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

January 6, 2021 updated by: Kanwaldeep K Mallhi, Fred Hutchinson Cancer Center

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

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.

Study Overview

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.

Study Type

Interventional

Enrollment (Actual)

14

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • Tennessee
      • Nashville, Tennessee, United States, 37232
        • Vanderbilt University/Ingram Cancer Center
      • Nashville, Tennessee, United States, 37203
        • The Children's Hospital at TriStar Centennial
    • Washington
      • Seattle, Washington, United States, 98109
        • Fred Hutch/University of Washington Cancer Consortium

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 55 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Treatment (chemo, total-body irradiation, transplant)
See Detailed Description
Correlative studies
Given IV
Other Names:
  • Cytoxan
  • CTX
  • (-)-Cyclophosphamide
  • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
  • Carloxan
  • Ciclofosfamida
  • Ciclofosfamide
  • Cicloxal
  • Clafen
  • Claphene
  • CP monohydrate
  • CYCLO-cell
  • Cycloblastin
  • Cycloblastine
  • Cyclophospham
  • Cyclophosphamid monohydrate
  • Cyclophosphamidum
  • Cyclophosphan
  • Cyclophosphane
  • Cyclophosphanum
  • Cyclostin
  • Cyclostine
  • Cytophosphan
  • Cytophosphane
  • Fosfaseron
  • Genoxal
  • Genuxal
  • Ledoxina
  • Mitoxan
  • Neosar
  • Revimmune
  • Syklofosfamid
  • WR- 138719
Given PO
Other Names:
  • Cellcept
  • MMF
Given IV
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara
  • 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-
  • SH T 586
Given IV or PO
Other Names:
  • Prograf
  • Hecoria
  • FK 506
  • Fujimycin
  • Protopic
Given PO
Other Names:
  • Rapamycin
  • Rapamune
  • AY 22989
  • RAPA
  • SILA 9268A
  • WY-090217
Undergo total-body irradiation
Other Names:
  • Whole-Body Irradiation
  • TOTAL BODY IRRADIATION
Undergo allogeneic bone marrow transplantation
Other Names:
  • Allo BMT
  • Allogeneic BMT
Undergo allogeneic bone marrow transplantation
Other Names:
  • NST
  • Non-myeloablative allogeneic transplant
  • Nonmyeloablative Stem Cell Transplantation

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Graft Rejection
Time Frame: Day 84
Number of patients with graft rejection (CD3 donor chimerisms <5%).
Day 84
Graft Failure
Time Frame: Day 84
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).
Day 84

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Proportion of Patients Who Achieve Greater Than 5% Donor T-cell Chimerism
Time Frame: By day 84
Number of patients who achieve greater than 5% donor T-cell (CD3+) chimerisms
By day 84
Number of Patients With Transplant Related Mortality
Time Frame: Day 100 post transplant
The number of patients with transplant related mortality
Day 100 post transplant
Incidence of Grade I/II Acute Graft Versus Host Disease (GVHD)
Time Frame: Day 100 post transplant
Number of patients diagnosed with overall GI/G2 acute GVHD by Day 100
Day 100 post transplant
Incidence of Grade III/IV Acute Graft Versus Host Disease (GVHD)
Time Frame: Day 100 post transplant
Number of patients diagnosed with overall GIII/IV acute GVHD by Day 100
Day 100 post transplant
Incidence of Chronic GVHD
Time Frame: 1 year post transplant
Number of patients diagnosed with chronic GVHD by 1 year post transplant
1 year post transplant
Immune Reconstitution
Time Frame: 1 year post transplant
Number of patients with normal range CD3 @ 1 year post transplant
1 year post transplant
Number of Patients With Infections
Time Frame: Through day 200 after HCT
Number of patients with clinically significant infections requiring treatment within 200 days after HCT
Through day 200 after HCT

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Kanwaldeep Mallhi, Fred Hutch/University of Washington Cancer Consortium

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 24, 2006

Primary Completion (Actual)

August 17, 2018

Study Completion (Actual)

May 25, 2019

Study Registration Dates

First Submitted

July 28, 2006

First Submitted That Met QC Criteria

July 28, 2006

First Posted (Estimate)

August 1, 2006

Study Record Updates

Last Update Posted (Actual)

January 26, 2021

Last Update Submitted That Met QC Criteria

January 6, 2021

Last Verified

January 1, 2021

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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