Busulfan, Fludarabine Phosphate, and Anti-Thymocyte Globulin Followed By Donor Stem Cell Transplant and Azacitidine in Treating Patients With High-Risk Myelodysplastic Syndrome and Older Patients With Acute Myeloid Leukemia

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT01168219
• Collaborator: (none)
• Enrollment: 68
• Locations: 17
• Arm: 1
• Actual Duration (Months): 114.6
• Patients Per Site: 4
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This phase II clinical trial is studying how well giving busulfan, fludarabine phosphate, and anti-thymocyte globulin followed by donor stem cell transplant and azacitidine works in treating patients with high-risk myelodysplastic syndrome and older patients with acute myeloid leukemia. Giving low doses of chemotherapy, such as busulfan and fludarabine phosphate, before a donor stem cell transplant 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-vs-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving anti-thymocyte globulin before transplant and giving azacitidine, tacrolimus, and methotrexate after the transplant may stop this from happening.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia; Adult Acute Megakaryoblastic Leukemia; Adult Acute Monoblastic Leukemia; Adult Acute Monocytic Leukemia; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With Maturation; Adult Acute Myeloid Leukemia With Minimal Differentiation; Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(8;21); (q22; q22.1); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p21.3;q23.3); MLLT3-MLL; Adult Acute Myeloid Leukemia Without Maturation; Adult Acute Myelomonocytic Leukemia; Adult Erythroleukemia; Adult Pure Erythroid Leukemia; Alkylating Agent-Related Acute Myeloid Leukemia; de Novo Myelodysplastic Syndrome; Myelodysplastic Syndrome; Myelodysplastic Syndrome With Excess Blasts; Recurrent Adult Acute Myeloid Leukemia; Secondary Myelodysplastic Syndrome	Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Biological: Anti-Thymocyte Globulin; Drug: Azacitidine; Drug: Busulfan; Drug: Fludarabine Phosphate; Other: Laboratory Biomarker Analysis; Drug: Methotrexate; Other: Pharmacological Study; Drug: Tacrolimus	Phase 2

Detailed Description

PRIMARY OBJECTIVE:

1. To determine if this treatment can improve 2-year progression-free survival (PFS) in patients with high risk myelodysplastic syndrome (MDS) and in patients with acute myeloid leukemia (AML) >= 60 yrs age

SECONDARY OBJECTIVES:

1. To determine the safety and feasibility of using post-transplantation azacitidine.

2. To determine the ability to use pharmacokinetic-directed busulfan to achieve area under the curve (AUC) within 20% of target AUC in > 80% of patients.

3. To determine the rate of grade II-IV and III-IV acute graft-vs-host disease (GVHD).

4. To determine the incidence of extensive chronic GVHD. V. To determine treatment-related mortality at 100 days and at 1 year. VI. To determine 5-year overall survival.

OUTLINE:

REDUCED-INTENSITY CONDITIONING: Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -7 to -3, busulfan IV over 45 minutes on days -6 to -3, and anti-thymocyte globulin IV over 4-10 hours on days -6 to -5 (matched sibling donor [MSD]) or -6 to -4 (matched unrelated donor [MUD]).

TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0 or on days 0-1.

GRAFT-VS-HOST DISEASE PROPHYLAXIS: Patients receive tacrolimus orally (PO) or IV on days -2 to 90 with taper on days 150-180. Patients also receive methotrexate IV on days 1, 3, 6 (MSD), and 11 (MUD).

CONSOLIDATION: Beginning on day 42, patients receive azacitidine subcutaneously (SC) or IV on days 1-5.

Treatment repeats every 4 weeks for 6 courses. Blood and bone marrow samples may be collected periodically for correlative and pharmacokinetic studies.

After completion of study treatment, patients are followed up every 6 months for 5 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 68 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of the Addition of Azacitidine (NSC#102816) to Reduced-Intensity Conditioning Allogeneic Transplantation for Myelodysplasia (MDS) and Older Patients With AML
• Actual Study Start Date: Jul 15, 2010
• Actual Primary Completion Date: Nov 14, 2015
• Actual Study Completion Date: Feb 1, 2020

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (chemotherapy and transplant) REDUCED-INTENSITY CONDITIONING: Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3, busulfan IV over 45 minutes on days -6 to -3, and anti-thymocyte globulin IV over 4-10 hours on days -6 to -5 (matched sibling donor [MSD]) or -6 to -4 (matched unrelated donor [MUD]). TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0 or on days 0-1. GRAFT-VS-HOST DISEASE PROPHYLAXIS: Patients receive tacrolimus PO or IV on days -2 to 90 with taper on days 150-180. Patients also receive methotrexate IV on days 1, 3, 6 (MSD), and 11 (MUD). CONSOLIDATION: Beginning on day 42, patients receive azacitidine SC or IV on days 1.

Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Undergo allogeneic hematopoietic stem cell transplantation; Other Names: Allogeneic Allogeneic Hematopoietic Cell Transplantation Allogeneic Stem Cell Transplantation HSC HSCT Stem Cell Transplantation, Allogeneic ; Biological: Anti-Thymocyte Globulin; Given IV; Other Names: Antithymocyte Globulin Antithymocyte Serum ATG ATS ; Drug: Azacitidine; Given SC or IV; Other Names: 5 AZC 5-AC 5-Azacytidine 5-AZC Azacytidine Azacytidine, 5- Ladakamycin Mylosar Onureg U-18496 Vidaza ; Drug: Busulfan; Given IV; Other Names: 1, 4-Bis[methanesulfonoxy]butane BUS Bussulfam Busulfanum Busulfex Busulphan CB 2041 CB-2041 Glyzophrol GT 41 GT-41 Joacamine Methanesulfonic Acid Tetramethylene Ester Methanesulfonic acid, tetramethylene ester Mielucin Misulban Misulfan Mitosan Myeleukon Myeloleukon Myelosan Mylecytan Myleran Sulfabutin Tetramethylene Bis(methanesulfonate) Tetramethylene bis[methanesulfonate] WR-19508 ; Drug: Fludarabine Phosphate; Given IV; Other Names: 2-F-ara-AMP 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)- Beneflur Fludara SH T 586 ; Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Methotrexate; Given IV; Other Names: Abitrexate Alpha-Methopterin Amethopterin Brimexate CL 14377 CL-14377 Emtexate Emthexat Emthexate Farmitrexat Fauldexato Folex Folex PFS Lantarel Ledertrexate Lumexon Maxtrex Medsatrexate Metex Methoblastin Methotrexate LPF Methotrexate Methylaminopterin Methotrexatum Metotrexato Metrotex Mexate Mexate-AQ MTX Novatrex Rheumatrex Texate Tremetex Trexeron Trixilem WR-19039 ; Other: Pharmacological Study; Correlative studies; Drug: Tacrolimus; Given PO or IV; Other Names: FK 506 Fujimycin Hecoria Prograf Protopic

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival [Up to 5 years]

   Progression-free survival rate (percentage) at 2 and 5 years is defined as the percentage of patients who are alive and progression free at 2 and 5 years from date of transplantation respectively. AML progression is defined as: Reappearance of leukemia blast cells in peripheral blood and > 5% blasts in marrow If no circulating blasts, but the marrow contains 5-20% blasts, a repeat bone marrow >= 1 week later with > 5% blasts Development of extramedullary leukemia MDS progression is defined as For patients with <5% bone marrow blasts: ≥50% increase in blasts to >5% blasts For patients with 5-10% bone marrow blasts: ≥50% increase to >10% blasts Any of the following: Reappearance of prior documented characteristic cytogenetic abnormality or refractory cytopenias with unequivocal evidence of dysplasia on bone marrow biopsy/aspirate

Secondary Outcome Measures

1. Overall Survival (OS) [Up to 5 years]

   Overall survival rate (percentage) at 2 and 5 years is defined as the percentage of patients who are still alive 2 and 5 years after date of transplantation respectively. Estimated using the Kaplan-Meier product limit estimator.

2. 100-day Mortality [Up to 100 days post-treatment]

   The number of death reported within the first 100 days after transplant.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 74 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Meets one of the following sets of criteria:

• Myelodysplastic syndromes (MDS):

• Disease with high-risk features (found either at diagnosis or before initiation of cytotoxic therapy), defined as one of the following:

• International prognostic scoring system (IPSS) risk >= intermediate-2

• Refractory anemia with excess blasts by French-American-British (FAB) classification

• High-risk cytogenetics (either complex or -7)

• Less than 10% bone marrow blasts as determined by bone marrow biopsy within the past 4 weeks (reduction in marrow blast percentage may be achieved with chemotherapy or other therapy)

• Less than 75 years old

• Acute myeloid leukemia (AML):

• No FAB M3

• No acute leukemia following blast transformation of prior chronic myelogenous leukemia or other myeloproliferative disease

• Patients with preceding MDS or treatment-related AML are eligible

• Prior central nervous system (CNS) involvement is allowed provided the disease is in remission at transplantation

• Morphologic complete remission (leukemia-free state) is defined as meeting all of the following criteria:

• Bone marrow blasts < 5% (as determined by bone marrow within the past 4 weeks), but without requirement for normal peripheral blood counts

• No extramedullary leukemia

• No blasts in peripheral blood

• Achieved complete remission (CR) after no more than 2 courses of induction chemotherapy

• Patients treated with azacitidine or decitabine who achieve a leukemia-free state are eligible (may have required up to 4 courses of therapy to reach this status)

• Age 60 to 74 years

• Donors must meet the following criteria:

• One of the following:

• HLA-identical sibling (6/6) by serologic typing for class (A, B) and low-resolution molecular typing for class II (DRB1)

• Matched unrelated donor (8/8) by high-resolution molecular typing at HLA-A, -B, -C, and DRB1

• No syngeneic donors

• Eastern Cooperative Oncology Group (ECOG) performance status 0-2

• Calculated creatinine clearance ≥ 40 mL/min

• Bilirubin < 2 mg/dL OR bilirubin 2-3 mg/dL provided direct bilirubin is normal

• Aspartate aminotransferase (AST) < 3 times upper limit of normal

• Diffusing capacity of the lung for carbon monoxide (DLCO) > 40% with no symptomatic pulmonary disease

• Left ventricle ejection fraction (LVEF) >= 30% by echocardiogram (ECHO) or multigated acquisition (MUGA)

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• No uncontrolled diabetes mellitus or active serious infections

• No known hypersensitivity to E. coli-derived products, azacitidine, or mannitol

• No human immunodeficiency virus (HIV) infection or active hepatitis B or C

• Prior azacitidine or decitabine allowed

• No patients who progressed from MDS to AML during treatment with azacitidine or decitabine

• At least 4 weeks since prior deoxyribonucleic acid (DNA)-hypomethylating chemotherapy, radiotherapy, and/or surgery

• No more than 2 courses of consolidation therapy before transplantation (for patients with AML)

• Any consolidation regimen that does not require transplantation can be used

• No more than 6 months from documentation of morphologic CR to transplantation

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Beebe Medical Center	Lewes	Delaware	United States	19958
2	Christiana Care Health System-Christiana Hospital	Newark	Delaware	United States	19718
3	AdventHealth Orlando	Orlando	Florida	United States	32803
4	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa	United States	52242
5	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland	United States	21201
6	Christiana Care - Union Hospital	Elkton	Maryland	United States	21921
7	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
8	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
9	Cooper Hospital University Medical Center	Camden	New Jersey	United States	08103
10	Northwell Health NCORP	Lake Success	New York	United States	11042
11	Northwell Health/Center for Advanced Medicine	Lake Success	New York	United States	11042
12	North Shore University Hospital	Manhasset	New York	United States	11030
13	Mount Sinai Hospital	New York	New York	United States	10029
14	NYP/Weill Cornell Medical Center	New York	New York	United States	10065
15	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina	United States	27599
16	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
17	Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Ravi Vij, Alliance for Clinical Trials in Oncology

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01168219
• Other Study ID Numbers: NCI-2011-02053; NCI-2011-02053; CDR0000681025; CALGB-100801; CALGB 100801; CALGB-100801; U10CA180821; U10CA031946
• First Posted: Jul 23, 2010
• Last Update Posted: Aug 4, 2022
• Last Verified: Aug 1, 2022

• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Leukemia, Monocytic, Acute; Leukemia, Myelomonocytic, Acute; Leukemia, Megakaryoblastic, Acute; Leukemia, Erythroblastic, Acute; Myelodysplastic Syndromes; Anemia, Refractory, with Excess of Blasts; Syndrome; Methotrexate; Fludarabine phosphate; Azacitidine; Fludarabine; Busulfan; Tacrolimus; Antilymphocyte Serum

Study Results

Participant Flow

Recruitment Details	From July 2010 and October 2013, a total of 68 participants were recruited to this study.

Arm/Group Title	Treatment (Chemotherapy and Transplant)
Arm/Group Description	REDUCED-INTENSITY CONDITIONING: Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3, busulfan IV over 45 minutes on days -6 to -3, and anti-thymocyte globulin IV over 4-10 hours on days -6 to -5 (matched sibling donor [MSD]) or -6 to -4 (matched unrelated donor [MUD]). TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0 or on days 0-1. GRAFT-VS-HOST DISEASE PROPHYLAXIS: Patients receive tacrolimus PO or IV on days -2 to 90 with taper on days 150-180. Patients also receive methotrexate IV on days 1, 3, 6 (MSD), and 11 (MUD). CONSOLIDATION: Beginning on day 42, patients receive azacitidine SC or IV on days 1.
Period Title: Overall Study
STARTED	68
COMPLETED	63
NOT COMPLETED	5

Baseline Characteristics

Arm/Group Title	Treatment (Chemotherapy and Transplant)
Arm/Group Description	REDUCED-INTENSITY CONDITIONING: Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3, busulfan IV over 45 minutes on days -6 to -3, and anti-thymocyte globulin IV over 4-10 hours on days -6 to -5 (matched sibling donor [MSD]) or -6 to -4 (matched unrelated donor [MUD]). TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0 or on days 0-1. GRAFT-VS-HOST DISEASE PROPHYLAXIS: Patients receive tacrolimus PO or IV on days -2 to 90 with taper on days 150-180. Patients also receive methotrexate IV on days 1, 3, 6 (MSD), and 11 (MUD). CONSOLIDATION: Beginning on day 42, patients receive azacitidine SC or IV on days 1.
Overall Participants	68
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	62.9
Sex: Female, Male (Count of Participants)
Female	15 22.1%
Male	53 77.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 4.4%
Not Hispanic or Latino	61 89.7%
Unknown or Not Reported	4 5.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 1.5%
Asian	2 2.9%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 1.5%
White	60 88.2%
More than one race	2 2.9%
Unknown or Not Reported	2 2.9%
Region of Enrollment (Count of Participants)
United States	68 100%
Disease type (Count of Participants)
Myelodysplastic Syndrome (MDS)	24 35.3%
Acute Myeloid Leukemia (AML)	44 64.7%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival
Description	Progression-free survival rate (percentage) at 2 and 5 years is defined as the percentage of patients who are alive and progression free at 2 and 5 years from date of transplantation respectively. AML progression is defined as: Reappearance of leukemia blast cells in peripheral blood and > 5% blasts in marrow If no circulating blasts, but the marrow contains 5-20% blasts, a repeat bone marrow >= 1 week later with > 5% blasts Development of extramedullary leukemia MDS progression is defined as For patients with <5% bone marrow blasts: ≥50% increase in blasts to >5% blasts For patients with 5-10% bone marrow blasts: ≥50% increase to >10% blasts Any of the following: Reappearance of prior documented characteristic cytogenetic abnormality or refractory cytopenias with unequivocal evidence of dysplasia on bone marrow biopsy/aspirate
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

Patients who received transplant were evaluable for the primary endpoint.

Arm/Group Title	Treatment (Chemotherapy and Transplant)
Arm/Group Description	REDUCED-INTENSITY CONDITIONING: Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3, busulfan IV over 45 minutes on days -6 to -3, and anti-thymocyte globulin IV over 4-10 hours on days -6 to -5 (matched sibling donor [MSD]) or -6 to -4 (matched unrelated donor [MUD]). TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0 or on days 0-1. GRAFT-VS-HOST DISEASE PROPHYLAXIS: Patients receive tacrolimus PO or IV on days -2 to 90 with taper on days 150-180. Patients also receive methotrexate IV on days 1, 3, 6 (MSD), and 11 (MUD). CONSOLIDATION: Beginning on day 42, patients receive azacitidine SC or IV on days 1.
Measure Participants	63
PFS at 2 years	41.2
PFS at 5 years	26.9

2. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall survival rate (percentage) at 2 and 5 years is defined as the percentage of patients who are still alive 2 and 5 years after date of transplantation respectively. Estimated using the Kaplan-Meier product limit estimator.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

Patients who received transplant were evaluable for this endpoint.

Arm/Group Title	Treatment (Chemotherapy and Transplant)
Arm/Group Description	REDUCED-INTENSITY CONDITIONING: Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3, busulfan IV over 45 minutes on days -6 to -3, and anti-thymocyte globulin IV over 4-10 hours on days -6 to -5 (matched sibling donor [MSD]) or -6 to -4 (matched unrelated donor [MUD]). TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0 or on days 0-1. GRAFT-VS-HOST DISEASE PROPHYLAXIS: Patients receive tacrolimus PO or IV on days -2 to 90 with taper on days 150-180. Patients also receive methotrexate IV on days 1, 3, 6 (MSD), and 11 (MUD). CONSOLIDATION: Beginning on day 42, patients receive azacitidine SC or IV on days 1.
Measure Participants	63
OS at 2 years	45.7
OS at 5 years	31.2

3. Secondary Outcome

Title	100-day Mortality
Description	The number of death reported within the first 100 days after transplant.
Time Frame	Up to 100 days post-treatment

Outcome Measure Data

Analysis Population Description

Patients who received transplant and died are included in this analysis.

Arm/Group Title	Treatment (Chemotherapy and Transplant)
Arm/Group Description	REDUCED-INTENSITY CONDITIONING: Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3, busulfan IV over 45 minutes on days -6 to -3, and anti-thymocyte globulin IV over 4-10 hours on days -6 to -5 (matched sibling donor [MSD]) or -6 to -4 (matched unrelated donor [MUD]). TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0 or on days 0-1. GRAFT-VS-HOST DISEASE PROPHYLAXIS: Patients receive tacrolimus PO or IV on days -2 to 90 with taper on days 150-180. Patients also receive methotrexate IV on days 1, 3, 6 (MSD), and 11 (MUD). CONSOLIDATION: Beginning on day 42, patients receive azacitidine SC or IV on days 1.
Measure Participants	63
Count of Participants [Participants]	10 14.7%

Adverse Events

Adverse Event Reporting Description	2 patients who cancelled prior to receiving any study treatment are excluded from this analysis
Arm/Group Title	Treatment (Chemotherapy and Transplant)
Arm/Group Description	REDUCED-INTENSITY CONDITIONING: Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3, busulfan IV over 45 minutes on days -6 to -3, and anti-thymocyte globulin IV over 4-10 hours on days -6 to -5 (matched sibling donor [MSD]) or -6 to -4 (matched unrelated donor [MUD]). TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0 or on days 0-1. GRAFT-VS-HOST DISEASE PROPHYLAXIS: Patients receive tacrolimus PO or IV on days -2 to 90 with taper on days 150-180. Patients also receive methotrexate IV on days 1, 3, 6 (MSD), and 11 (MUD). CONSOLIDATION: Beginning on day 42, patients receive azacitidine SC or IV on days 1.
All Cause Mortality
	Treatment (Chemotherapy and Transplant)
	Affected / at Risk (%)	# Events
Total	42/66 (63.6%)
Serious Adverse Events
	Treatment (Chemotherapy and Transplant)
	Affected / at Risk (%)	# Events
Total	22/66 (33.3%)
Blood and lymphatic system disorders
Anemia	18/66 (27.3%)	19
Blood and lymphatic system disorders - Other, specify	1/66 (1.5%)	1
Disseminated intravascular coagulation	1/66 (1.5%)	1
Febrile neutropenia	3/66 (4.5%)	3
Cardiac disorders
Atrial fibrillation	3/66 (4.5%)	3
Cardiac arrest	2/66 (3%)	2
Conduction disorder	1/66 (1.5%)	1
Heart failure	2/66 (3%)	2
Left ventricular systolic dysfunction	1/66 (1.5%)	1
Sinus bradycardia	4/66 (6.1%)	4
Sinus tachycardia	7/66 (10.6%)	7
Supraventricular tachycardia	1/66 (1.5%)	1
Ear and labyrinth disorders
Ear and labyrinth disorders - Other, specify	1/66 (1.5%)	1
Ear pain	3/66 (4.5%)	3
Hearing impaired	1/66 (1.5%)	1
Endocrine disorders
Cushingoid	1/66 (1.5%)	1
Growth accelerated	1/66 (1.5%)	1
Eye disorders
Blurred vision	1/66 (1.5%)	1
Cataract	1/66 (1.5%)	1
Dry eye	1/66 (1.5%)	1
Eye disorders - Other, specify	4/66 (6.1%)	4
Scleral disorder	1/66 (1.5%)	1
Vitreous hemorrhage	1/66 (1.5%)	1
Gastrointestinal disorders
Abdominal distension	2/66 (3%)	2
Abdominal pain	7/66 (10.6%)	7
Ascites	1/66 (1.5%)	1
Constipation	5/66 (7.6%)	5
Diarrhea	12/66 (18.2%)	13
Dry mouth	4/66 (6.1%)	4
Dyspepsia	2/66 (3%)	2
Enterocolitis	1/66 (1.5%)	1
Esophagitis	1/66 (1.5%)	1
Fecal incontinence	3/66 (4.5%)	3
Gastrointestinal disorders - Other, specify	6/66 (9.1%)	7
Hemorrhoids	3/66 (4.5%)	3
Intra-abdominal hemorrhage	1/66 (1.5%)	1
Lower gastrointestinal hemorrhage	1/66 (1.5%)	1
Mucositis oral	4/66 (6.1%)	4
Nausea	11/66 (16.7%)	13
Oral hemorrhage	1/66 (1.5%)	1
Oral pain	1/66 (1.5%)	1
Rectal hemorrhage	1/66 (1.5%)	1
Rectal pain	1/66 (1.5%)	1
Vomiting	8/66 (12.1%)	9
General disorders
Chills	4/66 (6.1%)	4
Death NOS	1/66 (1.5%)	1
Edema face	2/66 (3%)	2
Edema limbs	10/66 (15.2%)	12
Edema trunk	3/66 (4.5%)	3
Fatigue	12/66 (18.2%)	13
Fever	2/66 (3%)	2
General disorders and administration site conditions - Other, specify	2/66 (3%)	2
Hypothermia	1/66 (1.5%)	1
Localized edema	1/66 (1.5%)	1
Malaise	2/66 (3%)	2
Non-cardiac chest pain	1/66 (1.5%)	2
Pain	3/66 (4.5%)	3
Hepatobiliary disorders
Cholecystitis	1/66 (1.5%)	1
Hepatic failure	2/66 (3%)	2
Hepatic hemorrhage	1/66 (1.5%)	1
Portal vein thrombosis	1/66 (1.5%)	1
Infections and infestations
Catheter related infection	1/66 (1.5%)	1
Enterocolitis infectious	1/66 (1.5%)	1
Infections and infestations - Other, specify	6/66 (9.1%)	6
Lung infection	6/66 (9.1%)	7
Mucosal infection	2/66 (3%)	2
Sepsis	4/66 (6.1%)	4
Sinusitis	1/66 (1.5%)	1
Upper respiratory infection	1/66 (1.5%)	1
Urinary tract infection	1/66 (1.5%)	1
Injury, poisoning and procedural complications
Bruising	4/66 (6.1%)	4
Fall	2/66 (3%)	2
Investigations
Activated partial thromboplastin time prolonged	5/66 (7.6%)	5
Alanine aminotransferase increased	11/66 (16.7%)	11
Alkaline phosphatase increased	10/66 (15.2%)	10
Aspartate aminotransferase increased	11/66 (16.7%)	11
Blood bilirubin increased	7/66 (10.6%)	7
Cholesterol high	1/66 (1.5%)	1
Creatinine increased	10/66 (15.2%)	11
Ejection fraction decreased	1/66 (1.5%)	1
Electrocardiogram QT corrected interval prolonged	1/66 (1.5%)	1
Fibrinogen decreased	2/66 (3%)	2
INR increased	3/66 (4.5%)	3
Investigations - Other, specify	3/66 (4.5%)	9
Lymphocyte count decreased	5/66 (7.6%)	5
Neutrophil count decreased	10/66 (15.2%)	11
Platelet count decreased	16/66 (24.2%)	17
Weight gain	1/66 (1.5%)	1
Weight loss	5/66 (7.6%)	7
White blood cell decreased	8/66 (12.1%)	8
Metabolism and nutrition disorders
Acidosis	3/66 (4.5%)	4
Alkalosis	2/66 (3%)	2
Anorexia	9/66 (13.6%)	9
Dehydration	1/66 (1.5%)	1
Hypercalcemia	1/66 (1.5%)	1
Hyperglycemia	14/66 (21.2%)	15
Hyperkalemia	5/66 (7.6%)	5
Hypermagnesemia	1/66 (1.5%)	1
Hypernatremia	3/66 (4.5%)	3
Hypertriglyceridemia	1/66 (1.5%)	1
Hyperuricemia	1/66 (1.5%)	1
Hypoalbuminemia	10/66 (15.2%)	11
Hypocalcemia	7/66 (10.6%)	8
Hypoglycemia	3/66 (4.5%)	3
Hypokalemia	4/66 (6.1%)	4
Hypomagnesemia	11/66 (16.7%)	12
Hyponatremia	9/66 (13.6%)	10
Hypophosphatemia	5/66 (7.6%)	5
Metabolism and nutrition disorders - Other, specify	6/66 (9.1%)	8
Musculoskeletal and connective tissue disorders
Arthralgia	4/66 (6.1%)	4
Back pain	3/66 (4.5%)	3
Generalized muscle weakness	5/66 (7.6%)	6
Musculoskeletal and connective tissue disorder - Other, specify	1/66 (1.5%)	1
Myalgia	2/66 (3%)	2
Pain in extremity	3/66 (4.5%)	4
Soft tissue necrosis lower limb	1/66 (1.5%)	1
Soft tissue necrosis upper limb	1/66 (1.5%)	1
Nervous system disorders
Akathisia	1/66 (1.5%)	1
Depressed level of consciousness	2/66 (3%)	2
Dizziness	2/66 (3%)	2
Dysgeusia	6/66 (9.1%)	6
Encephalopathy	1/66 (1.5%)	1
Extrapyramidal disorder	1/66 (1.5%)	1
Headache	2/66 (3%)	2
Hypersomnia	1/66 (1.5%)	1
Lethargy	1/66 (1.5%)	1
Neuralgia	1/66 (1.5%)	1
Paresthesia	1/66 (1.5%)	1
Peripheral sensory neuropathy	3/66 (4.5%)	3
Presyncope	1/66 (1.5%)	1
Sinus pain	1/66 (1.5%)	1
Somnolence	1/66 (1.5%)	1
Syncope	1/66 (1.5%)	1
Tremor	1/66 (1.5%)	1
Psychiatric disorders
Anxiety	4/66 (6.1%)	4
Confusion	2/66 (3%)	2
Delirium	1/66 (1.5%)	1
Depression	3/66 (4.5%)	3
Hallucinations	1/66 (1.5%)	1
Insomnia	4/66 (6.1%)	4
Psychiatric disorders - Other, specify	1/66 (1.5%)	1
Renal and urinary disorders
Acute kidney injury	4/66 (6.1%)	4
Chronic kidney disease	2/66 (3%)	2
Hematuria	1/66 (1.5%)	1
Renal and urinary disorders - Other, specify	2/66 (3%)	2
Urinary frequency	1/66 (1.5%)	1
Urinary incontinence	1/66 (1.5%)	1
Urinary retention	1/66 (1.5%)	1
Respiratory, thoracic and mediastinal disorders
Atelectasis	3/66 (4.5%)	3
Cough	6/66 (9.1%)	6
Dyspnea	8/66 (12.1%)	8
Epistaxis	3/66 (4.5%)	3
Hypoxia	7/66 (10.6%)	8
Nasal congestion	3/66 (4.5%)	3
Pleural effusion	2/66 (3%)	2
Pleural hemorrhage	1/66 (1.5%)	1
Pneumonitis	3/66 (4.5%)	3
Pneumothorax	3/66 (4.5%)	3
Postnasal drip	1/66 (1.5%)	1
Productive cough	2/66 (3%)	2
Pulmonary fibrosis	1/66 (1.5%)	1
Pulmonary hypertension	1/66 (1.5%)	1
Respiratory failure	5/66 (7.6%)	5
Respiratory, thoracic and mediastinal disorders - Other, specify	3/66 (4.5%)	5
Skin and subcutaneous tissue disorders
Dry skin	4/66 (6.1%)	4
Nail loss	1/66 (1.5%)	1
Pain of skin	3/66 (4.5%)	3
Rash maculo-papular	5/66 (7.6%)	6
Skin and subcutaneous tissue disorders - Other, specify	3/66 (4.5%)	9
Skin hypopigmentation	1/66 (1.5%)	1
Skin ulceration	1/66 (1.5%)	1
Surgical and medical procedures
Surgical and medical procedures - Other, specify	1/66 (1.5%)	1
Vascular disorders
Flushing	1/66 (1.5%)	1
Hot flashes	1/66 (1.5%)	1
Hypertension	9/66 (13.6%)	9
Hypotension	10/66 (15.2%)	12
Thromboembolic event	3/66 (4.5%)	3
Other (Not Including Serious) Adverse Events
	Treatment (Chemotherapy and Transplant)
	Affected / at Risk (%)	# Events
Total	61/66 (92.4%)
Blood and lymphatic system disorders
Anemia	58/66 (87.9%)	219
Blood and lymphatic system disorders - Other, specify	2/66 (3%)	3
Febrile neutropenia	21/66 (31.8%)	24
Hemolysis	1/66 (1.5%)	5
Leukocytosis	4/66 (6.1%)	5
Thrombotic thrombocytopenic purpura	1/66 (1.5%)	2
Cardiac disorders
Atrial fibrillation	8/66 (12.1%)	21
Atrial flutter	1/66 (1.5%)	1
Cardiac disorders - Other, specify	1/66 (1.5%)	1
Chest pain - cardiac	2/66 (3%)	2
Heart failure	1/66 (1.5%)	1
Left ventricular systolic dysfunction	1/66 (1.5%)	1
Myocarditis	1/66 (1.5%)	1
Palpitations	1/66 (1.5%)	1
Paroxysmal atrial tachycardia	1/66 (1.5%)	1
Pericardial effusion	1/66 (1.5%)	1
Restrictive cardiomyopathy	1/66 (1.5%)	1
Sinus bradycardia	15/66 (22.7%)	20
Sinus tachycardia	17/66 (25.8%)	28
Supraventricular tachycardia	1/66 (1.5%)	1
Ventricular arrhythmia	1/66 (1.5%)	1
Ventricular tachycardia	1/66 (1.5%)	1
Ear and labyrinth disorders
Ear and labyrinth disorders - Other, specify	1/66 (1.5%)	2
Ear pain	3/66 (4.5%)	3
Hearing impaired	3/66 (4.5%)	13
Vertigo	1/66 (1.5%)	1
Endocrine disorders
Adrenal insufficiency	1/66 (1.5%)	2
Endocrine disorders - Other, specify	3/66 (4.5%)	3
Hypothyroidism	1/66 (1.5%)	7
Eye disorders
Blurred vision	18/66 (27.3%)	45
Cataract	2/66 (3%)	4
Conjunctivitis	2/66 (3%)	2
Dry eye	10/66 (15.2%)	21
Eye disorders - Other, specify	8/66 (12.1%)	8
Eye pain	4/66 (6.1%)	5
Glaucoma	2/66 (3%)	9
Photophobia	2/66 (3%)	2
Scleral disorder	1/66 (1.5%)	1
Uveitis	1/66 (1.5%)	4
Vitreous hemorrhage	1/66 (1.5%)	1
Watering eyes	5/66 (7.6%)	6
Gastrointestinal disorders
Abdominal distension	5/66 (7.6%)	8
Abdominal pain	23/66 (34.8%)	36
Anal pain	1/66 (1.5%)	1
Bloating	3/66 (4.5%)	6
Colitis	1/66 (1.5%)	1
Constipation	32/66 (48.5%)	54
Diarrhea	52/66 (78.8%)	87
Dry mouth	19/66 (28.8%)	42
Dyspepsia	11/66 (16.7%)	28
Dysphagia	10/66 (15.2%)	10
Esophageal pain	1/66 (1.5%)	1
Fecal incontinence	3/66 (4.5%)	3
Flatulence	3/66 (4.5%)	3
Gastritis	2/66 (3%)	2
Gastroesophageal reflux disease	9/66 (13.6%)	15
Gastrointestinal disorders - Other, specify	12/66 (18.2%)	22
Gastrointestinal pain	1/66 (1.5%)	1
Hemorrhoidal hemorrhage	4/66 (6.1%)	4
Hemorrhoids	6/66 (9.1%)	7
Ileus	1/66 (1.5%)	1
Mucositis oral	47/66 (71.2%)	56
Nausea	48/66 (72.7%)	111
Oral hemorrhage	7/66 (10.6%)	7
Oral pain	11/66 (16.7%)	14
Periodontal disease	1/66 (1.5%)	1
Proctitis	1/66 (1.5%)	1
Rectal hemorrhage	1/66 (1.5%)	1
Rectal pain	3/66 (4.5%)	4
Rectal ulcer	1/66 (1.5%)	1
Stomach pain	1/66 (1.5%)	1
Toothache	1/66 (1.5%)	1
Vomiting	40/66 (60.6%)	57
General disorders
Chills	21/66 (31.8%)	30
Edema face	7/66 (10.6%)	8
Edema limbs	24/66 (36.4%)	56
Edema trunk	3/66 (4.5%)	3
Facial pain	1/66 (1.5%)	1
Fatigue	50/66 (75.8%)	155
Fever	26/66 (39.4%)	28
Flu like symptoms	1/66 (1.5%)	1
General disorders and administration site conditions - Other, specify	5/66 (7.6%)	5
Infusion related reaction	5/66 (7.6%)	7
Injection site reaction	8/66 (12.1%)	13
Localized edema	2/66 (3%)	2
Malaise	1/66 (1.5%)	1
Neck edema	1/66 (1.5%)	1
Non-cardiac chest pain	12/66 (18.2%)	16
Pain	11/66 (16.7%)	20
Hepatobiliary disorders
Hepatobiliary disorders - Other, specify	3/66 (4.5%)	10
Immune system disorders
Immune system disorders - Other, specify	1/66 (1.5%)	4
Infections and infestations
Bladder infection	3/66 (4.5%)	4
Bronchial infection	1/66 (1.5%)	1
Catheter related infection	1/66 (1.5%)	1
Device related infection	1/66 (1.5%)	1
Enterocolitis infectious	2/66 (3%)	2
Infections and infestations - Other, specify	29/66 (43.9%)	46
Lip infection	1/66 (1.5%)	1
Lung infection	6/66 (9.1%)	8
Meningitis	1/66 (1.5%)	1
Mucosal infection	6/66 (9.1%)	16
Nail infection	1/66 (1.5%)	1
Papulopustular rash	3/66 (4.5%)	3
Rash pustular	1/66 (1.5%)	1
Sepsis	5/66 (7.6%)	7
Sinusitis	1/66 (1.5%)	4
Skin infection	3/66 (4.5%)	3
Soft tissue infection	2/66 (3%)	3
Tooth infection	1/66 (1.5%)	1
Upper respiratory infection	7/66 (10.6%)	8
Urinary tract infection	4/66 (6.1%)	5
Injury, poisoning and procedural complications
Bruising	12/66 (18.2%)	21
Fall	2/66 (3%)	2
Injury, poisoning and procedural complications - Other, specify	1/66 (1.5%)	1
Spinal fracture	1/66 (1.5%)	1
Investigations
Activated partial thromboplastin time prolonged	7/66 (10.6%)	15
Alanine aminotransferase increased	40/66 (60.6%)	99
Alkaline phosphatase increased	23/66 (34.8%)	48
Aspartate aminotransferase increased	36/66 (54.5%)	90
Blood bilirubin increased	21/66 (31.8%)	26
Cholesterol high	1/66 (1.5%)	1
Creatinine increased	35/66 (53%)	74
Fibrinogen decreased	1/66 (1.5%)	1
GGT increased	3/66 (4.5%)	10
INR increased	6/66 (9.1%)	11
Investigations - Other, specify	4/66 (6.1%)	32
Lymphocyte count decreased	28/66 (42.4%)	92
Neutrophil count decreased	56/66 (84.8%)	115
Platelet count decreased	56/66 (84.8%)	194
Weight gain	3/66 (4.5%)	5
Weight loss	20/66 (30.3%)	44
White blood cell decreased	35/66 (53%)	77
Metabolism and nutrition disorders
Anorexia	39/66 (59.1%)	91
Dehydration	8/66 (12.1%)	9
Glucose intolerance	1/66 (1.5%)	1
Hypercalcemia	5/66 (7.6%)	10
Hyperglycemia	54/66 (81.8%)	156
Hyperkalemia	24/66 (36.4%)	36
Hypermagnesemia	2/66 (3%)	2
Hypernatremia	5/66 (7.6%)	5
Hypertriglyceridemia	1/66 (1.5%)	1
Hyperuricemia	3/66 (4.5%)	9
Hypoalbuminemia	38/66 (57.6%)	69
Hypocalcemia	40/66 (60.6%)	64
Hypoglycemia	5/66 (7.6%)	6
Hypokalemia	33/66 (50%)	45
Hypomagnesemia	41/66 (62.1%)	104
Hyponatremia	36/66 (54.5%)	72
Hypophosphatemia	18/66 (27.3%)	22
Metabolism and nutrition disorders - Other, specify	12/66 (18.2%)	37
Obesity	1/66 (1.5%)	6
Musculoskeletal and connective tissue disorders
Arthralgia	9/66 (13.6%)	21
Arthritis	1/66 (1.5%)	7
Back pain	14/66 (21.2%)	29
Bone pain	8/66 (12.1%)	10
Buttock pain	2/66 (3%)	4
Flank pain	4/66 (6.1%)	7
Generalized muscle weakness	21/66 (31.8%)	41
Muscle weakness left-sided	1/66 (1.5%)	1
Muscle weakness lower limb	2/66 (3%)	2
Musculoskeletal and connective tissue disorder - Other, specify	11/66 (16.7%)	22
Myalgia	7/66 (10.6%)	12
Myositis	1/66 (1.5%)	1
Neck pain	4/66 (6.1%)	5
Osteoporosis	1/66 (1.5%)	1
Pain in extremity	11/66 (16.7%)	31
Nervous system disorders
Akathisia	2/66 (3%)	2
Amnesia	1/66 (1.5%)	3
Dizziness	16/66 (24.2%)	24
Dysgeusia	25/66 (37.9%)	51
Encephalopathy	1/66 (1.5%)	1
Headache	29/66 (43.9%)	42
Hydrocephalus	1/66 (1.5%)	1
Hypersomnia	1/66 (1.5%)	1
Intracranial hemorrhage	1/66 (1.5%)	1
Lethargy	4/66 (6.1%)	4
Memory impairment	2/66 (3%)	3
Nervous system disorders - Other, specify	1/66 (1.5%)	1
Neuralgia	1/66 (1.5%)	2
Paresthesia	2/66 (3%)	3
Peripheral motor neuropathy	5/66 (7.6%)	6
Peripheral sensory neuropathy	13/66 (19.7%)	36
Presyncope	1/66 (1.5%)	1
Sinus pain	3/66 (4.5%)	4
Somnolence	3/66 (4.5%)	3
Stroke	1/66 (1.5%)	1
Syncope	2/66 (3%)	2
Transient ischemic attacks	1/66 (1.5%)	2
Tremor	13/66 (19.7%)	20
Vasovagal reaction	1/66 (1.5%)	1
Psychiatric disorders
Agitation	1/66 (1.5%)	3
Anxiety	18/66 (27.3%)	39
Confusion	13/66 (19.7%)	14
Delirium	1/66 (1.5%)	1
Depression	11/66 (16.7%)	35
Hallucinations	2/66 (3%)	2
Insomnia	24/66 (36.4%)	54
Psychiatric disorders - Other, specify	1/66 (1.5%)	1
Renal and urinary disorders
Acute kidney injury	12/66 (18.2%)	23
Bladder spasm	2/66 (3%)	2
Chronic kidney disease	2/66 (3%)	3
Cystitis noninfective	2/66 (3%)	2
Hematuria	6/66 (9.1%)	6
Proteinuria	3/66 (4.5%)	4
Renal and urinary disorders - Other, specify	3/66 (4.5%)	4
Renal calculi	1/66 (1.5%)	2
Urinary frequency	10/66 (15.2%)	18
Urinary incontinence	3/66 (4.5%)	3
Urinary retention	5/66 (7.6%)	6
Urinary tract obstruction	1/66 (1.5%)	2
Urinary tract pain	7/66 (10.6%)	8
Urinary urgency	4/66 (6.1%)	4
Reproductive system and breast disorders
Genital edema	3/66 (4.5%)	3
Irregular menstruation	1/66 (1.5%)	1
Penile pain	3/66 (4.5%)	3
Prostatic obstruction	1/66 (1.5%)	1
Reproductive system and breast disorders - Other, specify	1/66 (1.5%)	2
Scrotal pain	1/66 (1.5%)	1
Vaginal discharge	1/66 (1.5%)	1
Vaginal dryness	2/66 (3%)	2
Vaginal hemorrhage	1/66 (1.5%)	1
Vaginal inflammation	3/66 (4.5%)	3
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	6/66 (9.1%)	11
Atelectasis	1/66 (1.5%)	1
Bronchopulmonary hemorrhage	1/66 (1.5%)	1
Cough	21/66 (31.8%)	30
Dyspnea	29/66 (43.9%)	52
Epistaxis	12/66 (18.2%)	13
Hiccups	5/66 (7.6%)	5
Hypoxia	9/66 (13.6%)	9
Laryngeal hemorrhage	2/66 (3%)	2
Laryngeal mucositis	1/66 (1.5%)	1
Nasal congestion	15/66 (22.7%)	21
Pharyngeal mucositis	3/66 (4.5%)	4
Pleural effusion	4/66 (6.1%)	4
Pneumonitis	2/66 (3%)	2
Postnasal drip	4/66 (6.1%)	4
Productive cough	3/66 (4.5%)	3
Pulmonary edema	4/66 (6.1%)	4
Respiratory failure	1/66 (1.5%)	1
Respiratory, thoracic and mediastinal disorders - Other, specify	7/66 (10.6%)	9
Sneezing	1/66 (1.5%)	1
Sore throat	16/66 (24.2%)	24
Wheezing	3/66 (4.5%)	3
Skin and subcutaneous tissue disorders
Alopecia	5/66 (7.6%)	16
Bullous dermatitis	3/66 (4.5%)	4
Dry skin	21/66 (31.8%)	43
Erythema multiforme	5/66 (7.6%)	11
Erythroderma	1/66 (1.5%)	2
Hyperhidrosis	3/66 (4.5%)	3
Nail loss	3/66 (4.5%)	9
Pain of skin	6/66 (9.1%)	8
Palmar-plantar erythrodysesthesia syndrome	1/66 (1.5%)	1
Pruritus	31/66 (47%)	50
Purpura	3/66 (4.5%)	4
Rash acneiform	6/66 (9.1%)	7
Rash maculo-papular	34/66 (51.5%)	58
Skin and subcutaneous tissue disorders - Other, specify	20/66 (30.3%)	55
Skin hyperpigmentation	8/66 (12.1%)	25
Skin hypopigmentation	3/66 (4.5%)	10
Skin ulceration	8/66 (12.1%)	12
Urticaria	3/66 (4.5%)	3
Surgical and medical procedures
Surgical and medical procedures - Other, specify	1/66 (1.5%)	1
Vascular disorders
Flushing	2/66 (3%)	2
Hot flashes	2/66 (3%)	2
Hypertension	40/66 (60.6%)	106
Hypotension	21/66 (31.8%)	39
Phlebitis	1/66 (1.5%)	1
Superficial thrombophlebitis	1/66 (1.5%)	1
Thromboembolic event	7/66 (10.6%)	21
Vascular disorders - Other, specify	1/66 (1.5%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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