Bortezomib and Combination Chemotherapy in Treating Younger Patients With Recurrent, Refractory, or Secondary Acute Myeloid Leukemia

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00666588
• Collaborator: (none)
• Enrollment: 52
• Locations: 82
• Arms: 4
• Duration (Months): 56
• Patients Per Site: 0.6
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This phase II trial is studying the side effects and best dose of bortezomib and to see how well it works when given together with combination chemotherapy in treating younger patients with recurrent, refractory, or secondary acute myeloid leukemia (AML). Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as idarubicin, cytarabine, and etoposide, 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) together with bortezomib may kill more cancer cells

Condition or Disease	Intervention/Treatment	Phase
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 t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myelomonocytic Leukemia (M4); Childhood Acute Basophilic Leukemia; Childhood Acute Eosinophilic Leukemia; Childhood Acute Erythroleukemia (M6); Childhood Acute Megakaryocytic Leukemia (M7); Childhood Acute Minimally Differentiated Myeloid Leukemia (M0); Childhood Acute Monoblastic Leukemia (M5a); Childhood Acute Monocytic Leukemia (M5b); Childhood Acute Myeloblastic Leukemia With Maturation (M2); Childhood Acute Myeloblastic Leukemia Without Maturation (M1); Childhood Acute Myelomonocytic Leukemia (M4); Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia	Drug: idarubicin; Drug: cytarabine; Drug: bortezomib; Drug: etoposide; Other: laboratory biomarker analysis	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To determine the toxicities and tolerability of bortezomib in combination with standard-relapse AML therapy (idarubicin/cytarabine or etoposide/high-dose cytarabine) in pediatric and young adult patients with relapsed or primary-refractory or secondary AML.

2. To estimate the complete response rate to the Arm A and Arm B regimens.

SECONDARY OBJECTIVES:

1. To determine whether bortezomib inhibits proteasome activity, NF-kB activity and induces apoptosis pathway proteins in leukemia myeloblasts. II. To determine the feasibility of measuring AML stem cells in relapsed and recovering bone marrow.

OUTLINE: This is a multicenter, dose-escalation study of bortezomib. Patients are stratified according to anthracycline*-equivalent cumulative exposure (≤ 400 mg/m² vs > 400 mg/m²). Patients are assigned to 1 of 2 groups.

GROUP I (efficacy phase, patients with ≤ 400 mg/m² anthracycline-equivalent cumulative exposure - Closed as of 08/01/10): Patients receive idarubicin IV over 15 minutes on days 1-3, low-dose cytarabine IV continuously over days 1-7, and bortezomib IV on days 1, 4, and 8.

GROUP II (dose-finding phase (closed as of 10/10) and efficacy phase, patients with > 400 mg/m² anthracycline*-equivalent cumulative exposure): Patients receive etoposide IV over 1 hour on days 1-5, high-dose cytarabine IV over 1 hour twice daily on days 1-5, and bortezomib IV on days 1, 4, and 8.

NOTE: * Anthracycline restriction no longer required for group 2 as of 10/02/10.

All patients receive intrathecal cytarabine prior to courses 1 and 2. In both arms, treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed periodically for at least 5 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 52 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Pilot Study of Bortezomib (PS-341, Velcade) Combined With Reinduction Chemotherapy in Children and Young Adults With Recurrent, Refractory or Secondary Acute Myeloid Leukemia
• Study Start Date: Apr 1, 2008
• Actual Primary Completion Date: Dec 1, 2012
• Actual Study Completion Date: Dec 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Bortezomib 1.3mg/m2-assess efficacy-low anthracycline exposure Bortezomib 1.3mg/m2 to assess efficacy in low prior anthracycline exposure. Patients receive idarubicin IV (12 mg/m2/day) over 15 minutes on days 1-3, low-dose cytarabine IV (100 mg/m2/day) continuously over days 1-7, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (closed as of 08/01/10). Dosage modification based on age < 3 years old.	Drug: idarubicin; Given IV; Other Names: 4-demethoxydaunorubicin 4-DMDR DMDR IDA ; Drug: cytarabine; Given IV or IT; Other Names: ARA-C arabinofuranosylcytosine arabinosylcytosine Cytosar-U cytosine arabinoside ; Drug: bortezomib; Given IV; Other Names: LDP 341 MLN341 VELCADE ; Other: laboratory biomarker analysis; Correlative studies
Experimental: Bortezomib 1.0mg/m2-assess feasibility high anthracycline exp Bortezomib 1.0 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.0 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity.	Drug: cytarabine; Given IV or IT; Other Names: ARA-C arabinofuranosylcytosine arabinosylcytosine Cytosar-U cytosine arabinoside ; Drug: bortezomib; Given IV; Other Names: LDP 341 MLN341 VELCADE ; Drug: etoposide; Given IV; Other Names: EPEG VP-16 VP-16-213 ; Other: laboratory biomarker analysis; Correlative studies
Experimental: Bortezomib 1.3 mg/m2-assess feasibility high anthracycline exp Bortezomib 1.3 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (dose-finding phase closed as of 10/10).	Drug: cytarabine; Given IV or IT; Other Names: ARA-C arabinofuranosylcytosine arabinosylcytosine Cytosar-U cytosine arabinoside ; Drug: bortezomib; Given IV; Other Names: LDP 341 MLN341 VELCADE ; Drug: etoposide; Given IV; Other Names: EPEG VP-16 VP-16-213 ; Other: laboratory biomarker analysis; Correlative studies
Experimental: Bortezomib 1.3 mg/m2-assess efficacy high anthracycline exp Bortezomib 1.3 mg/m2 to assess efficacy in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity	Drug: cytarabine; Given IV or IT; Other Names: ARA-C arabinofuranosylcytosine arabinosylcytosine Cytosar-U cytosine arabinoside ; Drug: bortezomib; Given IV; Other Names: LDP 341 MLN341 VELCADE ; Drug: etoposide; Given IV; Other Names: EPEG VP-16 VP-16-213 ; Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Dose Limiting Toxicity [During Course 1]

   Number of participants with dose limiting toxicity.

2. Overall Response (Complete Remission [CR] and CR With Partial Recovery [CRp]) During Course 1 [After course 1]

   Overall response (complete remission [CR] and CR with partial recovery [CRp]) during course 1.

Secondary Outcome Measures

1. NF-kB Activity by Enzyme-linked Immunosorbent Assay (ELISA) [At baseline, prior to and up to 24 hours after bortezomib treatment]

   NF-kB activity will be measured as a continuous variable (ng NF-kB/Mg protein). Differences in NF-κB activity between time points will be assessed using summary statistics such as mean, standard deviation, and range. We may perform exploratory analyses to determine if single time point measurements, or the difference between time points, correlate with treatment response.

2. Proteasome Inhibition Activity [At baseline]

   Mean and standard deviation of β1 and β5- Results are ratios (proteasome subunit/β-actin based on loading of 15 µg total protein, normalized to CEM).

3. Protein Expression Assessed by Western Blot [At baseline, prior to and up to 24 hours after bortezomib treatment]

   Relative expression of apoptotic and cell cycle proteins will be characterized using descriptive statistics. If differences are noted between pre and post-treatment protein expression, pairwise comparisons will be made using paired t-test or an equivalent nonparametric test if the data are non-normally distributed. The normality assumption will be assessed on the log-transformed data prior to paired t-test evaluation.

4. Feasibility of Stem Cell Quantitation: Percentage of Leukemia Initiation Cells (LIC) Depletion [At baseline and after completion of course 1]

   Descriptive statistics to assess mean +/- standard deviation for the percentage leukemia initiation cells (LIC) depletion.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Year to 21 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of acute myeloid leukemia (AML) according to WHO classification

• At least 5% blasts in the bone marrow

• With or without extramedullary disease

• To be eligible for the dose-finding phase (closed as of 10/10) :

• Relapsed patients must meet the following criteria:

• Must have had a prior diagnosis of AML, but may NOT have inv(16) or t(8;21) cytogenetics

• May be in first or any subsequent relapse

• If in first relapse, remission duration must be less than one year

• Refractory patients must meet the following criteria:

• Must have had a prior diagnosis of AML

• May have received one or more attempt at remission induction

• Patients with treatment-related AML may be previously treated or untreated for secondary AML

• To be eligible for the efficacy phase:

• Relapsed patients must meet the following criteria:

• Must have had a prior diagnosis of AML, with no restriction on prior cytogenetics

• Must be in first relapse

• Must not have received prior reinduction therapy

• Refractory patients must meet the following criteria:

• Must have had a prior diagnosis of AML

• Must not have received more than one attempt at remission induction (which may consist of up to two therapy courses)

• Patients with treatment-related AML must be previously untreated for secondary AML

• No juvenile myelomonocytic leukemia or acute promyelocytic leukemia (APL; FAB M3)

• Patients with the following CNS status are eligible only in the absence of neurologic symptoms suggestive of CNS leukemia, such as cranial nerve palsy:

• CNS 1, defined as absence of blasts in cerebral spinal fluid (CSF) on cytospin preparation, regardless of the number of WBCs

• CNS 2, defined as presence of < 5/μL WBCs in CSF and cytospin positive for blasts, or > 5/uL WBCs but negative by Steinherz/Bleyer algorithm:

• CNS 2a: < 10/μL RBCs; < 5/μL WBCs and cytospin positive for blasts

• CNS 2b: ≥ 10/μL RBCs; < 5/μL WBCs and cytospin positive for blasts

• CNS 2c: ≥ 10/μL RBCs; ≥ 5/μL WBCs and cytospin positive for blasts but negative by Steinherz/Bleyer algorithm

• Patients with CNS3 disease (presence of ≥ 5/μL WBCs in CSF and cytospin positive for blasts [in the absence of a traumatic lumbar puncture] and/or clinical signs of CNS leukemia) are not eligible

• CNS toxicity ≤ grade 2

• Lansky (patients ≤ 16 years of age) or Karnofsky (patients > 16 years of age) performance status (PS) 50-100%

• ECOG PS 0-2

• No Down syndrome

• No Fanconi anemia, Kostmann syndrome, Shwachman syndrome, or any other known bone marrow failure syndrome

• No evidence of active graft-vs-host disease

• Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min OR serum creatinine based on age/gender as follows:

• 0.4 mg/dL for patients 1 month to < 6 months of age

• 0.5 mg/dL for patients 6 months to < 1 year of age

• 0.6 mg/dL for patients 1 to < 2 years of age

• 0.8 mg/dL for patients 2 to < 6 years of age

• 1 mg/dL for patients 6 to < 10 years of age

• 1.2 mg/dL for patients 10 to < 13 years of age

• 1.5 mg/dL (male) or 1.4 mg/dL (female) for patients 13 to < 16 years of age

• 1.7 mg/dL (male) or 1.4 mg/dL (female) for patients ≥ 16 years of age

• Total bilirubin ≤ 1.5 times upper limit of normal (ULN) for age

• ALT < 3.0 times ULN for age (unless elevation due to leukemia involvement)

• Shortening fraction ≥ 27% by ECHO OR LVEF ≥ 50% by gated radionuclide

• Normal respiratory rate and pulse oximetry > 94% on room air

• FEV_1 ≥ 80% of predicted

• FVC and DLCO > 50% (corrected for hemoglobin)

• Patients who are unable to perform pulmonary function tests (PFTs) (e.g., because of young age) will be excluded provided they have a medical history of significant prior pulmonary events or chronic pulmonary disease (e.g., pneumonia requiring mechanical ventilation support, pulmonary GVHD, pneumonectomy, or pulmonary toxin exposure)

• Children with histories of resolved bronchiolitis, resolved viral pneumonias and well-controlled asthma are eligible, even if they are unable to perform PFTs

• Patients with seizure disorder may be enrolled if on a non-enzyme-inducing anticonvulsant and if seizures are well-controlled

• No uncontrolled infection

• No known allergy to idarubicin, cytarabine, etoposide, boron, mannitol or bortezomib

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• Concurrent radiotherapy allowed for patients who present with a chloroma that is producing or threatens to produce an irreversible neurologic deficit

• Recovered from all prior chemotherapy, immunotherapy, or radiotherapy

• More than 2 weeks since prior cytotoxic chemotherapy (4 weeks for nitrosoureas), except for hydroxyurea, which is allowed up to 24 hours prior to first dose of study drug, and intrathecal chemotherapy, which is allowed immediately up to administration of study drug

• Prior steroid allowed as clinically indicated for patients with asthma

• Hydrocortisone and methylprednisolone allowed as premedication in patients with a history of severe allergic reactions

• At least 7 days since prior biologic agents, such as steroids, retinoids, or donor lymphocyte infusion without conditioning

• At least 2 weeks since prior local palliative radiotherapy (small port)

• At least 8 weeks since prior craniospinal radiotherapy or ≥ 50% radiation of pelvis

• At least 6 weeks since prior other bone marrow radiation

• At least 1 day since prior green tea containing products, any products containing vitamin C, flavanoids or other antioxidants (e.g., vitamins, herbal supplements), and foods with high vitamin C content

• No prior radiotherapy to > 25% of lung volume

• No prior total-body irradiation as part of a hematopoietic stem cell conditioning regimen

• At least 2 months since prior stem cell transplantation

• No concurrent graft-vs-host disease prophylactic medication

• No prior bortezomib or other proteasome inhibitors

• No other concurrent investigational drugs

• More than 4 days since prior growth factors that support platelet or white cell number or function

• No concurrent enzyme-inducing anticonvulsant medications known to be potent inducers of the cytochrome P450 system, including phenytoin, carbamazepine, and phenobarbital

• Concurrent benzodiazepines and gabapentin allowed

• No concurrent grapefruit juice with bortezomib

• No other concurrent cancer chemotherapy or immunomodulating agents

• No concurrent corticosteroids as anti-emetic therapy

• Concurrent corticosteroids therapy allowed as treatment or prophylaxis for anaphylactic reactions, symptoms of cytarabine syndrome, and as treatment for presumptive bortezomib-induced pulmonary toxicity.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35293
2	Phoenix Childrens Hospital	Phoenix	Arizona	United States	85016
3	University of Arkansas for Medical Sciences	Little Rock	Arkansas	United States	72205
4	Southern California Permanente Medical Group	Downey	California	United States	90242
5	Miller Children's Hospital	Long Beach	California	United States	90806
6	Children's Hospital and Research Center at Oakland	Oakland	California	United States	94609-1809
7	Childrens Hospital of Orange County	Orange	California	United States	92868-3874
8	Packard Children's Hospital Stanford University	Palo Alto	California	United States	94304
9	University of California San Francisco Medical Center	San Francisco	California	United States	94143
10	Connecticut Children's Medical Center	Hartford	Connecticut	United States	06106
11	Alfred I duPont Hospital for Children	Wilmington	Delaware	United States	19803
12	Children's National Medical Center	Washington	District of Columbia	United States	20010
13	Broward General Medical Center	Fort Lauderdale	Florida	United States	33316
14	Lee Memorial Health System	Fort Myers	Florida	United States	33901
15	Nemours Children's Clinic - Jacksonville	Jacksonville	Florida	United States	32207-8426
16	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida	United States	33136
17	Nemours Childrens Clinic - Orlando	Orlando	Florida	United States	32806
18	Nemours Children's Clinic - Pensacola	Pensacola	Florida	United States	32504
19	All Children's Hospital	Saint Petersburg	Florida	United States	33701
20	Saint Joseph Children's Hospital of Tampa	Tampa	Florida	United States	33607
21	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia	United States	30322
22	Memorial Health University Medical Center	Savannah	Georgia	United States	31403
23	University of Hawaii	Honolulu	Hawaii	United States	96813
24	Childrens Memorial Hospital	Chicago	Illinois	United States	60614
25	Southern Illinois University	Springfield	Illinois	United States	62702
26	Riley Hospital for Children	Indianapolis	Indiana	United States	46202
27	University of Kentucky	Lexington	Kentucky	United States	40536
28	Tulane University Health Sciences Center	New Orleans	Louisiana	United States	70112
29	Sinai Hospital of Baltimore	Baltimore	Maryland	United States	21215
30	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115
31	C S Mott Children's Hospital	Ann Arbor	Michigan	United States	48109
32	Michigan State University - Breslin Cancer Center	East Lansing	Michigan	United States	48824-1313
33	Helen DeVos Children's Hospital at Spectrum Health	Grand Rapids	Michigan	United States	49503
34	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota	United States	55404
35	University of Minnesota Medical Center-Fairview	Minneapolis	Minnesota	United States	55455
36	Mayo Clinic	Rochester	Minnesota	United States	55905
37	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
38	The Childrens Mercy Hospital	Kansas City	Missouri	United States	64108
39	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
40	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198-7830
41	Nevada Cancer Research Foundation CCOP	Las Vegas	Nevada	United States	89106
42	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
43	UMDNJ - Robert Wood Johnson University Hospital	New Brunswick	New Jersey	United States	08903
44	Newark Beth Israel Medical Center	Newark	New Jersey	United States	07112
45	Overlook Hospital	Summit	New Jersey	United States	07902
46	University of New Mexico	Albuquerque	New Mexico	United States	87106
47	Columbia University Medical Center	New York	New York	United States	10032
48	State University of New York Upstate Medical University	Syracuse	New York	United States	13210
49	University of North Carolina	Chapel Hill	North Carolina	United States	27599
50	Carolinas Medical Center	Charlotte	North Carolina	United States	28203
51	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
52	Children's Hospital Medical Center of Akron	Akron	Ohio	United States	44308
53	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
54	Rainbow Babies and Childrens Hospital	Cleveland	Ohio	United States	44106
55	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
56	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
57	The Children's Medical Center of Dayton	Dayton	Ohio	United States	45404
58	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
59	Legacy Emanuel Hospital and Health Center	Portland	Oregon	United States	97227
60	Penn State Hershey Children's Hospital	Hershey	Pennsylvania	United States	17033
61	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
62	Childrens Hospital of Pittsburgh	Pittsburgh	Pennsylvania	United States	15224
63	Rhode Island Hospital	Providence	Rhode Island	United States	02903
64	Palmetto Health Richland	Columbia	South Carolina	United States	29203
65	Sanford University of South Dakota Medical Center	Sioux Falls	South Dakota	United States	57117-5134
66	East Tennessee Childrens Hospital	Knoxville	Tennessee	United States	37916
67	St. Jude Children's Research Hospital	Memphis	Tennessee	United States	38105
68	Driscoll Children's Hospital	Corpus Christi	Texas	United States	78411
69	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390
70	Cook Children's Medical Center	Fort Worth	Texas	United States	76104
71	Baylor College of Medicine	Houston	Texas	United States	77030
72	University of Texas Health Science Center	San Antonio	Texas	United States	78229-3900
73	Primary Children's Medical Center	Salt Lake City	Utah	United States	84113
74	Seattle Children's Hospital	Seattle	Washington	United States	98105
75	Saint Vincent Hospital	Green Bay	Wisconsin	United States	54301
76	Marshfield Clinic	Marshfield	Wisconsin	United States	54449
77	Midwest Children's Cancer Center	Milwaukee	Wisconsin	United States	53226
78	Princess Margaret Hospital for Children	Perth	Western Australia	Australia	6008
79	CancerCare Manitoba	Winnipeg	Manitoba	Canada	R3E 0V9
80	IWK Health Centre	Halifax	Nova Scotia	Canada	B3J 3G9
81	Hospital for Sick Children	Toronto	Ontario	Canada	M5G 1X8
82	Hospital Sainte-Justine	Montreal	Quebec	Canada	H3T 1C5

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Jeffrey Moscow, Children's Oncology Group

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00666588
• Other Study ID Numbers: NCI-2009-00323; U10CA098543; CDR0000594224; COG-AAML07P1; NCI-2009-00323
• First Posted: Apr 25, 2008
• Last Update Posted: May 22, 2018
• Last Verified: May 1, 2018

• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Neoplasm Metastasis; Leukemia, Myelomonocytic, Acute; Leukemia, Myelomonocytic, Chronic; Leukemia, Monocytic, Acute; Leukemia, Erythroblastic, Acute; Leukemia, Basophilic, Acute; Leukemia, Eosinophilic, Acute; Leukemia, Megakaryoblastic, Acute; Hypereosinophilic Syndrome; Recurrence; Cytarabine; Etoposide; Idarubicin; Bortezomib; Etoposide phosphate

Study Results

Participant Flow

Arm/Group Title	Bortezomib 1.3mg/m2-assess Efficacy-low Anthracycline Exposure	Bortezomib 1.0mg/m2-assess Feasibility High Anthracycline Exp	Bortezomib 1.3 mg/m2-assess Feasibility High Anthracycline Exp	Bortezomib 1.3 mg/m2-assess Efficacy High Anthracycline Exp
Arm/Group Description	Bortezomib 1.3mg/m2 to assess efficacy in low prior anthracycline exposure. Patients receive idarubicin IV (12 mg/m2/day) over 15 minutes on days 1-3, low-dose cytarabine IV (100 mg/m2/day) continuously over days 1-7, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (closed as of 08/01/10). Dosage modification based on age < 3 years old. idarubicin: Given IV cytarabine: Given IV or IT bortezomib: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.0 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.0 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity. cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.3 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (dose-finding phase closed as of 10/10). cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.3 mg/m2 to assess efficacy in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies
Period Title: Overall Study
STARTED	18	6	6	22
COMPLETED	14	6	6	20
NOT COMPLETED	4	0	0	2

Baseline Characteristics

Arm/Group Title	Bortezomib 1.3mg/m2-assess Efficacy-low Anthracycline Exposure	Bortezomib 1.0mg/m2-assess Feasibility High Anthracycline Exp	Bortezomib 1.3 mg/m2-assess Feasibility High Anthracycline Exp	Bortezomib 1.3 mg/m2-assess Efficacy High Anthracycline Exp	Total
Arm/Group Description	Bortezomib 1.3mg/m2 to assess efficacy in low prior anthracycline exposure. Patients receive idarubicin IV (12 mg/m2/day) over 15 minutes on days 1-3, low-dose cytarabine IV (100 mg/m2/day) continuously over days 1-7, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (closed as of 08/01/10). Dosage modification based on age < 3 years old. idarubicin: Given IV cytarabine: Given IV or IT bortezomib: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.0 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.0 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity. cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.3 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (dose-finding phase closed as of 10/10). cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.3 mg/m2 to assess efficacy in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies	Total of all reporting groups
Overall Participants	18	6	6	22	52
Age (days) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [days]	4121.72 (2569.95)	5637.0 (1757.39)	2812.5 (1769.83)	3365.0 (2227.99)	3984.06 (2081.29)
Age (Count of Participants)
<=18 years	15 83.3%	4 66.7%	6 100%	21 95.5%	46 88.5%
Between 18 and 65 years	3 16.7%	2 33.3%	0 0%	1 4.5%	6 11.5%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	11 61.1%	2 33.3%	4 66.7%	13 59.1%	30 57.7%
Male	7 38.9%	4 66.7%	2 33.3%	9 40.9%	22 42.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	1 5.6%	2 33.3%	1 16.7%	1 4.5%	5 9.6%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	3 16.7%	1 16.7%	1 16.7%	2 9.1%	7 13.5%
White	11 61.1%	3 50%	3 50%	18 81.8%	35 67.3%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	3 16.7%	0 0%	1 16.7%	1 4.5%	5 9.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 16.7%	0 0%	1 16.7%	3 13.6%	7 13.5%
Not Hispanic or Latino	13 72.2%	6 100%	5 83.3%	17 77.3%	41 78.8%
Unknown or Not Reported	2 11.1%	0 0%	0 0%	2 9.1%	4 7.7%
Region of Enrollment (participants) [Number]
United States	17 94.4%	5 83.3%	6 100%	20 90.9%	48 92.3%
Canada	1 5.6%	1 16.7%	0 0%	1 4.5%	3 5.8%
Australia	0 0%	0 0%	0 0%	1 4.5%	1 1.9%

Outcome Measures

1. Primary Outcome

Title	Dose Limiting Toxicity
Description	Number of participants with dose limiting toxicity.
Time Frame	During Course 1

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bortezomib 1.3mg/m2-assess Efficacy-low Anthracycline Exposure	Bortezomib 1.0mg/m2-assess Feasibility High Anthracycline Exp	Bortezomib 1.3 mg/m2-assess Feasibility High Anthracycline Exp	Bortezomib 1.3 mg/m2-assess Efficacy High Anthracycline Exp
Arm/Group Description	Bortezomib 1.3mg/m2 to assess efficacy in low prior anthracycline exposure. Patients receive idarubicin IV (12 mg/m2/day) over 15 minutes on days 1-3, low-dose cytarabine IV (100 mg/m2/day) continuously over days 1-7, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (closed as of 08/01/10). Dosage modification based on age < 3 years old. idarubicin: Given IV cytarabine: Given IV or IT bortezomib: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.0 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.0 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity. cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.3 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (dose-finding phase closed as of 10/10). cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.3 mg/m2 to assess efficacy in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies
Measure Participants	14	6	6	20
Number [participants]	0 0%	1 16.7%	0 0%	0 0%

2. Primary Outcome

Title	Overall Response (Complete Remission [CR] and CR With Partial Recovery [CRp]) During Course 1
Description	Overall response (complete remission [CR] and CR with partial recovery [CRp]) during course 1.
Time Frame	After course 1

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bortezomib 1.3mg/m2-assess Efficacy-low Anthracycline Exposure	Bortezomib 1.0mg/m2-assess Feasibility High Anthracycline Exp	Bortezomib 1.3 mg/m2-assess Feasibility High Anthracycline Exp	Bortezomib 1.3 mg/m2-assess Efficacy High Anthracycline Exp
Arm/Group Description	Bortezomib 1.3mg/m2 to assess efficacy in low prior anthracycline exposure. Patients receive idarubicin IV (12 mg/m2/day) over 15 minutes on days 1-3, low-dose cytarabine IV (100 mg/m2/day) continuously over days 1-7, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (closed as of 08/01/10). Dosage modification based on age < 3 years old. idarubicin: Given IV cytarabine: Given IV or IT bortezomib: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.0 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.0 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity. cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.3 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (dose-finding phase closed as of 10/10). cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.3 mg/m2 to assess efficacy in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies
Measure Participants	14	6	6	20
Number [participants]	4 22.2%	2 33.3%	2 33.3%	9 40.9%

3. Secondary Outcome

Title	NF-kB Activity by Enzyme-linked Immunosorbent Assay (ELISA)
Description	NF-kB activity will be measured as a continuous variable (ng NF-kB/Mg protein). Differences in NF-κB activity between time points will be assessed using summary statistics such as mean, standard deviation, and range. We may perform exploratory analyses to determine if single time point measurements, or the difference between time points, correlate with treatment response.
Time Frame	At baseline, prior to and up to 24 hours after bortezomib treatment

Outcome Measure Data

Analysis Population Description

Ineligible patients (n=4) are excluded. Patients without available data (n=36) are excluded.

Arm/Group Title	Bortezomib 1.3mg/m2-assess Efficacy-low Anthracycline Exposure	Bortezomib 1.0mg/m2-assess Feasibility High Anthracycline Exp	Bortezomib 1.3 mg/m2-assess Feasibility High Anthracycline Exp	Bortezomib 1.3 mg/m2-assess Efficacy High Anthracycline Exp
Arm/Group Description	Bortezomib 1.3mg/m2 to assess efficacy in low prior anthracycline exposure. Patients receive idarubicin IV (12 mg/m2/day) over 15 minutes on days 1-3, low-dose cytarabine IV (100 mg/m2/day) continuously over days 1-7, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (closed as of 08/01/10). Dosage modification based on age < 3 years old. idarubicin: Given IV cytarabine: Given IV or IT bortezomib: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.0 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.0 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity. cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.3 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (dose-finding phase closed as of 10/10). cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.3 mg/m2 to assess efficacy in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies
Measure Participants	5	1	1	5
Baseline	718.218 (418.149339)	655.4	974.66	408.144 (484.084297)
24 Hrs after treatment	774.1925 (410.667711)	345.46	855.96	497.31 (449.312899)

4. Secondary Outcome

Title	Proteasome Inhibition Activity
Description	Mean and standard deviation of β1 and β5- Results are ratios (proteasome subunit/β-actin based on loading of 15 µg total protein, normalized to CEM).
Time Frame	At baseline

Outcome Measure Data

Analysis Population Description

Ineligible patients (n=4) are excluded. Patients without available data (n=36) are excluded. The data summarized are only at baseline as that is the only data available.

Arm/Group Title	Bortezomib 1.3mg/m2-assess Efficacy-low Anthracycline Exposure	Bortezomib 1.0mg/m2-assess Feasibility High Anthracycline Exp	Bortezomib 1.3 mg/m2-assess Feasibility High Anthracycline Exp	Bortezomib 1.3 mg/m2-assess Efficacy High Anthracycline Exp
Arm/Group Description	Bortezomib 1.3mg/m2 to assess efficacy in low prior anthracycline exposure. Patients receive idarubicin IV (12 mg/m2/day) over 15 minutes on days 1-3, low-dose cytarabine IV (100 mg/m2/day) continuously over days 1-7, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (closed as of 08/01/10). Dosage modification based on age < 3 years old. idarubicin: Given IV cytarabine: Given IV or IT bortezomib: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.0 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.0 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity. cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.3 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (dose-finding phase closed as of 10/10). cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.3 mg/m2 to assess efficacy in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies
Measure Participants	4	1	0	7
Baseline β1	0.08115 (0.0860893)	0.7894	0.2895143 (0.2974052)
Baseline β5	0.121575 (0.0691725)	0.2576	0.3721286 (0.7140883)

5. Secondary Outcome

Title	Protein Expression Assessed by Western Blot
Description	Relative expression of apoptotic and cell cycle proteins will be characterized using descriptive statistics. If differences are noted between pre and post-treatment protein expression, pairwise comparisons will be made using paired t-test or an equivalent nonparametric test if the data are non-normally distributed. The normality assumption will be assessed on the log-transformed data prior to paired t-test evaluation.
Time Frame	At baseline, prior to and up to 24 hours after bortezomib treatment

Outcome Measure Data

Analysis Population Description

These data will never be collected because the investigators decided not to perform quantitative biologic analysis.

Arm/Group Title	Bortezomib 1.3mg/m2-assess Efficacy-low Anthracycline Exposure	Bortezomib 1.0mg/m2-assess Feasibility High Anthracycline Exp	Bortezomib 1.3 mg/m2-assess Feasibility High Anthracycline Exp	Bortezomib 1.3 mg/m2-assess Efficacy High Anthracycline Exp
Arm/Group Description	Bortezomib 1.3mg/m2 to assess efficacy in low prior anthracycline exposure. Patients receive idarubicin IV (12 mg/m2/day) over 15 minutes on days 1-3, low-dose cytarabine IV (100 mg/m2/day) continuously over days 1-7, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (closed as of 08/01/10). Dosage modification based on age < 3 years old. idarubicin: Given IV cytarabine: Given IV or IT bortezomib: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.0 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.0 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity. cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.3 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (dose-finding phase closed as of 10/10). cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.3 mg/m2 to assess efficacy in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies
Measure Participants	0	0	0	0

6. Secondary Outcome

Title	Feasibility of Stem Cell Quantitation: Percentage of Leukemia Initiation Cells (LIC) Depletion
Description	Descriptive statistics to assess mean +/- standard deviation for the percentage leukemia initiation cells (LIC) depletion.
Time Frame	At baseline and after completion of course 1

Outcome Measure Data

Analysis Population Description

Ineligible patients (n=4) are excluded. Patients without available data (n=42) are excluded.

Arm/Group Title	Bortezomib 1.3mg/m2-assess Efficacy-low Anthracycline Exposure	Bortezomib 1.0mg/m2-assess Feasibility High Anthracycline Exp	Bortezomib 1.3 mg/m2-assess Feasibility High Anthracycline Exp	Bortezomib 1.3 mg/m2-assess Efficacy High Anthracycline Exp
Arm/Group Description	Bortezomib 1.3mg/m2 to assess efficacy in low prior anthracycline exposure. Patients receive idarubicin IV (12 mg/m2/day) over 15 minutes on days 1-3, low-dose cytarabine IV (100 mg/m2/day) continuously over days 1-7, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (closed as of 08/01/10). Dosage modification based on age < 3 years old. idarubicin: Given IV cytarabine: Given IV or IT bortezomib: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.0 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.0 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity. cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.3 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (dose-finding phase closed as of 10/10). cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies	Bortezomib 1.3 mg/m2 to assess efficacy in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies
Measure Participants	3	0	1	2
Prior to Treatment	0.013667 (0.02108)	0.2	1.6385 (2.06887)
Post Treatment	0.021 (0.036373)	0.43	0.0435 (0.0615183)

Adverse Events

Adverse Event Reporting Description	The ineligible patients are not included in the adverse event reporting.
Arm/Group Title	Bortezomib 1.3mg/m2-assess Efficacy-low Anthracycline Exposure		Bortezomib 1.0mg/m2-assess Feasibility High Anthracycline Exp		Bortezomib 1.3 mg/m2-assess Feasibility High Anthracycline Exp		Bortezomib 1.3 mg/m2-assess Efficacy High Anthracycline Exp
Arm/Group Description	Bortezomib 1.3mg/m2 to assess efficacy in low prior anthracycline exposure. Patients receive idarubicin IV (12 mg/m2/day) over 15 minutes on days 1-3, low-dose cytarabine IV (100 mg/m2/day) continuously over days 1-7, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (closed as of 08/01/10). Dosage modification based on age < 3 years old. idarubicin: Given IV cytarabine: Given IV or IT bortezomib: Given IV laboratory biomarker analysis: Correlative studies		Bortezomib 1.0 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.0 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity. cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies		Bortezomib 1.3 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (dose-finding phase closed as of 10/10). cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies		Bortezomib 1.3 mg/m2 to assess efficacy in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity cytarabine: Given IV or IT bortezomib: Given IV etoposide: Given IV laboratory biomarker analysis: Correlative studies
All Cause Mortality
	Bortezomib 1.3mg/m2-assess Efficacy-low Anthracycline Exposure		Bortezomib 1.0mg/m2-assess Feasibility High Anthracycline Exp		Bortezomib 1.3 mg/m2-assess Feasibility High Anthracycline Exp		Bortezomib 1.3 mg/m2-assess Efficacy High Anthracycline Exp
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Bortezomib 1.3mg/m2-assess Efficacy-low Anthracycline Exposure		Bortezomib 1.0mg/m2-assess Feasibility High Anthracycline Exp		Bortezomib 1.3 mg/m2-assess Feasibility High Anthracycline Exp		Bortezomib 1.3 mg/m2-assess Efficacy High Anthracycline Exp
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/16 (18.8%)		3/6 (50%)		1/6 (16.7%)		5/20 (25%)
Blood and lymphatic system disorders
Disseminated intravascular coagulation	1/16 (6.3%)		0/6 (0%)		0/6 (0%)		0/20 (0%)
Cardiac disorders
Left ventricular systolic dysfunction	1/16 (6.3%)		0/6 (0%)		0/6 (0%)		0/20 (0%)
Myocarditis	1/16 (6.3%)		0/6 (0%)		0/6 (0%)		0/20 (0%)
Right ventricular dysfunction	1/16 (6.3%)		0/6 (0%)		0/6 (0%)		0/20 (0%)
Gastrointestinal disorders
Abdominal pain	0/16 (0%)		0/6 (0%)		1/6 (16.7%)		0/20 (0%)
Anal pain	0/16 (0%)		0/6 (0%)		1/6 (16.7%)		0/20 (0%)
Diarrhea	0/16 (0%)		0/6 (0%)		1/6 (16.7%)		0/20 (0%)
Mucositis oral	0/16 (0%)		1/6 (16.7%)		0/6 (0%)		0/20 (0%)
Oral pain	0/16 (0%)		0/6 (0%)		1/6 (16.7%)		0/20 (0%)
General disorders
Death NOS	0/16 (0%)		0/6 (0%)		0/6 (0%)		1/20 (5%)
Infections and infestations
Catheter related infection	0/16 (0%)		0/6 (0%)		0/6 (0%)		1/20 (5%)
Infections and infestations - Other, specify	0/16 (0%)		2/6 (33.3%)		0/6 (0%)		1/20 (5%)
Sepsis	0/16 (0%)		1/6 (16.7%)		0/6 (0%)		2/20 (10%)
Investigations
Alanine aminotransferase increased	0/16 (0%)		0/6 (0%)		1/6 (16.7%)		0/20 (0%)
Aspartate aminotransferase increased	0/16 (0%)		0/6 (0%)		1/6 (16.7%)		0/20 (0%)
Blood bilirubin increased	0/16 (0%)		1/6 (16.7%)		0/6 (0%)		0/20 (0%)
Creatinine increased	0/16 (0%)		1/6 (16.7%)		0/6 (0%)		1/20 (5%)
GGT increased	0/16 (0%)		1/6 (16.7%)		0/6 (0%)		1/20 (5%)
Metabolism and nutrition disorders
Anorexia	0/16 (0%)		0/6 (0%)		0/6 (0%)		1/20 (5%)
Hyperglycemia	0/16 (0%)		0/6 (0%)		0/6 (0%)		2/20 (10%)
Hyperkalemia	0/16 (0%)		0/6 (0%)		0/6 (0%)		1/20 (5%)
Hyperuricemia	1/16 (6.3%)		0/6 (0%)		0/6 (0%)		0/20 (0%)
Hypoalbuminemia	0/16 (0%)		0/6 (0%)		0/6 (0%)		1/20 (5%)
Hypocalcemia	0/16 (0%)		1/6 (16.7%)		0/6 (0%)		1/20 (5%)
Hypokalemia	0/16 (0%)		1/6 (16.7%)		0/6 (0%)		2/20 (10%)
Hypomagnesemia	0/16 (0%)		1/6 (16.7%)		0/6 (0%)		0/20 (0%)
Hypophosphatemia	0/16 (0%)		1/6 (16.7%)		0/6 (0%)		1/20 (5%)
Nervous system disorders
Headache	0/16 (0%)		0/6 (0%)		0/6 (0%)		1/20 (5%)
Psychiatric disorders
Psychosis	1/16 (6.3%)		0/6 (0%)		0/6 (0%)		0/20 (0%)
Renal and urinary disorders
Acute kidney injury	1/16 (6.3%)		1/6 (16.7%)		0/6 (0%)		1/20 (5%)
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome	1/16 (6.3%)		1/6 (16.7%)		0/6 (0%)		0/20 (0%)
Cough	0/16 (0%)		0/6 (0%)		0/6 (0%)		1/20 (5%)
Dyspnea	0/16 (0%)		0/6 (0%)		0/6 (0%)		1/20 (5%)
Hypoxia	1/16 (6.3%)		0/6 (0%)		1/6 (16.7%)		2/20 (10%)
Pneumonitis	1/16 (6.3%)		0/6 (0%)		1/6 (16.7%)		0/20 (0%)
Pulmonary edema	0/16 (0%)		0/6 (0%)		0/6 (0%)		1/20 (5%)
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysesthesia syndrome	0/16 (0%)		1/6 (16.7%)		0/6 (0%)		0/20 (0%)
Vascular disorders
Hypotension	1/16 (6.3%)		0/6 (0%)		0/6 (0%)		1/20 (5%)
Other (Not Including Serious) Adverse Events
	Bortezomib 1.3mg/m2-assess Efficacy-low Anthracycline Exposure		Bortezomib 1.0mg/m2-assess Feasibility High Anthracycline Exp		Bortezomib 1.3 mg/m2-assess Feasibility High Anthracycline Exp		Bortezomib 1.3 mg/m2-assess Efficacy High Anthracycline Exp
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/16 (87.5%)		5/6 (83.3%)		5/6 (83.3%)		14/20 (70%)
Blood and lymphatic system disorders
Anemia	3/16 (18.8%)		1/6 (16.7%)		0/6 (0%)		0/20 (0%)
Febrile neutropenia	6/16 (37.5%)		2/6 (33.3%)		2/6 (33.3%)		5/20 (25%)
Gastrointestinal disorders
Abdominal pain	1/16 (6.3%)		1/6 (16.7%)		0/6 (0%)		0/20 (0%)
Constipation	1/16 (6.3%)		0/6 (0%)		0/6 (0%)		0/20 (0%)
Diarrhea	0/16 (0%)		0/6 (0%)		0/6 (0%)		1/20 (5%)
Esophageal pain	0/16 (0%)		1/6 (16.7%)		0/6 (0%)		0/20 (0%)
Gastric hemorrhage	0/16 (0%)		0/6 (0%)		0/6 (0%)		1/20 (5%)
Ileus	1/16 (6.3%)		0/6 (0%)		0/6 (0%)		0/20 (0%)
Mucositis oral	1/16 (6.3%)		0/6 (0%)		1/6 (16.7%)		1/20 (5%)
Nausea	0/16 (0%)		2/6 (33.3%)		1/6 (16.7%)		2/20 (10%)
Vomiting	1/16 (6.3%)		2/6 (33.3%)		0/6 (0%)		2/20 (10%)
General disorders
Fatigue	0/16 (0%)		1/6 (16.7%)		0/6 (0%)		0/20 (0%)
Fever	0/16 (0%)		0/6 (0%)		0/6 (0%)		4/20 (20%)
Non-cardiac chest pain	0/16 (0%)		0/6 (0%)		0/6 (0%)		1/20 (5%)
Pain	0/16 (0%)		0/6 (0%)		0/6 (0%)		1/20 (5%)
Immune system disorders
Allergic reaction	0/16 (0%)		0/6 (0%)		0/6 (0%)		1/20 (5%)
Anaphylaxis	0/16 (0%)		0/6 (0%)		0/6 (0%)		1/20 (5%)
Infections and infestations
Anorectal infection	1/16 (6.3%)		0/6 (0%)		0/6 (0%)		0/20 (0%)
Catheter related infection	0/16 (0%)		0/6 (0%)		0/6 (0%)		2/20 (10%)
Enterocolitis infectious	0/16 (0%)		1/6 (16.7%)		0/6 (0%)		1/20 (5%)
Infections and infestations - Other, specify	9/16 (56.3%)		3/6 (50%)		4/6 (66.7%)		3/20 (15%)
Lung infection	0/16 (0%)		0/6 (0%)		0/6 (0%)		2/20 (10%)
Soft tissue infection	0/16 (0%)		0/6 (0%)		0/6 (0%)		1/20 (5%)
Upper respiratory infection	0/16 (0%)		0/6 (0%)		0/6 (0%)		1/20 (5%)
Injury, poisoning and procedural complications
Vascular access complication	1/16 (6.3%)		0/6 (0%)		0/6 (0%)		0/20 (0%)
Investigations
Activated partial thromboplastin time prolonged	1/16 (6.3%)		0/6 (0%)		1/6 (16.7%)		0/20 (0%)
Alanine aminotransferase increased	2/16 (12.5%)		1/6 (16.7%)		0/6 (0%)		2/20 (10%)
Aspartate aminotransferase increased	1/16 (6.3%)		1/6 (16.7%)		0/6 (0%)		1/20 (5%)
Blood bilirubin increased	1/16 (6.3%)		0/6 (0%)		0/6 (0%)		0/20 (0%)
Fibrinogen decreased	1/16 (6.3%)		0/6 (0%)		0/6 (0%)		0/20 (0%)
GGT increased	0/16 (0%)		1/6 (16.7%)		0/6 (0%)		0/20 (0%)
INR increased	1/16 (6.3%)		0/6 (0%)		0/6 (0%)		0/20 (0%)
Investigations - Other, specify	0/16 (0%)		0/6 (0%)		1/6 (16.7%)		0/20 (0%)
Lymphocyte count decreased	1/16 (6.3%)		0/6 (0%)		0/6 (0%)		0/20 (0%)
Neutrophil count decreased	3/16 (18.8%)		2/6 (33.3%)		1/6 (16.7%)		0/20 (0%)
Platelet count decreased	1/16 (6.3%)		1/6 (16.7%)		1/6 (16.7%)		0/20 (0%)
White blood cell decreased	3/16 (18.8%)		2/6 (33.3%)		1/6 (16.7%)		0/20 (0%)
Metabolism and nutrition disorders
Anorexia	2/16 (12.5%)		1/6 (16.7%)		3/6 (50%)		1/20 (5%)
Hyperglycemia	3/16 (18.8%)		0/6 (0%)		1/6 (16.7%)		0/20 (0%)
Hypoalbuminemia	2/16 (12.5%)		0/6 (0%)		0/6 (0%)		0/20 (0%)
Hypocalcemia	1/16 (6.3%)		0/6 (0%)		0/6 (0%)		0/20 (0%)
Hypokalemia	4/16 (25%)		3/6 (50%)		2/6 (33.3%)		3/20 (15%)
Hypomagnesemia	0/16 (0%)		1/6 (16.7%)		0/6 (0%)		0/20 (0%)
Hyponatremia	0/16 (0%)		1/6 (16.7%)		0/6 (0%)		0/20 (0%)
Hypophosphatemia	0/16 (0%)		1/6 (16.7%)		0/6 (0%)		0/20 (0%)
Musculoskeletal and connective tissue disorders
Back pain	0/16 (0%)		1/6 (16.7%)		0/6 (0%)		1/20 (5%)
Bone pain	1/16 (6.3%)		1/6 (16.7%)		1/6 (16.7%)		0/20 (0%)
Generalized muscle weakness	0/16 (0%)		0/6 (0%)		1/6 (16.7%)		0/20 (0%)
Pain in extremity	2/16 (12.5%)		0/6 (0%)		1/6 (16.7%)		0/20 (0%)
Nervous system disorders
Dysphasia	1/16 (6.3%)		0/6 (0%)		0/6 (0%)		0/20 (0%)
Headache	0/16 (0%)		1/6 (16.7%)		0/6 (0%)		0/20 (0%)
Peripheral motor neuropathy	1/16 (6.3%)		0/6 (0%)		0/6 (0%)		0/20 (0%)
Peripheral sensory neuropathy	1/16 (6.3%)		1/6 (16.7%)		1/6 (16.7%)		0/20 (0%)
Syncope	0/16 (0%)		0/6 (0%)		1/6 (16.7%)		1/20 (5%)
Vasovagal reaction	0/16 (0%)		0/6 (0%)		0/6 (0%)		1/20 (5%)
Psychiatric disorders
Agitation	0/16 (0%)		0/6 (0%)		1/6 (16.7%)		0/20 (0%)
Anxiety	0/16 (0%)		1/6 (16.7%)		0/6 (0%)		0/20 (0%)
Depression	0/16 (0%)		1/6 (16.7%)		0/6 (0%)		0/20 (0%)
Reproductive system and breast disorders
Uterine hemorrhage	0/16 (0%)		1/6 (16.7%)		0/6 (0%)		0/20 (0%)
Respiratory, thoracic and mediastinal disorders
Atelectasis	1/16 (6.3%)		0/6 (0%)		0/6 (0%)		0/20 (0%)
Dyspnea	0/16 (0%)		0/6 (0%)		0/6 (0%)		1/20 (5%)
Hypoxia	1/16 (6.3%)		1/6 (16.7%)		0/6 (0%)		1/20 (5%)
Skin and subcutaneous tissue disorders
Alopecia	0/16 (0%)		0/6 (0%)		1/6 (16.7%)		0/20 (0%)
Rash maculo-papular	0/16 (0%)		0/6 (0%)		0/6 (0%)		1/20 (5%)
Vascular disorders
Capillary leak syndrome	1/16 (6.3%)		0/6 (0%)		0/6 (0%)		0/20 (0%)
Hypertension	0/16 (0%)		0/6 (0%)		0/6 (0%)		1/20 (5%)
Hypotension	1/16 (6.3%)		0/6 (0%)		0/6 (0%)		0/20 (0%)
Vascular disorders - Other, specify	1/16 (6.3%)		0/6 (0%)		0/6 (0%)		0/20 (0%)

Limitations/Caveats

The secondary outcome measure "Protein Expression Assessed by Western Blot" will never be reported as the investigators decided not to perform quantitative biologic analysis.

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.