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Fludarabine Phosphate, Cyclophosphamide, and Total-Body Irradiation Followed by Donor Bone Marrow Transplant and Cyclophosphamide, Mycophenolate Mofetil, Tacrolimus, and Sirolimus in Treating Patients With Primary Immunodeficiency Disorders or Noncancerous Inherited Disorders

Primary Purpose

Immunodeficiency Syndrome, Severe Aplastic Anemia, Genetic Disorder

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Allogeneic Bone Marrow Transplantation
Cyclophosphamide
Fludarabine Phosphate
Laboratory Biomarker Analysis
Mycophenolate Mofetil
Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation
Sirolimus
Tacrolimus
Total-Body Irradiation
Sponsored by
Fred Hutchinson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Immunodeficiency Syndrome

Eligibility Criteria

undefined - 55 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Primary immunodeficiency disorder or other nonmalignant inherited disease (except Fanconi anemia) treatable by allogeneic HCT Patients with pre-existing medical conditions or other factors that renders them at high risk for regimen related toxicity or ineligible for conventional myeloablative HCT and who do not have HLA-matched related or unrelated donors Patients with a related donor who is identical for one HLA haplotype Acquired aplastic anemia: severe aplastic anemia (SAA) is defined as follows: Bone marrow cellularity < 25%, or marrow cellularity < 50% but with < 30% residual hematopoietic cells Two out of three of the following (in peripheral blood): neutrophils < 0.5 x 10^9/L; platelets < 20 x 10^9/L; reticulocytes < 20 x 10^9/L SAA diagnostic criteria may be applied to assessment at initial diagnosis or follow-up assessments DONOR: Related donors who are identical for one HLA haplotype DONOR: Bone marrow will be the only allowed stem cell source Exclusion Criteria: Fanconi anemia Suitably HLA-matched related or unrelated donors Patients with metabolic storage diseases who have severe central nervous system (CNS) involvement of disease, defined as intelligence quotient (IQ) score < 70 Cardiac ejection fraction < 30% (or, if unable to obtain ejection fraction, shortening fraction < 26%) on multiple-gated acquisition (MUGA) scan or cardiac echocardiogram (echo), symptomatic coronary artery disease, or other cardiac failure requiring therapy; patients with a history of, or current cardiac disease should be evaluated with appropriate cardiac studies and/or cardiology consult; patients with a shortening fraction of < 26% must be seen by cardiology for approval Poorly controlled hypertension despite anti-hypertensive medications Patients with clinical or laboratory evidence of liver disease will need to be evaluated for the cause of the liver disease, its clinical severity in terms of liver function and the degree of portal hypertension; patients will be excluded if they are found to have fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, bridging fibrosis, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction evidenced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin > 3 mg/dl, or symptomatic biliary disease Positive for human immunodeficiency virus (HIV) Females who are pregnant (beta-human chorionic gonadotropin positive [beta-HCG+]) or breast-feeding Fertile men or women who are unwilling to use contraceptives during HCT and up to 12 months post-treatment Patients with fungal pneumonia with radiological progression after receipt of amphotericin formulation or mold-active azoles for greater than 1 month will not be eligible for this protocol (either regimen A or B) DONOR: Donor-recipient pairs in which the HLA-mismatch is only in the host-versus-graft (HVG) direction; patients are homozygous and donor is heterozygous DONOR: Donors who are not expected to meet the minimum target dose of marrow cells (1 x 10^8 nucleated cells/kg recipient ideal body weight) DONOR: HIV-positive donors DONOR: A positive anti-donor cytotoxic cross match is absolute donor exclusion DONOR: < 6 months old and > 75 years old

Sites / Locations

  • The Children's Hospital at TriStar Centennial
  • Vanderbilt University/Ingram Cancer Center
  • Fred Hutch/University of Washington Cancer Consortium

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (chemo, total-body irradiation, transplant)

Arm Description

See Detailed Description

Outcomes

Primary Outcome Measures

Graft Rejection
Number of patients with graft rejection (CD3 donor chimerisms <5%).
Graft Failure
Number of patients with graft failure (grade IV thrombocytopenia and neutropenia after day 21 that lasts > 2 weeks andn is refractory to growth factor support).

Secondary Outcome Measures

Proportion of Patients Who Achieve Greater Than 5% Donor T-cell Chimerism
Number of patients who achieve greater than 5% donor T-cell (CD3+) chimerisms
Number of Patients With Transplant Related Mortality
The number of patients with transplant related mortality
Incidence of Grade I/II Acute Graft Versus Host Disease (GVHD)
Number of patients diagnosed with overall GI/G2 acute GVHD by Day 100
Incidence of Grade III/IV Acute Graft Versus Host Disease (GVHD)
Number of patients diagnosed with overall GIII/IV acute GVHD by Day 100
Incidence of Chronic GVHD
Number of patients diagnosed with chronic GVHD by 1 year post transplant
Immune Reconstitution
Number of patients with normal range CD3 @ 1 year post transplant
Number of Patients With Infections
Number of patients with clinically significant infections requiring treatment within 200 days after HCT

Full Information

First Posted
July 28, 2006
Last Updated
January 6, 2021
Sponsor
Fred Hutchinson Cancer Center
Collaborators
National Cancer Institute (NCI), National Heart, Lung, and Blood Institute (NHLBI)
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1. Study Identification

Unique Protocol Identification Number
NCT00358657
Brief Title
Fludarabine Phosphate, Cyclophosphamide, and Total-Body Irradiation Followed by Donor Bone Marrow Transplant and Cyclophosphamide, Mycophenolate Mofetil, Tacrolimus, and Sirolimus in Treating Patients With Primary Immunodeficiency Disorders or Noncancerous Inherited Disorders
Official Title
HLA-Haploidentical Related Marrow Grafts for the Treatment of Primary Immunodeficiencies and Other Nonmalignant Disorders Using Conditioning With Low-Dose Cyclophosphamide, TBI and Fludarabine and Postgrafting Cyclophosphamide
Study Type
Interventional

2. Study Status

Record Verification Date
January 2021
Overall Recruitment Status
Terminated
Why Stopped
Low accrual
Study Start Date
May 24, 2006 (Actual)
Primary Completion Date
August 17, 2018 (Actual)
Study Completion Date
May 25, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Fred Hutchinson Cancer Center
Collaborators
National Cancer Institute (NCI), National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This phase I/II trial studies the side effects of fludarabine phosphate, cyclophosphamide and total-body irradiation followed by donor bone marrow transplant and cyclophosphamide, mycophenolate mofetil, tacrolimus, and sirolimus in treating patients with primary immunodeficiency disorders or noncancerous inherited disorders. Giving low doses of chemotherapy and total-body irradiation before a bone marrow transplant helps prepare the patient's body to accept the incoming donor's bone marrow and decrease the risk that the patient's immune system will reject the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells called graft versus host disease. Giving cyclophosphamide, mycophenolate mofetil, tacrolimus, and sirolimus after the transplant may help decrease this from happening.
Detailed Description
PRIMARY OBJECTIVE: I. Determine safety of nonmyeloablative conditioning and hematopoietic cell transplantation (HCT) from human leukocyte antigen (HLA)-haploidentical related donors for patients with nonmalignant inherited disorders who do not have an HLA-matched related or unrelated donor. SECONDARY OBJECTIVES: I. Determine whether nonmyeloablative conditioning and HCT from an HLA-haploidentical related donor graft can establish mixed chimerism (> 5% cluster of differentiation [CD]3+ donor T-cell chimerism) in patients with nonmalignant inherited disorders. II. Transplant related mortality at day 100. III. Incidence and severity of graft-versus-host disease (GHVD). IV. Immune reconstitution. V. Infections during the first 200 days after HCT. OUTLINE: NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) over 1 hour on days -6 to -2; cyclophosphamide IV over 1 hour on days -6 and -5; and undergo total body irradiation on day -1. TRANSPLANTATION: Patients undergo allogeneic bone marrow transplant on day 0. POST-TRANSPLANT IMMUNOSUPPRESSION: Patients receive cyclophosphamide IV over 1 hour on days 3 and 4, and mycophenolate mofetil orally (PO) every 8 hours on days 5-30 then twice daily (BID) to day 40, and then if there is no evidence of active GVHD and donor engraftment is > 95% (or by principal investigator [PI] approval) taper until approximately day 96, or faster at discretion of PI. Patients also receive tacrolimus IV continuously over 22-24 hours starting on day 5 post-transplant and continue on tacrolimus through day 100 followed by a taper to approximately day 180 if there is no evidence of GVHD and their graft is doing well. Patients may convert to oral tacrolimus given BID or three times daily (TID) when the patient is able to take medications orally and has a therapeutic drug level. In addition, patients will receive sirolimus PO beginning on day 5 through day 180 followed by a taper to approximately day 210 if there is no evidence of GVHD and their graft is doing well. After completion of study treatment, patients are followed up at 6, 12, 18, and 24 months, and then annually for 5 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Immunodeficiency Syndrome, Severe Aplastic Anemia, Genetic Disorder

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
14 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (chemo, total-body irradiation, transplant)
Arm Type
Experimental
Arm Description
See Detailed Description
Intervention Type
Procedure
Intervention Name(s)
Allogeneic Bone Marrow Transplantation
Other Intervention Name(s)
Allo BMT, Allogeneic BMT
Intervention Description
Undergo allogeneic bone marrow transplantation
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
(-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Fludarabine Phosphate
Other Intervention Name(s)
2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586
Intervention Description
Given IV
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Intervention Type
Drug
Intervention Name(s)
Mycophenolate Mofetil
Other Intervention Name(s)
Cellcept, MMF
Intervention Description
Given PO
Intervention Type
Procedure
Intervention Name(s)
Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation
Other Intervention Name(s)
Non-myeloablative allogeneic transplant, Nonmyeloablative Stem Cell Transplantation, NST
Intervention Description
Undergo allogeneic bone marrow transplantation
Intervention Type
Drug
Intervention Name(s)
Sirolimus
Other Intervention Name(s)
AY 22989, RAPA, Rapamune, Rapamycin, SILA 9268A, WY-090217
Intervention Description
Given PO
Intervention Type
Drug
Intervention Name(s)
Tacrolimus
Other Intervention Name(s)
FK 506, Fujimycin, Hecoria, Prograf, Protopic
Intervention Description
Given IV or PO
Intervention Type
Radiation
Intervention Name(s)
Total-Body Irradiation
Other Intervention Name(s)
TOTAL BODY IRRADIATION, Whole-Body Irradiation
Intervention Description
Undergo total-body irradiation
Primary Outcome Measure Information:
Title
Graft Rejection
Description
Number of patients with graft rejection (CD3 donor chimerisms <5%).
Time Frame
Day 84
Title
Graft Failure
Description
Number of patients with graft failure (grade IV thrombocytopenia and neutropenia after day 21 that lasts > 2 weeks andn is refractory to growth factor support).
Time Frame
Day 84
Secondary Outcome Measure Information:
Title
Proportion of Patients Who Achieve Greater Than 5% Donor T-cell Chimerism
Description
Number of patients who achieve greater than 5% donor T-cell (CD3+) chimerisms
Time Frame
By day 84
Title
Number of Patients With Transplant Related Mortality
Description
The number of patients with transplant related mortality
Time Frame
Day 100 post transplant
Title
Incidence of Grade I/II Acute Graft Versus Host Disease (GVHD)
Description
Number of patients diagnosed with overall GI/G2 acute GVHD by Day 100
Time Frame
Day 100 post transplant
Title
Incidence of Grade III/IV Acute Graft Versus Host Disease (GVHD)
Description
Number of patients diagnosed with overall GIII/IV acute GVHD by Day 100
Time Frame
Day 100 post transplant
Title
Incidence of Chronic GVHD
Description
Number of patients diagnosed with chronic GVHD by 1 year post transplant
Time Frame
1 year post transplant
Title
Immune Reconstitution
Description
Number of patients with normal range CD3 @ 1 year post transplant
Time Frame
1 year post transplant
Title
Number of Patients With Infections
Description
Number of patients with clinically significant infections requiring treatment within 200 days after HCT
Time Frame
Through day 200 after HCT

10. Eligibility

Sex
All
Maximum Age & Unit of Time
55 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Primary immunodeficiency disorder or other nonmalignant inherited disease (except Fanconi anemia) treatable by allogeneic HCT Patients with pre-existing medical conditions or other factors that renders them at high risk for regimen related toxicity or ineligible for conventional myeloablative HCT and who do not have HLA-matched related or unrelated donors Patients with a related donor who is identical for one HLA haplotype Acquired aplastic anemia: severe aplastic anemia (SAA) is defined as follows: Bone marrow cellularity < 25%, or marrow cellularity < 50% but with < 30% residual hematopoietic cells Two out of three of the following (in peripheral blood): neutrophils < 0.5 x 10^9/L; platelets < 20 x 10^9/L; reticulocytes < 20 x 10^9/L SAA diagnostic criteria may be applied to assessment at initial diagnosis or follow-up assessments DONOR: Related donors who are identical for one HLA haplotype DONOR: Bone marrow will be the only allowed stem cell source Exclusion Criteria: Fanconi anemia Suitably HLA-matched related or unrelated donors Patients with metabolic storage diseases who have severe central nervous system (CNS) involvement of disease, defined as intelligence quotient (IQ) score < 70 Cardiac ejection fraction < 30% (or, if unable to obtain ejection fraction, shortening fraction < 26%) on multiple-gated acquisition (MUGA) scan or cardiac echocardiogram (echo), symptomatic coronary artery disease, or other cardiac failure requiring therapy; patients with a history of, or current cardiac disease should be evaluated with appropriate cardiac studies and/or cardiology consult; patients with a shortening fraction of < 26% must be seen by cardiology for approval Poorly controlled hypertension despite anti-hypertensive medications Patients with clinical or laboratory evidence of liver disease will need to be evaluated for the cause of the liver disease, its clinical severity in terms of liver function and the degree of portal hypertension; patients will be excluded if they are found to have fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, bridging fibrosis, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction evidenced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin > 3 mg/dl, or symptomatic biliary disease Positive for human immunodeficiency virus (HIV) Females who are pregnant (beta-human chorionic gonadotropin positive [beta-HCG+]) or breast-feeding Fertile men or women who are unwilling to use contraceptives during HCT and up to 12 months post-treatment Patients with fungal pneumonia with radiological progression after receipt of amphotericin formulation or mold-active azoles for greater than 1 month will not be eligible for this protocol (either regimen A or B) DONOR: Donor-recipient pairs in which the HLA-mismatch is only in the host-versus-graft (HVG) direction; patients are homozygous and donor is heterozygous DONOR: Donors who are not expected to meet the minimum target dose of marrow cells (1 x 10^8 nucleated cells/kg recipient ideal body weight) DONOR: HIV-positive donors DONOR: A positive anti-donor cytotoxic cross match is absolute donor exclusion DONOR: < 6 months old and > 75 years old
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Kanwaldeep Mallhi
Organizational Affiliation
Fred Hutch/University of Washington Cancer Consortium
Official's Role
Principal Investigator
Facility Information:
Facility Name
The Children's Hospital at TriStar Centennial
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37203
Country
United States
Facility Name
Vanderbilt University/Ingram Cancer Center
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States
Facility Name
Fred Hutch/University of Washington Cancer Consortium
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Fludarabine Phosphate, Cyclophosphamide, and Total-Body Irradiation Followed by Donor Bone Marrow Transplant and Cyclophosphamide, Mycophenolate Mofetil, Tacrolimus, and Sirolimus in Treating Patients With Primary Immunodeficiency Disorders or Noncancerous Inherited Disorders

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