Comparing Three Different Combination Chemotherapy Regimens in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00634244
• Collaborator: (none)
• Enrollment: 92
• Locations: 20
• Arms: 3
• Duration (Months): 72
• Patients Per Site: 4.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This randomized phase II trial is comparing three different combination chemotherapy regimens to see how well they work in treating patients with relapsed or refractory acute myeloid leukemia. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells. It is not yet known which combination chemotherapy regimen is more effective in treating patients with relapsed or refractory acute myeloid leukemia.

Condition or Disease	Intervention/Treatment	Phase
Adult Acute Megakaryoblastic Leukemia (M7); 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 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); Recurrent Adult Acute Myeloid Leukemia	Drug: alvocidib; Drug: mitoxantrone hydrochloride; Drug: carboplatin; Drug: cytarabine; Drug: sirolimus; Drug: etoposide; Drug: topotecan hydrochloride	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To determine the complete remission (CR) + cytogenic complete remission (CRc) + morphologic complete remission with incomplete blood count recovery (CRi) rate of carboplatin and topotecan; flavopiridol, mitoxantrone and cytosine arabinoside and sirolimus, mitoxantrone, etoposide and cytosine arabinoside in adult patients with refractory or relapsed acute myeloid leukemia (AML).

NOTE: Since the CRc patients are required to be either CR or CRi, we only report the rate of CR+CRi in the results section.

1. To determine the rate of treatment failure of these regimens. III. To determine the incidence and severity of toxicities of these regimens. IV. To analyze the predictive value of blast cell properties that have been suggested to determine response. (Correlative laboratory studies) V. To determine whether pretreatment levels of B-cell chronic lymphocytic leukemia (CLL)/lymphoma 2 (Bcl-2) or, alternatively, whether a therapy-induced change in topoisomerase I levels correlates with response to this regimen. (Correlative laboratory studies) VI. To assess the impact of clonal evolution by comparing cytogenetic abnormalities at the time of relapse with those at initial diagnosis and correlating these abnormalities and changes with response to the treatment regimens in this protocol. (Cytogenetic and fluorescent in situ hybridization [FISH] studies) VII. Panel FISH studies for common AML rearrangements will be performed on relapse AML specimens to determine the presence of these recurrent AML abnormalities and to evaluate for subtle additional abnormalities consistent with clonal evolution in these relapse specimens. (Cytogenetic and FISH studies)

OUTLINE: Patients are randomized to 1 of 3 treatment arms.

INDUCTION THERAPY:

ARM A: Patients receive carboplatin and topotecan hydrochloride intravenously (IV) continuously over 24 hours on days 1-5.

ARM B: Patients receive alvocidib IV over 4.5 hours once daily (QD) on days 1-3, cytarabine IV continuously over 72 hours on days 6-8, and mitoxantrone hydrochloride IV over 1-2 hours on day 9.

ARM C: Patients receive sirolimus orally (PO) QD on days 2-9, mitoxantrone hydrochloride IV over 15 minutes QD, etoposide IV over 1 hour QD, and cytarabine IV over 3 hours QD on days 4-8 or 5-9. (Closed to accrual)

After completion of induction therapy, patients in all arms undergo bone marrow aspirate and biopsy. Patients with persistent leukemia (i.e., leukemic blasts >= 10%) are removed from study and are offered alternative therapy at the discretion of the investigator. Patients who achieve CR proceed to consolidation therapy or receive alternative therapy at the discretion of the investigator.

CONSOLIDATION THERAPY: Beginning within 2-6 weeks after documentation of CR, patients may receive up to 2 additional courses of the same treatment they received during induction therapy. Courses repeat every 4-10 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed periodically for up to 3 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 92 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Randomized Trial of Carboplatin and Topotecan; Flavopiridol, Mitoxantrone and Cytosine Arabinoside; and Sirolimus, Mitoxantrone, Etoposide and Cytosine Arabinoside for the Treatment of Adults With Primary Refractory or Initial Relapse of Acute Myelogenous Leukemia (AML)
• Study Start Date: Oct 1, 2008
• Actual Primary Completion Date: Sep 1, 2014
• Actual Study Completion Date: Oct 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm A (carboplatin and topotecan hydrochloride) Patients receive carboplatin and topotecan hydrochloride IV continuously over 24 hours on days 1-5.	Drug: carboplatin; Given IV; Other Names: Carboplat CBDCA JM-8 Paraplat Paraplatin ; Drug: topotecan hydrochloride; Given IV; Other Names: hycamptamine Hycamtin SKF S-104864-A TOPO
Experimental: Arm B (alvocidib, mitoxantrone, cytarabine) Patients receive alvocidib IV over 4.5 hours QD on days 1-3, cytarabine IV continuously over 72 hours on days 6-8, and mitoxantrone hydrochloride IV over 1-2 hours on day 9.	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
Experimental: Arm C (sirolimus, mitoxantrone, etoposide, cytarabine) Patients receive sirolimus PO QD on days 2-9, mitoxantrone hydrochloride IV over 15 minutes QD, etoposide IV over 1 hour QD, and cytarabine IV over 3 hours QD on days 4-8 or 5-9. (Closed to accrual)	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 ; Drug: sirolimus; Given PO; Other Names: AY 22989 Rapamune rapamycin SLM ; Drug: etoposide; Given IV; Other Names: EPEG VP-16 VP-16-213

Outcome Measures

Primary Outcome Measures

1. The Rate of Complete Remission (CR+CRi) [Assessed every 3 months for the first 2 years and then every 6 months until relapse or death up to 3 years from registration.]

   CR requires: 1. peripheral blood counts: neutrophil count ≥ 1.0 x 10^9/L, platelet count ≥ 100 x 10^9/L, reduced hemoglobin concentration or hematocrit has no bearing on remission status, and leukemic blasts must not be present in the peripheral blood. 2. bone marrow aspirate and biopsy: maturation of all cell lines must be present, ≤ 5% blasts, auer rods must not be detectable. 3. extramedullary leukemia, such as central nervous system (CNS) or soft tissue involvement, must not be present. CRi requires that all criteria for complete remission be satisfied except patients can have residual neutropenia (<1 x 10^9/L) or thrombocytopenia (<100 x 10^9/L).

Secondary Outcome Measures

1. The Rate of Treatment Failure [Assessed every 3 months for the first 2 years and then every 6 months until relapse or death up to 3 years from registration.]

   The definition of treatment failure will include: ≥ 5% leukemic blasts at the time of pre-consolidation marrow Death during/following induction chemotherapy (pre-consolidation) Persisting marrow hypoplasia and pancytopenia for ≥ 2 months after chemotherapy CNS or extramedullary disease at the time of pre-consolidation Leukemia persistence after completion of induction treatment. Leukemia persistence is defined as greater than 10% residual blasts on marrow biopsy done 5-7 days after completion of induction chemotherapy

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria

Induction Therapy:

• Patients must have morphologic proof (from bone marrow aspirate, smears or touch preps of marrow biopsy) of acute myelogenous leukemia (AML) with >= 10% blasts within two weeks prior to induction randomization

• NOTE: Patients must be registered to E3903 (Ancillary Laboratory Protocol for Collecting Diagnostic Material on Patients Considered for Eastern Cooperative Oncology Group [ECOG]-American College of Radiology Imaging Network [ACRIN] Treatment Trials for Leukemia or Related Hematologic Disorders) and must undergo eligibility testing for the study by multiparameter flow cytometry

• All immunodiagnoses are eligible for E1906, except acute promyelocytic leukemia (APL) (proven by the presence of promyelocytic leukemia (PML)/retinoic acid receptor (RAR) alpha); cases of APL can become eligible if the patient is ineligible for an ECOG-ACRIN APL trial or if all-trans retinoic acid or arsenic trioxide is not planned as part of the treatment regimen

• Patients must qualify for one of the following:

• Relapse =< 6 months after first CR, dated from documentation of CR to documentation of relapse

• Relapse between 6-12 months after first CR

• Refractory to conventional initial induction chemotherapy (=< 2 courses) or to first reinduction (=< 1 course)

• Normal cardiac ejection fraction by pretreatment multi gated acquisition scan (MUGA) or echocardiogram within 4 weeks prior to randomization (resting ejection fraction >= 50% or >= 5% increase with exercise), shortening fraction by echocardiogram >= 24%, or to within the normal range of values for the institution

• Prior treatment to doses of any of the following:

• < 300 mg/m^2 of doxorubicin

• < 300 mg/m^2 of daunorubicin

• < 100 mg/m^2 of idarubicin

• < 100 mg/m^2 of mitoxantrone

• Serum creatinine =< 2.0 mg/dL

• Serum direct bilirubin < 2.0 mg/dL

• Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) < 4 x upper limit of normal

• The above stipulation for normal hepatic function does not apply if liver dysfunction is due to leukemia infiltration

• Prior to study entry, patients must have recovered from toxicities of prior chemotherapy and radiotherapy; for patients refractory to induction chemotherapy (patient subgroup outlined above), marrow documentation of residual leukemia post chemotherapy and qualification for remaining eligibility criteria are needed prior to study entry (this does not require >= 30% marrow blasts to be evident but a minimum of 10% blasts must be present in the marrow)

• NOTE: Hydroxyurea is permitted within 4 weeks of study entry

• ECOG performance status 0, 1 or 2

• Patients with a history of central nervous system (CNS) leukemia are eligible if there is documentation of no current CNS involvement on cerebrospinal fluid (CSF) examination, (i.e., negative CSF by lumbar puncture)

Consolidation therapy:

• Patients must have an ECOG performance status 0, 1 or 2

• Patients must have documented CR

• Patients must have an absence of infection or have infection controlled by antibiotics; patients who are septic will be excluded

• Patients must have a serum creatinine clearance > 50 cc/minute

• Patients must have a serum direct bilirubin < 2.0 mg/dl and alkaline phosphatase and SGOT (AST) < 4 x upper limits of normal

• Patients must have a normal cardiac ejection fraction by MUGA or echocardiogram prior to consolidation (resting ejection fraction >= 50% or >= 5% increase with exercise), shortening fraction by echocardiogram >= 24%, or to within normal range of values for the institution prior to the first and second cycle of consolidation for arms B and C

Exclusion Criteria

Induction therapy:

• Patients who have relapsed > 1 year after achieving first CR or are in >= second relapse

• Patients who have had a prior allogeneic OR autologous stem cell transplant

• History of recent myocardial infarction (within three months), uncontrolled congestive heart failure, or uncontrolled cardiac arrhythmia

• Prior treatment with carboplatin, topotecan, flavopiridol, or sirolimus

• Pregnant or breast feeding. Women of childbearing potential and sexually active males should use an accepted and effective method of contraception

• Intercurrent organ damage or medical problems that would prohibit therapy; no active or unresolved infection

• Current evidence of invasive fungal infection; such evidence includes positive blood or deep tissue cultures or stains

• Have another (i.e., prior) tumor which is currently active and likely to interfere with the patient's treatment for AML or which is likely to compromise the patient's morbidity or mortality substantially

Consolidation therapy:

• Intercurrent organ damage or medical problems that will jeopardize the outcome of therapy

• For arms B and C, patients have exceeded the following anthracycline doses or their equivalents:

• < 300 mg/m^2 of doxorubicin

• < 300 mg/m^2 of daunorubicin

• < 100 mg/m^2 of idarubicin

• < 100 mg/m^2 of mitoxantrone

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294
2	Mayo Clinic in Arizona	Scottsdale	Arizona	United States	85259
3	Mayo Clinic in Florida	Jacksonville	Florida	United States	32224-9980
4	Northwestern University	Chicago	Illinois	United States	60611
5	Siouxland Hematology Oncology Associates	Sioux City	Iowa	United States	51101
6	Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center	Baltimore	Maryland	United States	21287
7	Tufts Medical Center	Boston	Massachusetts	United States	02111
8	Mayo Clinic	Rochester	Minnesota	United States	55905
9	The Jewish Hospital	Cincinnati	Ohio	United States	45236
10	Geisinger Medical Center	Danville	Pennsylvania	United States	17822-2001
11	Geisinger Medical Center-Cancer Center Hazleton	Hazleton	Pennsylvania	United States	18201
12	Penn State Milton S Hershey Medical Center	Hershey	Pennsylvania	United States	17033-0850
13	Lewistown Hospital	Lewistown	Pennsylvania	United States	17044
14	Geisinger Medical Group	State College	Pennsylvania	United States	16801
15	Mount Nittany Medical Center	State College	Pennsylvania	United States	16803
16	Geisinger Wyoming Valley	Wilkes-Barre	Pennsylvania	United States	18711
17	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee	United States	37232
18	University of Wisconsin Hospital and Clinics	Madison	Wisconsin	United States	53792
19	Froedtert and the Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
20	Rambam Medical Center	Haifa		Israel	31096

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Mark Litzow, ECOG-ACRIN Cancer Research Group

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00634244
• Other Study ID Numbers: NCI-2009-00520; NCI-2009-00520; E1906; U10CA021115
• First Posted: Mar 12, 2008
• Last Update Posted: Jul 7, 2015
• Last Verified: Apr 1, 2015

• Keywords provided by National Cancer Institute (NCI): Acute Myelogenous Leukemia (AML), Carboplatin, Topotecan, Flavopiridol, Mitoxantrone, Cytosine Arabinoside, Sirolimus, Etoposide
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukemia, Monocytic, Acute; Leukemia, Myelomonocytic, Acute; Leukemia, Megakaryoblastic, Acute; Leukemia, Erythroblastic, Acute; Cytarabine; Sirolimus; Carboplatin; Etoposide; Etoposide phosphate; Topotecan; Mitoxantrone; Alvocidib

Study Results

Participant Flow

Recruitment Details	This study was activated on October 16, 2008 and closed on August 2, 2013 with a total of 92 patients accrued. Duration the response evaluation after meeting the first stage accrual goal, Arm C did not meet the criteria to continue onto the second stage and was closed to accrual at that time.

Arm/Group Title	Arm A (Carboplatin and Topotecan Hydrochloride)	Arm B (Alvocidib, Mitoxantrone Hydrochloride, Cytarabine)	Arm C (Mitoxantrone Hydrochloride, Cytarabine, Sirolimus)
Arm/Group Description	Patients receive carboplatin and topotecan hydrochloride IV continuously over 24 hours on days 1-5. carboplatin: Given IV topotecan hydrochloride: Given IV	Patients receive alvocidib IV over 4.5 hours qd on days 1-3, cytarabine IV continuously over 72 hours on days 6-8, and mitoxantrone hydrochloride IV over 1-2 hours on day 9. alvocidib: Given IV mitoxantrone hydrochloride: Given IV cytarabine: Given IV	Patients receive sirolimus PO qd on days 2-9, mitoxantrone hydrochloride IV over 15 minutes qd, etoposide IV over 1 hour qd, and cytarabine IV over 3 hours qd on days 4-8 or 5-9. (Closed to accrual) mitoxantrone hydrochloride: Given IV cytarabine: Given IV sirolimus: Given PO etoposide: Given IV
Period Title: Overall Study
STARTED	35	37	20
Eligible and Treated	35	36	20
COMPLETED	34	24	20
NOT COMPLETED	1	13	0

Baseline Characteristics

Arm/Group Title	Arm A (Carboplatin+Topotecan Hydrochloride)	Arm B (Alvocidib+Cytarabine+Mitoxantrone)	Arm C (Sirolimus+Mitoxantrone+Etoposide+Cytarabine)	Total
Arm/Group Description	Patients receive carboplatin and topotecan hydrochloride IV continuously over 24 hours on days 1-5.	Patients receive alvocidib IV over 4.5 hours qd on days 1-3, cytarabine IV continuously over 72 hours on days 6-8, and mitoxantrone hydrochloride IV over 1-2 hours on day 9.	Patients receive sirolimus PO qd on days 2-9, mitoxantrone hydrochloride IV over 15 minutes qd, etoposide IV over 1 hour qd, and cytarabine IV over 3 hours qd on days 4-8 or 5-9. (Closed to accrual)	Total of all reporting groups
Overall Participants	35	36	20	91
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	55	62	52	57
Sex: Female, Male (Count of Participants)
Female	14 40%	14 38.9%	9 45%	37 40.7%
Male	21 60%	22 61.1%	11 55%	54 59.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	1 2.9%	1 2.8%	2 10%	4 4.4%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	1 2.9%	4 11.1%	2 10%	7 7.7%
White	33 94.3%	30 83.3%	14 70%	77 84.6%
More than one race	0 0%	0 0%	1 5%	1 1.1%
Unknown or Not Reported	0 0%	1 2.8%	1 5%	2 2.2%
Disease status (participants) [Number]
< 6 months after 1st CR	9 25.7%	11 30.6%	6 30%	26 28.6%
6-12 mos after 1st CR	8 22.9%	8 22.2%	3 15%	19 20.9%
Refractory	18 51.4%	17 47.2%	10 50%	45 49.5%
Unknown/Missing	0 0%	0 0%	1 5%	1 1.1%

Outcome Measures

1. Primary Outcome

Title	The Rate of Complete Remission (CR+CRi)
Description	CR requires: 1. peripheral blood counts: neutrophil count ≥ 1.0 x 10^9/L, platelet count ≥ 100 x 10^9/L, reduced hemoglobin concentration or hematocrit has no bearing on remission status, and leukemic blasts must not be present in the peripheral blood. 2. bone marrow aspirate and biopsy: maturation of all cell lines must be present, ≤ 5% blasts, auer rods must not be detectable. 3. extramedullary leukemia, such as central nervous system (CNS) or soft tissue involvement, must not be present. CRi requires that all criteria for complete remission be satisfied except patients can have residual neutropenia (<1 x 10^9/L) or thrombocytopenia (<100 x 10^9/L).
Time Frame	Assessed every 3 months for the first 2 years and then every 6 months until relapse or death up to 3 years from registration.

Outcome Measure Data

Analysis Population Description

Eligible and treated

Arm/Group Title	Arm A (Carboplatin+Topotecan Hydrochloride)	Arm B (Alvocidib+Cytarabine+Mitoxantrone)	Arm C (Sirolimus+Mitoxantrone+Etoposide+Cytarabine)
Arm/Group Description	Patients receive carboplatin and topotecan hydrochloride IV continuously over 24 hours on days 1-5.	Patients receive alvocidib IV over 4.5 hours qd on days 1-3, cytarabine IV continuously over 72 hours on days 6-8, and mitoxantrone hydrochloride IV over 1-2 hours on day 9.	Patients receive sirolimus PO qd on days 2-9, mitoxantrone hydrochloride IV over 15 minutes qd, etoposide IV over 1 hour qd, and cytarabine IV over 3 hours qd on days 4-8 or 5-9. (Closed to accrual)
Measure Participants	35	36	20
Number (90% Confidence Interval) [proportion of participants]	0.143 0.4%	0.278 0.8%	0.15 0.8%

2. Secondary Outcome

Title	The Rate of Treatment Failure
Description	The definition of treatment failure will include: ≥ 5% leukemic blasts at the time of pre-consolidation marrow Death during/following induction chemotherapy (pre-consolidation) Persisting marrow hypoplasia and pancytopenia for ≥ 2 months after chemotherapy CNS or extramedullary disease at the time of pre-consolidation Leukemia persistence after completion of induction treatment. Leukemia persistence is defined as greater than 10% residual blasts on marrow biopsy done 5-7 days after completion of induction chemotherapy
Time Frame	Assessed every 3 months for the first 2 years and then every 6 months until relapse or death up to 3 years from registration.

Outcome Measure Data

Analysis Population Description

Eligible and treated

Arm/Group Title	Arm A (Carboplatin+Topotecan Hydrochloride)	Arm B (Alvocidib+Cytarabine+Mitoxantrone)	Arm C (Sirolimus+Mitoxantrone+Etoposide+Cytarabine)
Arm/Group Description	Patients receive carboplatin and topotecan hydrochloride IV continuously over 24 hours on days 1-5.	Patients receive alvocidib IV over 4.5 hours qd on days 1-3, cytarabine IV continuously over 72 hours on days 6-8, and mitoxantrone hydrochloride IV over 1-2 hours on day 9.	Patients receive sirolimus PO qd on days 2-9, mitoxantrone hydrochloride IV over 15 minutes qd, etoposide IV over 1 hour qd, and cytarabine IV over 3 hours qd on days 4-8 or 5-9. (Closed to accrual)
Measure Participants	35	36	20
Number (90% Confidence Interval) [proportion of participants]	0.86 2.5%	0.72 2%	0.84 4.2%

Adverse Events

Time Frame	Assessed every while on treatment and for 30 days after the end of treatment
Arm/Group Title	Arm A (Carboplatin+Topotecan Hydrochloride)		Arm B (Alvocidib+Cytarabine+Mitoxantrone)		Arm C (Sirolimus+Mitoxantrone+Etoposide+Cytarabine)
Arm/Group Description	Patients receive carboplatin and topotecan hydrochloride IV continuously over 24 hours on days 1-5.		Patients receive alvocidib IV over 4.5 hours qd on days 1-3, cytarabine IV continuously over 72 hours on days 6-8, and mitoxantrone hydrochloride IV over 1-2 hours on day 9.		Patients receive sirolimus PO qd on days 2-9, mitoxantrone hydrochloride IV over 15 minutes qd, etoposide IV over 1 hour qd, and cytarabine IV over 3 hours qd on days 4-8 or 5-9. (Closed to accrual)
All Cause Mortality
	Arm A (Carboplatin+Topotecan Hydrochloride)		Arm B (Alvocidib+Cytarabine+Mitoxantrone)		Arm C (Sirolimus+Mitoxantrone+Etoposide+Cytarabine)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm A (Carboplatin+Topotecan Hydrochloride)		Arm B (Alvocidib+Cytarabine+Mitoxantrone)		Arm C (Sirolimus+Mitoxantrone+Etoposide+Cytarabine)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	35/35 (100%)		36/36 (100%)		20/20 (100%)
Blood and lymphatic system disorders
Anemia	22/35 (62.9%)		27/36 (75%)		11/20 (55%)
Disseminated intravascular coagulation	0/35 (0%)		1/36 (2.8%)		0/20 (0%)
Febrile neutropenia	7/35 (20%)		8/36 (22.2%)		11/20 (55%)
Hemolysis	0/35 (0%)		0/36 (0%)		1/20 (5%)
Cardiac disorders
Atrial fibrillation	2/35 (5.7%)		1/36 (2.8%)		0/20 (0%)
Pericardial effusion	0/35 (0%)		0/36 (0%)		1/20 (5%)
Eye disorders
Blurred vision	0/35 (0%)		1/36 (2.8%)		0/20 (0%)
Cataract	1/35 (2.9%)		0/36 (0%)		0/20 (0%)
Gastrointestinal disorders
Abdominal pain	1/35 (2.9%)		2/36 (5.6%)		0/20 (0%)
Constipation	2/35 (5.7%)		0/36 (0%)		0/20 (0%)
Diarrhea	2/35 (5.7%)		8/36 (22.2%)		1/20 (5%)
Dysphagia	1/35 (2.9%)		1/36 (2.8%)		0/20 (0%)
Enterocolitis	0/35 (0%)		1/36 (2.8%)		0/20 (0%)
Mucositis oral	4/35 (11.4%)		2/36 (5.6%)		0/20 (0%)
Nausea	3/35 (8.6%)		4/36 (11.1%)		3/20 (15%)
Oral hemorrhage	0/35 (0%)		1/36 (2.8%)		0/20 (0%)
Oral pain	0/35 (0%)		1/36 (2.8%)		0/20 (0%)
Small intestinal obstruction	1/35 (2.9%)		1/36 (2.8%)		0/20 (0%)
Typhlitis	2/35 (5.7%)		1/36 (2.8%)		0/20 (0%)
Vomiting	2/35 (5.7%)		2/36 (5.6%)		3/20 (15%)
Gastrointestinal disorders - Other	1/35 (2.9%)		0/36 (0%)		0/20 (0%)
General disorders
Death NOS	0/35 (0%)		0/36 (0%)		1/20 (5%)
Fatigue	1/35 (2.9%)		5/36 (13.9%)		2/20 (10%)
Multi-organ failure	0/35 (0%)		3/36 (8.3%)		0/20 (0%)
Pain	0/35 (0%)		1/36 (2.8%)		0/20 (0%)
Immune system disorders
Cytokine release syndrome	0/35 (0%)		1/36 (2.8%)		1/20 (5%)
Infections and infestations
Catheter related infection	4/35 (11.4%)		1/36 (2.8%)		0/20 (0%)
Enterocolitis infectious	2/35 (5.7%)		1/36 (2.8%)		1/20 (5%)
Lung infection	1/35 (2.9%)		8/36 (22.2%)		0/20 (0%)
Sepsis	1/35 (2.9%)		7/36 (19.4%)		0/20 (0%)
Sinusitis	0/35 (0%)		1/36 (2.8%)		0/20 (0%)
Skin infection	1/35 (2.9%)		0/36 (0%)		0/20 (0%)
Upper respiratory infection	0/35 (0%)		1/36 (2.8%)		0/20 (0%)
Infections and infestations - Other	2/35 (5.7%)		9/36 (25%)		1/20 (5%)
Investigations
Activated PTT prolonged	0/35 (0%)		1/36 (2.8%)		0/20 (0%)
Alanine aminotransferase increased	1/35 (2.9%)		1/36 (2.8%)		0/20 (0%)
Alkaline phosphatase increased	0/35 (0%)		1/36 (2.8%)		0/20 (0%)
Aspartate aminotransferase increased	1/35 (2.9%)		2/36 (5.6%)		1/20 (5%)
Blood bilirubin increased	2/35 (5.7%)		4/36 (11.1%)		0/20 (0%)
Creatinine increased	1/35 (2.9%)		2/36 (5.6%)		0/20 (0%)
Fibrinogen decreased	0/35 (0%)		1/36 (2.8%)		0/20 (0%)
GGT increased	0/35 (0%)		0/36 (0%)		1/20 (5%)
Lymphocyte count decreased	10/35 (28.6%)		16/36 (44.4%)		7/20 (35%)
Neutrophil count decreased	34/35 (97.1%)		32/36 (88.9%)		19/20 (95%)
Platelet count decreased	35/35 (100%)		36/36 (100%)		20/20 (100%)
Weight loss	0/35 (0%)		2/36 (5.6%)		0/20 (0%)
White blood cell decreased	35/35 (100%)		36/36 (100%)		20/20 (100%)
Investigations - Other, specify	0/35 (0%)		0/36 (0%)		1/20 (5%)
Metabolism and nutrition disorders
Anorexia	1/35 (2.9%)		7/36 (19.4%)		4/20 (20%)
Hyperglycemia	1/35 (2.9%)		7/36 (19.4%)		1/20 (5%)
Hyperkalemia	0/35 (0%)		1/36 (2.8%)		0/20 (0%)
Hypermagnesemia	0/35 (0%)		1/36 (2.8%)		0/20 (0%)
Hypertriglyceridemia	0/35 (0%)		1/36 (2.8%)		0/20 (0%)
Hypoalbuminemia	0/35 (0%)		2/36 (5.6%)		0/20 (0%)
Hypocalcemia	1/35 (2.9%)		2/36 (5.6%)		0/20 (0%)
Hypokalemia	8/35 (22.9%)		9/36 (25%)		1/20 (5%)
Hyponatremia	4/35 (11.4%)		0/36 (0%)		0/20 (0%)
Hypophosphatemia	3/35 (8.6%)		9/36 (25%)		2/20 (10%)
Tumor lysis syndrome	0/35 (0%)		3/36 (8.3%)		0/20 (0%)
Metabolism and nutrition - Other	0/35 (0%)		1/36 (2.8%)		0/20 (0%)
Musculoskeletal and connective tissue disorders
Generalized muscle weakness	1/35 (2.9%)		1/36 (2.8%)		0/20 (0%)
Nervous system disorders
Dysphasia	0/35 (0%)		1/36 (2.8%)		0/20 (0%)
Headache	1/35 (2.9%)		0/36 (0%)		0/20 (0%)
Peripheral sensory neuropathy	0/35 (0%)		1/36 (2.8%)		0/20 (0%)
Syncope	1/35 (2.9%)		0/36 (0%)		0/20 (0%)
Nervous system disorders - Other	0/35 (0%)		1/36 (2.8%)		0/20 (0%)
Psychiatric disorders
Insomnia	1/35 (2.9%)		0/36 (0%)		0/20 (0%)
Renal and urinary disorders
Renal and urinary disorders - Other	0/35 (0%)		1/36 (2.8%)		0/20 (0%)
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome	0/35 (0%)		1/36 (2.8%)		0/20 (0%)
Atelectasis	0/35 (0%)		1/36 (2.8%)		0/20 (0%)
Bronchopulmonary hemorrhage	0/35 (0%)		1/36 (2.8%)		0/20 (0%)
Dyspnea	1/35 (2.9%)		2/36 (5.6%)		0/20 (0%)
Epistaxis	0/35 (0%)		0/36 (0%)		2/20 (10%)
Hypoxia	0/35 (0%)		3/36 (8.3%)		0/20 (0%)
Pharyngeal mucositis	0/35 (0%)		0/36 (0%)		1/20 (5%)
Pharyngolaryngeal pain	0/35 (0%)		0/36 (0%)		1/20 (5%)
Pleural effusion	0/35 (0%)		1/36 (2.8%)		0/20 (0%)
Pneumonitis	0/35 (0%)		1/36 (2.8%)		0/20 (0%)
Pulmonary edema	0/35 (0%)		1/36 (2.8%)		0/20 (0%)
Respiratory failure	0/35 (0%)		1/36 (2.8%)		0/20 (0%)
Skin and subcutaneous tissue disorders
Rash maculo-papular	1/35 (2.9%)		3/36 (8.3%)		1/20 (5%)
Vascular disorders
Hypotension	0/35 (0%)		5/36 (13.9%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	Arm A (Carboplatin+Topotecan Hydrochloride)		Arm B (Alvocidib+Cytarabine+Mitoxantrone)		Arm C (Sirolimus+Mitoxantrone+Etoposide+Cytarabine)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	35/35 (100%)		36/36 (100%)		20/20 (100%)
Blood and lymphatic system disorders
Anemia	34/35 (97.1%)		32/36 (88.9%)		20/20 (100%)
Cardiac disorders
Sinus tachycardia	0/35 (0%)		4/36 (11.1%)		2/20 (10%)
Gastrointestinal disorders
Abdominal pain	3/35 (8.6%)		3/36 (8.3%)		1/20 (5%)
Constipation	3/35 (8.6%)		6/36 (16.7%)		2/20 (10%)
Diarrhea	21/35 (60%)		23/36 (63.9%)		13/20 (65%)
Dry mouth	1/35 (2.9%)		3/36 (8.3%)		1/20 (5%)
Dyspepsia	2/35 (5.7%)		2/36 (5.6%)		1/20 (5%)
Mucositis oral	7/35 (20%)		11/36 (30.6%)		7/20 (35%)
Nausea	18/35 (51.4%)		18/36 (50%)		9/20 (45%)
Oral pain	2/35 (5.7%)		1/36 (2.8%)		0/20 (0%)
Vomiting	10/35 (28.6%)		10/36 (27.8%)		4/20 (20%)
General disorders
Chills	1/35 (2.9%)		10/36 (27.8%)		4/20 (20%)
Edema limbs	5/35 (14.3%)		8/36 (22.2%)		4/20 (20%)
Fatigue	16/35 (45.7%)		12/36 (33.3%)		9/20 (45%)
Fever	5/35 (14.3%)		2/36 (5.6%)		0/20 (0%)
Pain	0/35 (0%)		2/36 (5.6%)		1/20 (5%)
Immune system disorders
Cytokine release syndrome	0/35 (0%)		2/36 (5.6%)		0/20 (0%)
Infections and infestations
Infections and infestations - Other	0/35 (0%)		3/36 (8.3%)		0/20 (0%)
Investigations
Alanine aminotransferase increased	14/35 (40%)		12/36 (33.3%)		4/20 (20%)
Alkaline phosphatase increased	12/35 (34.3%)		14/36 (38.9%)		8/20 (40%)
Aspartate aminotransferase increased	15/35 (42.9%)		16/36 (44.4%)		5/20 (25%)
Blood bilirubin increased	2/35 (5.7%)		14/36 (38.9%)		4/20 (20%)
Creatinine increased	4/35 (11.4%)		9/36 (25%)		2/20 (10%)
ECG QT corrected interval prolonged	1/35 (2.9%)		2/36 (5.6%)		0/20 (0%)
INR increased	0/35 (0%)		2/36 (5.6%)		1/20 (5%)
Lymphocyte count decreased	3/35 (8.6%)		0/36 (0%)		0/20 (0%)
Neutrophil count decreased	18/35 (51.4%)		13/36 (36.1%)		12/20 (60%)
Platelet count decreased	26/35 (74.3%)		24/36 (66.7%)		17/20 (85%)
Weight loss	3/35 (8.6%)		3/36 (8.3%)		2/20 (10%)
White blood cell decreased	24/35 (68.6%)		18/36 (50%)		16/20 (80%)
Investigations - Other, specify	1/35 (2.9%)		2/36 (5.6%)		0/20 (0%)
Metabolism and nutrition disorders
Anorexia	12/35 (34.3%)		8/36 (22.2%)		6/20 (30%)
Hyperglycemia	10/35 (28.6%)		14/36 (38.9%)		8/20 (40%)
Hyperkalemia	2/35 (5.7%)		0/36 (0%)		0/20 (0%)
Hypernatremia	2/35 (5.7%)		3/36 (8.3%)		0/20 (0%)
Hyperuricemia	0/35 (0%)		3/36 (8.3%)		0/20 (0%)
Hypoalbuminemia	9/35 (25.7%)		11/36 (30.6%)		3/20 (15%)
Hypocalcemia	9/35 (25.7%)		10/36 (27.8%)		5/20 (25%)
Hypokalemia	4/35 (11.4%)		9/36 (25%)		5/20 (25%)
Hypomagnesemia	2/35 (5.7%)		7/36 (19.4%)		4/20 (20%)
Hyponatremia	6/35 (17.1%)		6/36 (16.7%)		2/20 (10%)
Hypophosphatemia	4/35 (11.4%)		5/36 (13.9%)		4/20 (20%)
Metabolism and nutrition - Other	4/35 (11.4%)		3/36 (8.3%)		1/20 (5%)
Musculoskeletal and connective tissue disorders
Back pain	0/35 (0%)		0/36 (0%)		2/20 (10%)
Myalgia	1/35 (2.9%)		2/36 (5.6%)		1/20 (5%)
Pain in extremity	1/35 (2.9%)		1/36 (2.8%)		2/20 (10%)
Nervous system disorders
Dizziness	0/35 (0%)		3/36 (8.3%)		1/20 (5%)
Dysgeusia	3/35 (8.6%)		4/36 (11.1%)		3/20 (15%)
Headache	5/35 (14.3%)		5/36 (13.9%)		3/20 (15%)
Peripheral sensory neuropathy	3/35 (8.6%)		1/36 (2.8%)		0/20 (0%)
Psychiatric disorders
Insomnia	3/35 (8.6%)		4/36 (11.1%)		2/20 (10%)
Renal and urinary disorders
Urinary frequency	1/35 (2.9%)		2/36 (5.6%)		0/20 (0%)
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	3/35 (8.6%)		0/36 (0%)		0/20 (0%)
Cough	0/35 (0%)		3/36 (8.3%)		2/20 (10%)
Dyspnea	1/35 (2.9%)		6/36 (16.7%)		0/20 (0%)
Epistaxis	3/35 (8.6%)		3/36 (8.3%)		0/20 (0%)
Hypoxia	0/35 (0%)		2/36 (5.6%)		0/20 (0%)
Productive cough	0/35 (0%)		2/36 (5.6%)		0/20 (0%)
Sore throat	0/35 (0%)		2/36 (5.6%)		1/20 (5%)
Skin and subcutaneous tissue disorders
Alopecia	4/35 (11.4%)		6/36 (16.7%)		2/20 (10%)
Erythema multiforme	2/35 (5.7%)		1/36 (2.8%)		0/20 (0%)
Hyperhidrosis	0/35 (0%)		3/36 (8.3%)		0/20 (0%)
Pruritus	0/35 (0%)		3/36 (8.3%)		3/20 (15%)
Rash maculo-papular	4/35 (11.4%)		9/36 (25%)		4/20 (20%)
Vascular disorders
Hematoma	1/35 (2.9%)		2/36 (5.6%)		0/20 (0%)
Hypertension	2/35 (5.7%)		0/36 (0%)		0/20 (0%)
Hypotension	9/35 (25.7%)		6/36 (16.7%)		4/20 (20%)

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.