- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01659606
Radiation- and Alkylator-free Bone Marrow Transplantation Regimen for Patients With Dyskeratosis Congenita
February 5, 2024 updated by: Suneet Agarwal, Boston Children's Hospital
Radiation- and Alkylator-free Hematopoietic Cell Transplantation for Bone Marrow Failure Due to Dyskeratosis Congenita / Telomere Disease
Dyskeratosis congenita is a disease that affects numerous parts of the body, most typically causing failure of the blood system.
Lung disease, liver disease and cancer are other frequent causes of illness and death.
Bone marrow transplantation (BMT) can cure the blood system but can make the lung and liver disease and risk of cancer worse, because of DNA damaging agents such as alkylators and radiation that are typically used in the procedure.
Based on the biology of DC, we hypothesize that it may be possible to avoid these DNA damaging agents in patients with DC, and still have a successful BMT.
In this protocol we will test whether a regimen that avoids DNA alkylators and radiation can permit successful BMT without compromising survival in patients with DC.
Study Overview
Status
Active, not recruiting
Intervention / Treatment
Detailed Description
Dyskeratosis congenita (DC) is an inherited multisystem disorder, which classically presents with a clinical triad of skin pigment abnormalities, nail dystrophy, and oral leukoplakia.
DC is part of a spectrum of telomere biology disorders, which include some forms of inherited idiopathic aplastic anemia, myelodysplastic syndrome, and pulmonary fibrosis and the congenital diseases Hoyeraal-Hreidarsson syndrome and Revesz syndrome.
Progressive bone marrow failure (BMF) occurs in more than 80% of patients under 30 years of age and is the primary cause of morbidity and mortality, followed by pulmonary failure and malignancies.
Allogeneic hematopoietic cell transplantation (HCT) is curative for the hematological defects, but several studies have demonstrated poor outcomes in DC patients due to increased early and late complications.
A predisposition to pulmonary failure, vascular disease and secondary malignancies may contribute to the high incidence of fatal complications following HCT in DC patients, and provides an impetus to reduce exposure to chemotherapy and radiotherapy in preparative regimens.
Recent studies suggest that fludarabine-based conditioning regimens provide stable engraftment and may avoid the toxicities seen after HCT for DC, but studies to date are limited to case reports, retrospective studies and a single prospective trial.
In this study, we propose to prospectively evaluate the efficacy of a fludarabine- and antibody-based conditioning regimen in HCT for DC patients, with the goals of maintaining donor hematopoiesis and transfusion independence while decreasing early and late complications of HCT for DC.
Study Type
Interventional
Enrollment (Estimated)
40
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
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Oslo, Norway
- Oslo University Hospital
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Stockholm, Sweden
- Karolinska University Hospital
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California
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Los Angeles, California, United States, 90027
- Children's Hospital Los Angeles
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Illinois
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Chicago, Illinois, United States, 60637
- University of Chicago
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Massachusetts
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Boston, Massachusetts, United States, 02114
- Massachusetts General Hospital
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Boston, Massachusetts, United States, 02115
- Boston Children's Hospital (pediatric patients)
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Boston, Massachusetts, United States, 02115
- Dana-Farber Cancer Institute (adult patients)
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Minnesota
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Rochester, Minnesota, United States, 55905
- Mayo Clinic
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Missouri
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Kansas City, Missouri, United States, 64108
- Children's Mercy Hospital Kansas City
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New Jersey
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Hackensack, New Jersey, United States, 07601
- Hackensack University Medical Center
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North Carolina
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Durham, North Carolina, United States, 27705
- Duke University Medical Center, Pediatric BMT
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Ohio
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Cincinnati, Ohio, United States, 45229
- Cincinnati Children's Hospital Medical Center
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Pennsylvania
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Philadelphia, Pennsylvania, United States, 19104
- Children's Hospital of Philadelphia
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Texas
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Houston, Texas, United States, 77030
- Baylor College of Medicine
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Washington
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Seattle, Washington, United States, 98109
- Fred Hutch/University of Washington/Seattle Children's Cancer Consortium
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Wisconsin
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Madison, Wisconsin, United States, 53792
- University of Wisconsin Hospital and Clinics
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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
4 weeks to 65 years (Child, Adult, Older Adult)
Accepts Healthy Volunteers
No
Description
Inclusion Criteria:
- Bone marrow hypocellular for age
- Moderate or severe aplastic anemia defined by one of the following: peripheral blood neutrophils < 0.5 x 10^9/L; platelets < 30 x 10^9/L or platelet transfusion dependence; reticulocytes < 50 x 10^9/L in anemic patients or red cell transfusion dependence
- Diagnosis of dyskeratosis congenita based on clinical triad of abnormalities of skin pigmentation, nail dystrophy, oral leukoplakia; OR one of clinical triad and presence of two or more associated features; OR a pathogenic mutation in DKC1,TERC, TERT, NOP10, NHP2, TCAB1, TINF2, CTC1, PARN, RTEL1, ACD, NAF1, STN1, or ZCCHC8, as reported by a CLIA-approved laboratory; OR age-adjusted mean telomere length < 1%ile in peripheral blood lymphocytes as reported by a CLIA-approved laboratory; OR Hoyeraal-Hreidarsson syndrome; OR Revesz syndrome
- Availability of a related or unrelated donor with a 7/8 or 8/8 match for HLA-A, B, C, and DRB1.
- Patient and/or legal guardian must be able to sign informed consent.
- Donor must provide a marrow allograft.
- Diagnosis of Fanconi anemia must be excluded by mitomycin C or diepoxybutane chromosomal breakage testing on peripheral blood at a CLIA-approved laboratory (not required for patients with a genetic mutation consistent with DC)
- Adequate renal function with glomerular filtration rate equal to or greater than 30 ml/min/1.73 m2
Exclusion Criteria:
- Clonal cytogenetic abnormalities associated with MDS or AML on bone marrow examination.
- Karnofsky/Lansky performance status < 40.
- Uncontrolled bacterial, viral or fungal infections.
- Positive test for the human immunodeficiency virus (HIV).
- Pregnancy or breastfeeding.
- Known severe or life-threatening allergy or intolerance to fludarabine, alemtuzumab, mycophenolate mofetil or both cyclosporine and tacrolimus.
- Positive patient anti-donor HLA antibody, which is deemed clinically significant.
- Prior allogeneic marrow or stem cell transplantation.
- Prior solid organ transplantation.
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 |
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Experimental: alemtuzumab/fludarabine conditioning
alemtuzumab/fludarabine conditioning; calcineurin-inhibitor/mycophenolate mofetil GVHD prophylaxis
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Other Names:
Conditioning: alemtuzumab 0.2 mg/kg/dose IV/SC x 5 doses
Other Names:
fludarabine 30 mg/m2/dose IV x 6 doses
Other Names:
Other Names:
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
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Primary engraftment
Time Frame: Up to day +100 post-BMT
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Up to day +100 post-BMT
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Survival to day+100 post-BMT
Time Frame: Up to day+100 post-BMT
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Up to day+100 post-BMT
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Viral reactivation and infection
Time Frame: Up to day +100 post-BMT
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Number of participants with DNA virus (cytomegalovirus, Epstein Barr virus, or adenovirus) reactivation/infection detected by PCR screening will be reported.
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Up to day +100 post-BMT
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Treatment related adverse events as assessed by CTCAE version 4.0
Time Frame: Up to 1 year post-BMT
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Up to 1 year post-BMT
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Secondary graft failure
Time Frame: Up to 15 years post-BMT
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Up to 15 years post-BMT
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Acute and chronic graft-versus-host disease (GVHD)
Time Frame: Up to 15 years post-BMT
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Up to 15 years post-BMT
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Engraftment monitoring (chimerism)
Time Frame: Up to 15 years post-BMT
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Up to 15 years post-BMT
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Immune reconstitution as assessed by quantitation of lymphocyte subsets
Time Frame: Up to 15 years post-BMT
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Number of participants with quantitative defects in lymphocyte subset numbers following BMT
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Up to 15 years post-BMT
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Changes in pulmonary function as assessed by pulmonary function testing
Time Frame: Up to 15 years post-BMT
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Up to 15 years post-BMT
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Secondary malignancies
Time Frame: Up to 15 years post-BMT
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Number of patients with malignancies following BMT
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Up to 15 years post-BMT
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Long-term survival
Time Frame: Up to 15 years post-BMT
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Up to 15 years post-BMT
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Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Collaborators
Investigators
- Principal Investigator: Suneet Agarwal, MD, PHD, Boston Children's Hospital
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
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
July 1, 2012
Primary Completion (Estimated)
April 1, 2024
Study Completion (Estimated)
December 1, 2034
Study Registration Dates
First Submitted
August 6, 2012
First Submitted That Met QC Criteria
August 6, 2012
First Posted (Estimated)
August 8, 2012
Study Record Updates
Last Update Posted (Estimated)
February 6, 2024
Last Update Submitted That Met QC Criteria
February 5, 2024
Last Verified
February 1, 2024
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Pathologic Processes
- Skin Diseases
- Disease
- Congenital Abnormalities
- Bone Marrow Diseases
- Hematologic Diseases
- Genetic Diseases, Inborn
- Genetic Diseases, X-Linked
- Anemia
- Skin Diseases, Genetic
- Skin Abnormalities
- Congenital Bone Marrow Failure Syndromes
- Bone Marrow Failure Disorders
- Syndrome
- Anemia, Aplastic
- Dyskeratosis Congenita
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Enzyme Inhibitors
- Antirheumatic Agents
- Antineoplastic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Antineoplastic Agents, Immunological
- Dermatologic Agents
- Anti-Bacterial Agents
- Antibiotics, Antineoplastic
- Antifungal Agents
- Antitubercular Agents
- Antibiotics, Antitubercular
- Calcineurin Inhibitors
- Fludarabine
- Tacrolimus
- Mycophenolic Acid
- Cyclosporine
- Cyclosporins
- Alemtuzumab
Other Study ID Numbers
- 12-950
- IRB-P00003466 (Other Identifier: Boston Children's Hospital)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
UNDECIDED
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
No
Studies a U.S. FDA-regulated device product
No
product manufactured in and exported from the U.S.
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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