Cyclophosphamide and Anti-thymocyte Globulin Followed By Methotrexate and Cyclosporine in Preventing Chronic Graft-Versus-Host Disease in Patients With Severe Aplastic Anemia Undergoing Donor Bone Marrow Transplant

• Sponsor: Fred Hutchinson Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00343785
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 21
• Locations: 3
• Arm: 1
• Duration (Months): 78
• Patients Per Site: 7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This clinical trial is studying how well giving cyclophosphamide together with anti-thymocyte globulin followed by methotrexate and cyclosporine works in preventing chronic graft-vs-host disease (GVHD) in patients with severe aplastic anemia undergoing donor bone marrow transplant. Giving low doses of chemotherapy, such as cyclophosphamide, before a donor bone marrow transplant helps stop the growth of abnormal 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 system and help destroy any remaining abnormal cells. Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving anti-thymocyte globulin before and methotrexate and cyclosporine after transplant may stop this from happening

Condition or Disease	Intervention/Treatment	Phase
Aplastic Anemia	Drug: cyclophosphamide; Biological: anti-thymocyte globulin; Drug: cyclosporine; Procedure: allogeneic bone marrow transplantation; Drug: methotrexate; Genetic: DNA analysis; Other: flow cytometry; Genetic: polymorphism analysis; Other: laboratory biomarker analysis	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. Minimize the incidence of chronic GVHD by restricting the transplanted marrow dose to 2.0-2.5 x 10^8 nucleated cells/kg.

SECONDARY OBJECTIVES:

1. Engraftment and overall survival.

OUTLINE:

CONDITIONING REGIMEN: Patients receive cyclophosphamide intravenously (IV) on days -5 to -2 and anti-thymocyte globulin IV over 4-10 hours on days -4 to -2.

TRANSPLANTATION: Patients undergo allogeneic bone marrow transplantation on day 0.

GVHD PROPHYLAXIS: Patients receive methotrexate IV on days 1, 3, 6, and 11 and cyclosporine IV over 1 hour or orally (PO) twice daily on days -1 to 50, followed by a taper until 6 months after grafting.

After completion of study treatment, patients are followed up at on day 180, 1 year, 1.5 years, 2 years, 3 years, and yearly thereafter.

Study Design

• Study Type: Interventional
• Actual Enrollment: 21 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Cyclophosphamide and Antithymocyte Globulin Conditioning Regimen for Marrow Transplantation From HLA-Matched Family Members for Severe Aplastic Anemia: Effect of Marrow Cell Dose on Chronic Graft-vs.-Host Disease: A Multi-Center Trial
• Study Start Date: Feb 1, 2006
• Actual Primary Completion Date: May 1, 2012
• Actual Study Completion Date: Aug 1, 2012

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (conditioning regimen, transplant, GVHD prophylaxis) Patients receive a conditioning regimen comprising cyclophosphamide IV on days -5 to -2 and anti-thymocyte globulin IV over 4-10 hours on days -4 to -2. Patients undergo allogeneic bone marrow transplantation on day 0. Patients then receive GVHD prophylaxis comprising methotrexate IV on days 1, 3, 6, and 11 and cyclosporine IV over 1 hour or PO twice daily on days -1 to 50, followed by a taper until 6 months after grafting.

Drug: cyclophosphamide; Given IV; Other Names: CPM CTX Cytoxan Endoxan Endoxana ; Biological: anti-thymocyte globulin; Given IV; Other Names: ATG ATGAM lymphocyte immune globulin Thymoglobulin ; Drug: cyclosporine; Given IV or PO; Other Names: ciclosporin cyclosporin cyclosporin A CYSP Sandimmune ; Procedure: allogeneic bone marrow transplantation; Undergo allogeneic bone marrow transplantation; Other Names: bone marrow therapy, allogeneic bone marrow therapy, allogenic transplantation, allogeneic bone marrow transplantation, allogenic bone marrow ; Drug: methotrexate; Given IV; Other Names: amethopterin Folex methylaminopterin Mexate MTX ; Genetic: DNA analysis; Correlative studies; Other: flow cytometry; Correlative studies; Genetic: polymorphism analysis; Correlative studies; Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Incidence of Chronic GVHD [2 years]

   Analyzed using cumulative incidence estimates, treating death or rejection as competing risk events.

Secondary Outcome Measures

1. Number of Days to Neutrophil Recovery to >500/uL [100 days post-transplant]

   First of 3 consecutive days of neutrophils >500/uL

2. Overall Survival [From the time of enrollment until death from any cause up to one year]

   Number of patients alive at one year

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Any patient who has aplastic anemia with marrow failure involving 2 of the three following criteria: granulocytes < 500/uL; a corrected reticulocyte count of < 1%; platelet count of < 20,000/uL

• Availability of an human leukocyte antigen (HLA)-matched family member

• DONOR: Family member who is HLA-matched

• DONOR: If more than one HLA-matched family member is available, priority will be given to a donor who is genotypically HLA-identical, of appropriate cytomegalovirus (CMV) serology, ABO compatible, and, in case of a female donor, non-parous

Exclusion Criteria:

• Severe disease other than aplastic anemia that would severely limit the probability of survival during the graft procedure:

• Patients who have developed clonal cytogenetic abnormalities or myelodysplastic syndrome (preleukemia)

• Patients with Fanconi's anemia

• Aplasia secondary to radiation or cytotoxic chemotherapy

• Patients with paroxysmal nocturnal hemoglobinuria who have not developed aplastic anemia

• Severe organ toxicities:

• Cardiac insufficiency requiring treatment or symptomatic coronary artery disease;

• Severe hypoxemia , partial pressure of oxygen (pO2) < 70 mm Hg, with decreased diffusion capacity of carbon monoxide (DLCO) < 70% of predicted; or mild hypoxemia, pO2 < 80 mm Hg with severely decreased DLCO < 60% of predicted;

• Impaired renal function (creatinine > 2 times upper limit of normal or estimated creatinine clearance < 60 ml/min)

• Fungal infections with radiological progression after receipt of amphotericin B or active triazole for greater than 1 month

• Human immunodeficiency virus (HIV)-positive patients

• Females who are pregnant or breast-feeding

• DONOR: Donors who have increase anesthetic risk and are not able psychologically and medically to tolerate the procedure

• DONOR: HIV-positive donors

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Huntsman Cancer Institute/University of Utah	Salt Lake City	Utah	United States	84112
2	Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium	Seattle	Washington	United States	98109
3	Froedtert and the Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226

Sponsors and Collaborators

• Fred Hutchinson Cancer Center
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Rainer Storb, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Rainer Storb, Principal Investigator, Fred Hutchinson Cancer Center
• ClinicalTrials.gov Identifier: NCT00343785
• Other Study ID Numbers: 2054.00; NCI-2010-01781; P01HL036444
• First Posted: Jun 23, 2006
• Last Update Posted: Apr 13, 2017
• Last Verified: Mar 1, 2017

• Additional relevant MeSH terms: Anemia; Anemia, Aplastic; Cyclosporine; Cyclophosphamide; Methotrexate; Cyclosporins; Thymoglobulin; Antilymphocyte Serum; Immunoglobulins

Study Results

Participant Flow

Arm/Group Title	Treatment (Conditioning Regimen, Transplant, GVHD Prophylaxis)
Arm/Group Description	Patients receive a conditioning regimen comprising cyclophosphamide IV on days -5 to -2 and anti-thymocyte globulin IV over 4-10 hours on days -4 to -2. Patients undergo allogeneic bone marrow transplantation on day 0. Patients then receive GVHD prophylaxis comprising methotrexate IV on days 1, 3, 6, and 11 and cyclosporine IV over 1 hour or PO twice daily on days -1 to 50, followed by a taper until 6 months after grafting.
Period Title: Overall Study
STARTED	21
COMPLETED	21
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treatment (Conditioning Regimen, Transplant, GVHD Prophylaxis)
Arm/Group Description	Patients receive a conditioning regimen comprising cyclophosphamide IV on days -5 to -2 and anti-thymocyte globulin IV over 4-10 hours on days -4 to -2. Patients undergo allogeneic bone marrow transplantation on day 0. Patients then receive GVHD prophylaxis comprising methotrexate IV on days 1, 3, 6, and 11 and cyclosporine IV over 1 hour or PO twice daily on days -1 to 50, followed by a taper until 6 months after grafting.
Overall Participants	21
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	15
Sex: Female, Male (Count of Participants)
Female	5 23.8%
Male	16 76.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	5 23.8%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	9 42.9%
More than one race	3 14.3%
Unknown or Not Reported	4 19%

Outcome Measures

1. Primary Outcome

Title	Incidence of Chronic GVHD
Description	Analyzed using cumulative incidence estimates, treating death or rejection as competing risk events.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

All Patients

Arm/Group Title	Patients Receive a Conditioning Regimen Comprising Cyclophosph
Arm/Group Description	Patients receive a conditioning regimen comprising cyclophosphamide IV on days -5 to -2 and anti-thymocyte globulin IV over 4-10 hours on days -4 to -2. Patients undergo allogeneic bone marrow transplantation on day 0. Patients then receive GVHD prophylaxis comprising methotrexate IV on days 1, 3, 6, and 11 and cyclosporine IV over 1 hour or PO twice daily on days -1 to 50, followed by a taper until 6 months after grafting.
Measure Participants	21
Number [number participants with chronic GVHD]	5 23.8%

2. Secondary Outcome

Title	Number of Days to Neutrophil Recovery to >500/uL
Description	First of 3 consecutive days of neutrophils >500/uL
Time Frame	100 days post-transplant

Outcome Measure Data

Analysis Population Description

All patients

Arm/Group Title	Treatment (Conditioning Regimen, Transplant, GVHD Prophylaxis)
Arm/Group Description	Patients receive a conditioning regimen comprising cyclophosphamide IV on days -5 to -2 and anti-thymocyte globulin IV over 4-10 hours on days -4 to -2. Patients undergo allogeneic bone marrow transplantation on day 0. Patients then receive GVHD prophylaxis comprising methotrexate IV on days 1, 3, 6, and 11 and cyclosporine IV over 1 hour or PO twice daily on days -1 to 50, followed by a taper until 6 months after grafting.
Measure Participants	21
Median (Full Range) [days]	26

3. Secondary Outcome

Title	Overall Survival
Description	Number of patients alive at one year
Time Frame	From the time of enrollment until death from any cause up to one year

Outcome Measure Data

Analysis Population Description

All Patients

Arm/Group Title	Treatment (Conditioning Regimen, Transplant, GVHD Prophylaxis)
Arm/Group Description	Patients receive a conditioning regimen comprising cyclophosphamide IV on days -5 to -2 and anti-thymocyte globulin IV over 4-10 hours on days -4 to -2. Patients undergo allogeneic bone marrow transplantation on day 0. Patients then receive GVHD prophylaxis comprising methotrexate IV on days 1, 3, 6, and 11 and cyclosporine IV over 1 hour or PO twice daily on days -1 to 50, followed by a taper until 6 months after grafting.
Measure Participants	21
Count of Participants [Participants]	21 100%

Adverse Events

Arm/Group Title	Treatment (Conditioning Regimen, Transplant, GVHD Prophylaxis)
Arm/Group Description	Patients receive a conditioning regimen comprising cyclophosphamide IV on days -5 to -2 and anti-thymocyte globulin IV over 4-10 hours on days -4 to -2. Patients undergo allogeneic bone marrow transplantation on day 0. Patients then receive GVHD prophylaxis comprising methotrexate IV on days 1, 3, 6, and 11 and cyclosporine IV over 1 hour or PO twice daily on days -1 to 50, followed by a taper until 6 months after grafting.
All Cause Mortality
	Treatment (Conditioning Regimen, Transplant, GVHD Prophylaxis)
	Affected / at Risk (%)	# Events
Total	0/21 (0%)
Serious Adverse Events
	Treatment (Conditioning Regimen, Transplant, GVHD Prophylaxis)
	Affected / at Risk (%)	# Events
Total	5/21 (23.8%)
Cardiac disorders
hypertension	2/21 (9.5%)	2
Ear and labyrinth disorders
Tinnitus	1/21 (4.8%)	1
Gastrointestinal disorders
parental nutrition	3/21 (14.3%)	3
Hepatobiliary disorders
hyperbilirubinemia	1/21 (4.8%)	1
Nervous system disorders
hypoxia	1/21 (4.8%)	1
Other (Not Including Serious) Adverse Events
	Treatment (Conditioning Regimen, Transplant, GVHD Prophylaxis)
	Affected / at Risk (%)	# Events
Total	21/21 (100%)
Gastrointestinal disorders
nausea	21/21 (100%)	21
vomiting	21/21 (100%)	21
mucositits	21/21 (100%)	21

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.