Donor Stem Cell Transplant in Treating Young Patients With Acute Myeloid Leukemia With Monosomy 7, -5/5q-, High FLT3-ITD AR, or Refractory or Relapsed Acute Myelogenous Leukemia

• Sponsor: Children's Oncology Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT00553202
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 158
• Locations: 52
• Arm: 1
• Duration (Months): 147
• Patients Per Site: 3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

RATIONALE: Giving chemotherapy before a donor stem cell transplant using stem cells that closely match the patient's stem cells, helps stop the growth of cancer cells. It also stops the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving antithymocyte globulin before transplant and cyclosporine, tacrolimus, and methotrexate before and after transplant may stop this from happening.

PURPOSE: Natural Killer (NK) cells from the donor's bone marrow may be important in fighting leukemia. Bone marrow donors can be selected based on the type of NK cells they have, specifically the killer immunoglobulin receptor (KIR) type. This study provides information on KIR type from potential donors, which can be used in selecting the bone marrow donor. This phase II trial of unrelated donor stem cell transplant in patients with high risk AML (monosomy 7, -5/5q-, high FLT3-ITD AR, or refractory or relapsed AML) in which KIR typing of the patients and potential donors will be available to the treating transplant physician at the time of donor selection.

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Biological: anti-thymocyte globulin; Drug: busulfan; Drug: cyclophosphamide; Drug: cyclosporine; Drug: methotrexate; Drug: methylprednisolone; Drug: tacrolimus; Other: laboratory biomarker analysis; Other: pharmacological study; Procedure: allogeneic bone marrow transplantation; Procedure: allogeneic hematopoietic stem cell transplantation	Phase 2

Detailed Description

OBJECTIVES:

• To define the relationship between the status of donor NK-cell receptor and patient outcomes after killer immunoglobulin-like receptor-incompatible unrelated donor (URD) and umbilical cord blood (UCB) hematopoietic cell transplantation (HCT) in young patients with acute myeloid leukemia with monosomy 7, -5/5q-, high FLT3 internal tandem duplication allelic ratio (High-FLT3-ITD AR), or refractory or relapsed acute myelogenous leukemia.

• To correlate the relationships between factors affecting NK receptor status and clinical events.

• To assess NK-cell development after URD and UCB HCT in patients with poor prognosis AML.

• To evaluate NK-cell reconstitution and receptor-acquisition pattern in these patients.

OUTLINE: This is a multicenter study.

• Preparative regimen: Patients receive 1 of the following regimens:

• Hematopoietic stem cell transplantation (SCT): Patients receive busulfan IV every 6 hours on days -9 to -6, high-dose cyclophosphamide IV over 1 hour on days -5 to -2, anti-thymocyte globulin IV once or twice daily over 4 hours on days -3 to -1, and methylprednisolone IV on days -3 to -1.

• Umbilical cord blood (UCB) transplantation: Conditioning regimen, infusion procedures, and post-transplant immunoprophylaxis for patients with an UCB donor are according to institutional guidelines and standards.

• Allogeneic hematopoietic stem cell transplantation (SCT) or umbilical cord blood (UCB) transplant: Patients undergo allogeneic SCT or UCB transplant on day 0.

• Graft-vs-host disease (GVHD) prophylaxis: Patients receive cyclosporine or tacrolimus IV or orally beginning on day -2 and continuing until day 50, followed by a taper until week 24. Patients also receive methotrexate IV on days 1, 3, 6, and 11.

Blood samples will be collected periodically from both patients and donors for studies of natural killer cells in support of the study objectives.

After completion of study treatment, patients are followed every 6 months for 2 years and then annually for 3 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 158 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Killer Immunoglobulin-like Receptor (KIR) Incompatible Unrelated Donor Hematopoietic Cell Transplantation (SCT) for AML With Monosomy 7, -5/5q-, High FLT3-ITD AR, or Refractory and Relapsed Acute Myelogenous Leukemia (AML) in Children: A Children's Oncology Group (COG) Study
• Study Start Date: Jan 1, 2008
• Actual Primary Completion Date: Jun 1, 2016
• Actual Study Completion Date: Mar 31, 2020

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (chemotherapy and allogeneic SCT) Patients receive busulfan IV every 6 hours on days -9 to -6, high-dose cyclophosphamide IV over 1 hour on days -5 to -2, anti-thymocyte globulin IV once or twice daily over 4 hours on days -3 to -1, and methylprednisolone IV on days -3 to -1. Patients undergo allogeneic hematopoietic stem cell transplantation (SCT) or allogeneic bone marrow transplantation (BMT) on day 0. Patients receive cyclosporine or tacrolimus IV or orally beginning on day -2 and continuing until day 50, followed by a taper until week 24. Patients also receive methotrexate IV on days 1, 3, 6, and 11. Blood samples will be collected periodically from both patients and donors for studies of natural killer cells in support of the pharmacological study objectives

Biological: anti-thymocyte globulin; Given IV; Other Names: Rabbit ATG RATG-Rabbit Antithymocyte Globulin Thymoglobulin NSC #720095 ; Drug: busulfan; Given IV; Other Names: Busulfex NSC #750 ; Drug: cyclophosphamide; Given IV; Other Names: Cytoxan NSC #26271 ; Drug: cyclosporine; Given IV or orally; Other Names: CYA Sandimmune Neoral Gengraf NSC #290193 ; Drug: methotrexate; Given IV; Other Names: MTX amethopterin NSC #000740 ; Drug: methylprednisolone; Given IV; Other Names: Solu-Medrol A-Methapred Medrol NSC #19987 ; Drug: tacrolimus; Given IV; Other Names: FK-506 Prograf NSC #717865 ; Other: laboratory biomarker analysis; Correlative studies; Other: pharmacological study; Correlative studies; Procedure: allogeneic bone marrow transplantation; allogeneic bone marrow transplantation; Other Names: bone marrow therapy allogeneic allogenic transplantation allogeneic bone marrow allogenic bone marrow ; Procedure: allogeneic hematopoietic stem cell transplantation; Undergo allogeneic hematopoietic SCT

Outcome Measures

Primary Outcome Measures

1. Overall Survival (OS) [At 5 years from HSCT date]

   OS - Time from HSCT until death

2. Cumulative Incidence of NK Cell Reconstitution [At 5 years from HSCT date]

   Cumulative incidence of successful reconstitution to donor level is calculated.

Other Outcome Measures

1. Disease-free Survival [From the date of SCT to the date of relapse, the date of death, or the date of last follow-up, whichever occurs first]

   The cumulative incidence of relapse or death after SCT will be calculated by considering relapse and death due to other causes as competing events.

2. Acute and Chronic Graft-versus-host Disease [Up to 5 years]

   Acute and chronic GVHD will be summarized.

3. Time to the Donor-specific NK-cell Receptor Expression [Up to 42 days after SCT]

   The presence of donor cells is demonstrated by the detection of informative variable-number tandem-repeat polymorphisms or by fluorescent in situ hybridization with a Y-chromosome-specific probe in cases of sex-mismatched transplants. Independent variables that will be examined include donor-recipient KIR mismatch, taking into consideration the interactions with donor-recipient human leukocyte antigen (HLA) compatibility, and the numbers of CD34+ cells and CD3+ cells in the graft.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 30 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Diagnosis of one of the following:

• Patients with primary refractory acute myeloid leukemia (AML), defined as ≥ 5% bone marrow blasts after two induction courses of chemotherapy

• Primary refractory AML, defined as ≥ 5% bone marrow blasts after two induction courses of chemotherapy

• AML or myelodysplastic syndrome with -5/5q- or monosomy 7 without inv(16)/t(16;16) or t(8;21) cytogenetics or NPM or CEBPα mutations

• Relapsed AML (≥ 5% bone marrow blasts) who meet the customary WHO criteria for AML

• AML and high FLT3 internal tandem duplication allelic ratio (high FLT3-ITD AR), defined as > 0.4

• All cases of therapy-related AML (therapy-related AML is considered high risk)

• Patients with AML, without inv(16)/t(16;16) or t(8;21), monosomy 7, -5/5q-, NPM, or CEPBα mutations, or high FLT3-ITD AR, but with evidence of residual AML (≥ 0.1%) at the end of Induction I; or if a minimal residual disease (MRD) is not performed, then with > 15% bone marrow blasts by morphology after one induction course of chemotherapy

• Any flow-based MRD is eligible for AAML05P1 for patients not on AAML1031, whereas patients on AAML1031 must utilize the central lab as per the AAML1031 protocol guidelines

• No Fanconi anemia

• Recipients of unrelated marrow or cord blood are eligible for this study

PATIENT CHARACTERISTICS:

• Karnofsky performance status (PS) (for patients over 16 years of age) or Lansky PS (for patients 16 and under) 50-100%

• Total bilirubin ≤ 2 mg/dL

• SGOT (AST) or SGPT (ALT) ≤ 2.5 times upper limit of normal

• DLCO ≥ 50% OR a normal chest x-ray and pulse oximetry in patients who are unable to undergo pulmonary function tests

• Shortening fraction ≥ 27% by ECHO

• Creatinine clearance or radioisotope glomerular filtration rate at least 60 mL/min OR creatinine adjusted according to age

• HIV negative

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• Patients with proven or suspected bacterial sepsis, pneumonia, or meningitis are eligible provided appropriate therapeutic measures have been initiated to control the presumed or proven infection, and systemic signs are not life-threatening

• No evidence or presence of a fungal infection within the past 30 days

PRIOR CONCURRENT THERAPY:

• Prior chemotherapy, radiotherapy or any antileukemic therapy allowed provided patients meet 1 of the following criteria:

• Received initial treatment for relapsed AML

• Patients with primary induction failure or relapse who have already received initial therapy and who may have gone on to have additional therapy prior to receiving protocol stipulated therapy on AAML05P1

• No treatment for fungal infection within the past 30 days

• Concurrent radiotherapy to localized painful lesions allowed

• No other concurrent cancer chemotherapy or immunomodulating agents

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UAB Comprehensive Cancer Center	Birmingham	Alabama	United States	35294
2	Phoenix Children's Hospital	Phoenix	Arizona	United States	85016-7710
3	Jonathan Jaques Children's Cancer Center at Miller Children's Hospital	Long Beach	California	United States	90801
4	Children's Hospital Central California	Madera	California	United States	93638-8762
5	Rady Children's Hospital - San Diego	San Diego	California	United States	92123-4282
6	Alfred I. duPont Hospital for Children	Wilmington	Delaware	United States	19803
7	Children's National Medical Center	Washington	District of Columbia	United States	20010-2970
8	Lee Cancer Care of Lee Memorial Health System	Fort Myers	Florida	United States	33901
9	Nemours Children's Clinic	Jacksonville	Florida	United States	32207
10	Nemours Children's Clinic - Orlando	Orlando	Florida	United States	32806
11	Nemours Children's Clinic - Pensacola	Pensacola	Florida	United States	32504
12	All Children's Hospital	Saint Petersburg	Florida	United States	33701
13	AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus	Atlanta	Georgia	United States	30322
14	Riley's Children Cancer Center at Riley Hospital for Children	Indianapolis	Indiana	United States	46202
15	Holden Comprehensive Cancer Center at University of Iowa	Iowa City	Iowa	United States	52242-1002
16	Lucille P. Markey Cancer Center at University of Kentucky	Lexington	Kentucky	United States	40536-0093
17	Kosair Children's Hospital	Louisville	Kentucky	United States	40232
18	Alvin and Lois Lapidus Cancer Institute at Sinai Hospital	Baltimore	Maryland	United States	21215
19	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan	United States	48201-1379
20	Mayo Clinic Cancer Center	Rochester	Minnesota	United States	55905
21	University of Mississippi Cancer Clinic	Jackson	Mississippi	United States	39216-4505
22	Children's Mercy Hospital	Kansas City	Missouri	United States	64108
23	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis	Saint Louis	Missouri	United States	63110
24	UNMC Eppley Cancer Center at the University of Nebraska Medical Center	Omaha	Nebraska	United States	68198-6805
25	CCOP - Nevada Cancer Research Foundation	Las Vegas	Nevada	United States	89109-2306
26	Hackensack University Medical Center Cancer Center	Hackensack	New Jersey	United States	07601
27	Roswell Park Cancer Institute	Buffalo	New York	United States	14263-0001
28	Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center	New York	New York	United States	10032
29	James P. Wilmot Cancer Center at University of Rochester Medical Center	Rochester	New York	United States	14642
30	Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill	Chapel Hill	North Carolina	United States	27599-7295
31	Blumenthal Cancer Center at Carolinas Medical Center	Charlotte	North Carolina	United States	28232-2861
32	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229-3039
33	Rainbow Babies and Children's Hospital	Cleveland	Ohio	United States	44106-5000
34	Nationwide Children's Hospital	Columbus	Ohio	United States	43205-2696
35	Dayton Children's - Dayton	Dayton	Ohio	United States	45404-1815
36	Oklahoma University Cancer Institute	Oklahoma City	Oklahoma	United States	73104
37	Penn State Children's Hospital	Hershey	Pennsylvania	United States	17033-0850
38	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
39	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania	United States	15213
40	East Tennessee Children's Hospital	Knoxville	Tennessee	United States	37916
41	St. Jude Children's Research Hospital	Memphis	Tennessee	United States	38105
42	Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas	Dallas	Texas	United States	75390
43	Cook Children's Medical Center - Fort Worth	Fort Worth	Texas	United States	76104
44	Methodist Children's Hospital of South Texas	San Antonio	Texas	United States	78229-3993
45	CCOP - Scott and White Hospital	Temple	Texas	United States	76508
46	Primary Children's Medical Center	Salt Lake City	Utah	United States	84113-1100
47	Virginia Commonwealth University Massey Cancer Center	Richmond	Virginia	United States	23298-0037
48	Midwest Children's Cancer Center at Children's Hospital of Wisconsin	Milwaukee	Wisconsin	United States	53226
49	Children's and Women's Hospital of British Columbia	Vancouver	British Columbia	Canada	V6H 3V4
50	McMaster Children's Hospital at Hamilton Health Sciences	Hamilton	Ontario	Canada	L8N 3Z5
51	Hospital for Sick Children	Toronto	Ontario	Canada	M5G 1X8
52	Hopital Sainte Justine	Montreal	Quebec	Canada	H3T 1C5

Sponsors and Collaborators

• Children's Oncology Group
• National Cancer Institute (NCI)

Investigators

• Study Chair: Stella M. Davies, MBBS, PhD, Children's Hospital Medical Center, Cincinnati

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Children's Oncology Group
• ClinicalTrials.gov Identifier: NCT00553202
• Other Study ID Numbers: AAML05P1; COG-AAML05P1; NCI-2009-00321
• First Posted: Nov 4, 2007
• Last Update Posted: Apr 16, 2020
• Last Verified: Jul 1, 2016

• Keywords provided by Children's Oncology Group: recurrent childhood acute myeloid leukemia; childhood myelodysplastic syndromes
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Monosomy; Cyclosporine; Methylprednisolone; Methylprednisolone Acetate; Methylprednisolone Hemisuccinate; Prednisolone; Prednisolone acetate; Cyclophosphamide; Busulfan; Methotrexate; Tacrolimus; Cyclosporins; Thymoglobulin; Antilymphocyte Serum; Prednisolone hemisuccinate; Prednisolone phosphate

Study Results

Participant Flow

Arm/Group Title	Treatment (Chemotherapy and Allogeneic SCT)
Arm/Group Description	All patients
Period Title: Overall Study
STARTED	158
COMPLETED	90
NOT COMPLETED	68

Baseline Characteristics

Arm/Group Title	Treatment (Chemotherapy and Allogeneic SCT)
Arm/Group Description	All Patients
Overall Participants	158
Age (Count of Participants)
<=18 years	149 94.3%
Between 18 and 65 years	9 5.7%
>=65 years	0 0%
Age (Days) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Days]	3215.34 (2240.48)
Sex: Female, Male (Count of Participants)
Female	75 47.5%
Male	83 52.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.6%
Asian	4 2.5%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	10 6.3%
White	128 81%
More than one race	0 0%
Unknown or Not Reported	15 9.5%
Region of Enrollment (participants) [Number]
Canada	11 7%
United States	147 93%

Outcome Measures

1. Primary Outcome

Title	Overall Survival (OS)
Description	OS - Time from HSCT until death
Time Frame	At 5 years from HSCT date

Outcome Measure Data

Analysis Population Description

Patients without completion of planned therapy (n=68) are excluded from analyses of OS

Arm/Group Title	Treatment (Chemotherapy and Allogeneic SCT)
Arm/Group Description	All Patients
Measure Participants	90
Number (95% Confidence Interval) [Percentage of participants]	45.9 29.1%

2. Primary Outcome

Title	Cumulative Incidence of NK Cell Reconstitution
Description	Cumulative incidence of successful reconstitution to donor level is calculated.
Time Frame	At 5 years from HSCT date

Outcome Measure Data

Analysis Population Description

Patients without completion of planned therapy (n=68) or without NK cell status (n=38) are excluded from analyses of TExp

Arm/Group Title	Treatment (Chemotherapy and Allogeneic SCT)
Arm/Group Description	All Patients
Measure Participants	52
Number (95% Confidence Interval) [Percentage of participants]	48.1 30.4%

3. Other Pre-specified Outcome

Title	Disease-free Survival
Description	The cumulative incidence of relapse or death after SCT will be calculated by considering relapse and death due to other causes as competing events.
Time Frame	From the date of SCT to the date of relapse, the date of death, or the date of last follow-up, whichever occurs first

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Chemotherapy and Allogeneic SCT)
Arm/Group Description	All patients
Measure Participants	0

4. Other Pre-specified Outcome

Title	Acute and Chronic Graft-versus-host Disease
Description	Acute and chronic GVHD will be summarized.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Chemotherapy and Allogeneic SCT)
Arm/Group Description	All patients
Measure Participants	0

5. Other Pre-specified Outcome

Title	Time to the Donor-specific NK-cell Receptor Expression
Description	The presence of donor cells is demonstrated by the detection of informative variable-number tandem-repeat polymorphisms or by fluorescent in situ hybridization with a Y-chromosome-specific probe in cases of sex-mismatched transplants. Independent variables that will be examined include donor-recipient KIR mismatch, taking into consideration the interactions with donor-recipient human leukocyte antigen (HLA) compatibility, and the numbers of CD34+ cells and CD3+ cells in the graft.
Time Frame	Up to 42 days after SCT

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Chemotherapy and Allogeneic SCT)
Arm/Group Description	All patients
Measure Participants	0

Adverse Events

Arm/Group Title	Group 1
Arm/Group Description	All patients
All Cause Mortality
	Group 1
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Group 1
	Affected / at Risk (%)	# Events
Total	7/90 (7.8%)
Gastrointestinal disorders
Ascites	1/90 (1.1%)
Mucositis oral	1/90 (1.1%)
General disorders
Death NOS	2/90 (2.2%)
Multi-organ failure	1/90 (1.1%)
Hepatobiliary disorders
Hepatobiliary disorders - Other, specify	1/90 (1.1%)
Portal hypertension	1/90 (1.1%)
Immune system disorders
Immune system disorders - Other, specify	1/90 (1.1%)
Infections and infestations
Infections and infestations - Other, specify	2/90 (2.2%)
Sepsis	2/90 (2.2%)
Investigations
Alanine aminotransferase increased	1/90 (1.1%)
Blood bilirubin increased	1/90 (1.1%)
Creatinine increased	1/90 (1.1%)
Metabolism and nutrition disorders
Hypercalcemia	1/90 (1.1%)
Renal and urinary disorders
Renal and urinary disorders - Other, specify	1/90 (1.1%)
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome	1/90 (1.1%)
Atelectasis	1/90 (1.1%)
Hypoxia	1/90 (1.1%)
Pleural effusion	1/90 (1.1%)
Productive cough	1/90 (1.1%)
Pulmonary edema	1/90 (1.1%)
Respiratory failure	3/90 (3.3%)
Respiratory, thoracic and mediastinal disorders - Other, specify	1/90 (1.1%)
Other (Not Including Serious) Adverse Events
	Group 1
	Affected / at Risk (%)	# Events
Total	32/90 (35.6%)
Blood and lymphatic system disorders
Febrile neutropenia	1/90 (1.1%)
Cardiac disorders
Cardiac disorders - Other, specify	2/90 (2.2%)
Heart failure	1/90 (1.1%)
Left ventricular systolic dysfunction	4/90 (4.4%)
Pericardial effusion	1/90 (1.1%)
Sinus tachycardia	1/90 (1.1%)
Gastrointestinal disorders
Abdominal distension	1/90 (1.1%)
Abdominal pain	1/90 (1.1%)
Ascites	8/90 (8.9%)
Diarrhea	3/90 (3.3%)
Gastric hemorrhage	1/90 (1.1%)
Ileus	1/90 (1.1%)
Lower gastrointestinal hemorrhage	1/90 (1.1%)
Mucositis oral	2/90 (2.2%)
Upper gastrointestinal hemorrhage	1/90 (1.1%)
General disorders
Death NOS	1/90 (1.1%)
Multi-organ failure	2/90 (2.2%)
Pain	1/90 (1.1%)
Hepatobiliary disorders
Hepatic pain	4/90 (4.4%)
Hepatobiliary disorders - Other, specify	2/90 (2.2%)
Portal hypertension	3/90 (3.3%)
Immune system disorders
Allergic reaction	1/90 (1.1%)
Cytokine release syndrome	1/90 (1.1%)
Infections and infestations
Encephalitis infection	1/90 (1.1%)
Infections and infestations - Other, specify	3/90 (3.3%)
Lung infection	1/90 (1.1%)
Sepsis	2/90 (2.2%)
Sinusitis	1/90 (1.1%)
Urinary tract infection	1/90 (1.1%)
Investigations
Aspartate aminotransferase increased	2/90 (2.2%)
Blood bilirubin increased	11/90 (12.2%)
Creatinine increased	1/90 (1.1%)
Electrocardiogram QT corrected interval prolonged	5/90 (5.6%)
Serum amylase increased	1/90 (1.1%)
Urine output decreased	2/90 (2.2%)
Weight gain	8/90 (8.9%)
White blood cell decreased	1/90 (1.1%)
Metabolism and nutrition disorders
Hyperglycemia	3/90 (3.3%)
Hypernatremia	2/90 (2.2%)
Hypoalbuminemia	2/90 (2.2%)
Hypoglycemia	2/90 (2.2%)
Hypokalemia	4/90 (4.4%)
Hyponatremia	1/90 (1.1%)
Hypophosphatemia	1/90 (1.1%)
Tumor lysis syndrome	1/90 (1.1%)
Nervous system disorders
Seizure	1/90 (1.1%)
Renal and urinary disorders
Acute kidney injury	5/90 (5.6%)
Bladder spasm	1/90 (1.1%)
Cystitis noninfective	3/90 (3.3%)
Hematuria	2/90 (2.2%)
Reproductive system and breast disorders
Vaginal hemorrhage	1/90 (1.1%)
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome	1/90 (1.1%)
Bronchopulmonary hemorrhage	1/90 (1.1%)
Hypoxia	3/90 (3.3%)
Pharyngeal hemorrhage	1/90 (1.1%)
Pleural effusion	1/90 (1.1%)
Pneumothorax	1/90 (1.1%)
Pulmonary edema	2/90 (2.2%)
Respiratory failure	5/90 (5.6%)
Respiratory, thoracic and mediastinal disorders - Other, specify	2/90 (2.2%)
Skin and subcutaneous tissue disorders
Rash maculo-papular	1/90 (1.1%)
Skin and subcutaneous tissue disorders - Other, specify	1/90 (1.1%)
Stevens-Johnson syndrome	1/90 (1.1%)
Vascular disorders
Hypotension	2/90 (2.2%)
Vascular disorders - Other, specify	2/90 (2.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Must obtain prior Sponsor approval.