocidib: Given IV mitoxantrone hydrochloride: Given IV cytarabine: Given IV	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. daunorubicin hydrochloride: Given IV cytarabine: Given IV
Period Title: Overall Study
STARTED	114	58
COMPLETED	109	56
NOT COMPLETED	5	2

Baseline Characteristics

Arm/Group Title	Arm I (Alvocidib, Cytarabine, Mitoxantrone Hydrochloride)	Arm II (Cytarabine, Daunorubicin Hydrochloride)	Total
Arm/Group 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. alvocidib: Given IV mitoxantrone hydrochloride: Given IV cytarabine: Given IV	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. daunorubicin hydrochloride: Given IV cytarabine: Given IV	Total of all reporting groups
Overall Participants	114	58	172
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	79 69.3%	43 74.1%	122 70.9%
>=65 years	35 30.7%	15 25.9%	50 29.1%
Sex: Female, Male (Count of Participants)
Female	53 46.5%	27 46.6%	80 46.5%
Male	61 53.5%	31 53.4%	92 53.5%

Outcome Measures

1. Primary Outcome

Title	Complete Response Rate
Description	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
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (Alvocidib, Cytarabine, Mitoxantrone Hydrochloride)	Arm II (Cytarabine, Daunorubicin Hydrochloride)
Arm/Group 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. alvocidib: Given IV mitoxantrone hydrochloride: Given IV cytarabine: Given IV	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. daunorubicin hydrochloride: Given IV cytarabine: Given IV
Measure Participants	109	56
Number [participants]	76 66.7%	24 41.4%

2. Secondary Outcome

Title	Incidence of Toxicities, Characterized by Number of Events by Treatment and Grade
Description	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.
Time Frame	Up to 14 days after completion of study treatment

Outcome Measure Data

Analysis Population Description

Number of evaluable subjects

Arm/Group Title	Arm I (Alvocidib, Cytarabine, Mitoxantrone Hydrochloride)	Arm II (Cytarabine, Daunorubicin Hydrochloride)
Arm/Group 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. alvocidib: Given IV mitoxantrone hydrochloride: Given IV cytarabine: Given IV	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. daunorubicin hydrochloride: Given IV cytarabine: Given IV
Measure Participants	109	56
Number [Number of events]	156	77

3. Secondary Outcome

Title	Disease-free Survival
Description	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 Frame	Time from randomization until death from any cause or relapse or recurrence, assessed up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (Alvocidib, Cytarabine, Mitoxantrone Hydrochloride)	Arm II (Cytarabine, Daunorubicin Hydrochloride)
Arm/Group 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. alvocidib: Given IV mitoxantrone hydrochloride: Given IV cytarabine: Given IV	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. daunorubicin hydrochloride: Given IV cytarabine: Given IV
Measure Participants	114	58
Median (Full Range) [years]	1.46	1.85

4. Secondary Outcome

Title	Overall Survival
Description	Probabilities will be estimated with the Kaplan-Meier estimate. Survival estimates at two years will be estimated.
Time Frame	4 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (Alvocidib, Cytarabine, Mitoxantrone Hydrochloride)	Arm II (Cytarabine, Daunorubicin Hydrochloride)
Arm/Group 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. alvocidib: Given IV mitoxantrone hydrochloride: Given IV cytarabine: Given IV	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. daunorubicin hydrochloride: Given IV cytarabine: Given IV
Measure Participants	109	56
Median (95% Confidence Interval) [years]	1.46	1.850

5. Secondary Outcome

Title	Number of Patients With Minimal Residual Disease
Description	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.
Time Frame	From study start to 14 days after the start of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (Alvocidib, Cytarabine, Mitoxantrone Hydrochloride)	Arm II (Cytarabine, Daunorubicin Hydrochloride)
Arm/Group 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. alvocidib: Given IV mitoxantrone hydrochloride: Given IV cytarabine: Given IV	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. daunorubicin hydrochloride: Given IV cytarabine: Given IV
Measure Participants	102	55
Count of Participants [Participants]	26 22.8%	24 41.4%

6. Secondary Outcome

Title	Progression-free Survival
Description	Probabilities will be estimated with the Kaplan-Meier estimate. Survival estimates at two years will be estimated.
Time Frame	4 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (Alvocidib, Cytarabine, Mitoxantrone Hydrochloride)	Arm II (Cytarabine, Daunorubicin Hydrochloride)
Arm/Group 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. alvocidib: Given IV mitoxantrone hydrochloride: Given IV cytarabine: Given IV	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. daunorubicin hydrochloride: Given IV cytarabine: Given IV
Measure Participants	76	26
Median (95% Confidence Interval) [years]	0.81	0.28

Adverse Events

Arm/Group Title	Arm I (Alvocidib, Cytarabine, Mitoxantrone Hydrochloride)		Arm II (Cytarabine, Daunorubicin Hydrochloride)
Arm/Group 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. alvocidib: Given IV mitoxantrone hydrochloride: Given IV cytarabine: Given IV		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. daunorubicin hydrochloride: Given IV cytarabine: Given IV
All Cause Mortality
	Arm I (Alvocidib, Cytarabine, Mitoxantrone Hydrochloride)		Arm II (Cytarabine, Daunorubicin Hydrochloride)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm I (Alvocidib, Cytarabine, Mitoxantrone Hydrochloride)		Arm II (Cytarabine, Daunorubicin Hydrochloride)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	53/114 (46.5%)		21/58 (36.2%)
Blood and lymphatic system disorders
bone marrow hypocellular	1/114 (0.9%)	1	0/58 (0%)	0
Disseminated Intravascular Coagulation	2/114 (1.8%)	2	1/58 (1.7%)	1
febrile neutropenia	1/114 (0.9%)	1	0/58 (0%)	0
Cardiac disorders
atrial fibrillation	1/114 (0.9%)	1	2/58 (3.4%)	2
cardiac chest pain	1/114 (0.9%)	1	0/58 (0%)	0
heart failure	2/114 (1.8%)	2	0/58 (0%)	0
left ventricular systolic dysfunction	5/114 (4.4%)	5	0/58 (0%)	0
myocardial infarction	2/114 (1.8%)	2	0/58 (0%)	0
pericardial effusion	1/114 (0.9%)	1	0/58 (0%)	0
pericarditis	1/114 (0.9%)	1	1/58 (1.7%)	1
Endocrine disorders
thyrotoxicosis	1/114 (0.9%)	1	0/58 (0%)	0
Gastrointestinal disorders
ileal perforation	1/114 (0.9%)	1	0/58 (0%)	0
peritoneal necrosis	1/114 (0.9%)	1	0/58 (0%)	0
small intestinal obstruction	1/114 (0.9%)	1	0/58 (0%)	0
gastrointestinal hemmorrhage	1/114 (0.9%)	1	1/58 (1.7%)	1
General disorders
death	1/114 (0.9%)	1	0/58 (0%)	0
fever	2/114 (1.8%)	2	0/58 (0%)	0
Immune system disorders
cytokine release syndrome	3/114 (2.6%)	3	2/58 (3.4%)	2
sogt tissue infection	1/114 (0.9%)	1	0/58 (0%)	0
Infections and infestations
appendicitis	1/114 (0.9%)	1	0/58 (0%)	0
lung infection	2/114 (1.8%)	2	0/58 (0%)	0
sepsis	1/114 (0.9%)	1	0/58 (0%)	0
Investigations
blood bilirubin increased	2/114 (1.8%)	2	0/58 (0%)	0
creatinine increased	1/114 (0.9%)	1	0/58 (0%)	0
QTc prolonged	1/114 (0.9%)	1	0/58 (0%)	0
alkaline phosphatase increased	0/114 (0%)	0	1/58 (1.7%)	1
Metabolism and nutrition disorders
dehydration	1/114 (0.9%)	1	0/58 (0%)	0
hyperglycemia	1/114 (0.9%)	1	1/58 (1.7%)	1
hypokalemia	0/114 (0%)	0	1/58 (1.7%)	1
hyponatremia	1/114 (0.9%)	1	1/58 (1.7%)	1
hypocalcemia	1/114 (0.9%)	1	0/58 (0%)	0
hypophosphatemia	2/114 (1.8%)	2	2/58 (3.4%)	2
tumor lysis syndrome	4/114 (3.5%)	4	1/58 (1.7%)	1
Nervous system disorders
seizure	1/114 (0.9%)	1	0/58 (0%)	0
Renal and urinary disorders
acute kidney injury	2/114 (1.8%)	2	2/58 (3.4%)	2
chronic kidney disease	0/114 (0%)	0	1/58 (1.7%)	1
renal insufficiency	1/114 (0.9%)	1	0/58 (0%)	0
necrotic bladder	1/114 (0.9%)	1	0/58 (0%)	0
Respiratory, thoracic and mediastinal disorders
adult respiratory distress syndrome	0/114 (0%)	0	1/58 (1.7%)	1
hypoxia	0/114 (0%)	0	1/58 (1.7%)	1
Vascular disorders
thrombotic event	1/114 (0.9%)	1	0/58 (0%)	0
capillary leak syndrome	0/114 (0%)	0	1/58 (1.7%)	1
hypertension	0/114 (0%)	0	1/58 (1.7%)	1
Other (Not Including Serious) Adverse Events
	Arm I (Alvocidib, Cytarabine, Mitoxantrone Hydrochloride)		Arm II (Cytarabine, Daunorubicin Hydrochloride)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	32/114 (28.1%)		21/58 (36.2%)
Blood and lymphatic system disorders
Febril eNeutropenia	5/114 (4.4%)	5	7/58 (12.1%)	7
Cardiac disorders
Mypocardial Infarction	0/114 (0%)	0	1/58 (1.7%)	1
Sinus Tachycardia	1/114 (0.9%)	1	0/58 (0%)	0
Gastrointestinal disorders
mucositis	1/114 (0.9%)	1	3/58 (5.2%)	3
Nausea	2/114 (1.8%)	2	0/58 (0%)	0
Vomiting	2/114 (1.8%)	2	0/58 (0%)	0
Diarrhea	4/114 (3.5%)	4	0/58 (0%)	0
General disorders
Fatigue	2/114 (1.8%)	2	0/58 (0%)	0
Multi-organ failure	2/114 (1.8%)	2	0/58 (0%)	0
Edema	2/114 (1.8%)	2	0/58 (0%)	0
Immune system disorders
Cytokine release syndrome	1/114 (0.9%)	1	0/58 (0%)	0
Infections and infestations
Sepsis	4/114 (3.5%)	4	1/58 (1.7%)	1
Catheter Related Infection	0/114 (0%)	0	1/58 (1.7%)	1
Bacteremia	2/114 (1.8%)	2	0/58 (0%)	0
Pneumonia	0/114 (0%)	0	1/58 (1.7%)	1
Infectious Enterocolitis	2/114 (1.8%)	2	0/58 (0%)	0
Investigations
Hypokalemia	1/114 (0.9%)	1	0/58 (0%)	0
Hypophosphatemia	0/114 (0%)	0	1/58 (1.7%)	1
Aspartate aminotransferase increased	3/114 (2.6%)	3	1/58 (1.7%)	1
Alanine aminotransferase increased	4/114 (3.5%)	4	0/58 (0%)	0
Hypocalcemia	1/114 (0.9%)	1	1/58 (1.7%)	1
GGT increased	1/114 (0.9%)	1	0/58 (0%)	0
Ejection fraction decreased	0/114 (0%)	0	1/58 (1.7%)	1
Creatinine increased	1/114 (0.9%)	1	1/58 (1.7%)	1
Blood bilirubin increased	3/114 (2.6%)	3	0/58 (0%)	0
INR increased	1/114 (0.9%)	1	0/58 (0%)	0
Metabolism and nutrition disorders
Tumor Lysis Syndrome	1/114 (0.9%)	1	3/58 (5.2%)	3
Hyperkalemia	1/114 (0.9%)	1	0/58 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/114 (0.9%)	1	0/58 (0%)	0
Adult respiratory distress syndrome	1/114 (0.9%)	1	0/58 (0%)	0
Hypoxia	1/114 (0.9%)	1	0/58 (0%)	0
Pulmonary Edema	1/114 (0.9%)	1	0/58 (0%)	0
Skin and subcutaneous tissue disorders
Pruritis	0/114 (0%)	0	1/58 (1.7%)	1
Rash maculo-papular	1/114 (0.9%)	1	2/58 (3.4%)	2
Vascular disorders
Hypotension	1/114 (0.9%)	1	1/58 (1.7%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.