Hematopoietic Stem Cell Transplantation for the Treatment of Patients With Fanconi Anemia Lacking a Genotypically Identical Donor, Using a Chemotherapy Only Cytoreduction With Busulfan, Cyclophosphamide and Fludarabine

This study is currently recruiting participants.
Verified February 2014 by Memorial Sloan-Kettering Cancer Center
Sponsor:
Collaborators:
Children's Hospital Boston
Children's Hospital Medical Center, Cincinnati
Children's Hospital and Health System Foundation, Wisconsin
Rockefeller University
Fred Hutchinson Cancer Research Center
Information provided by (Responsible Party):
Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier:
NCT00987480
First received: September 30, 2009
Last updated: February 20, 2014
Last verified: February 2014
  Purpose

This is a genetic disease (transmitted through the parents' genes) called Fanconi Anemia. Because of that genetic disease, the bone marrow has changed and now has failed, or has given rise to a preleukemia called myelodysplastic syndrome (MDS) or leukemia (acute myelogenous leukemia or AML).

Without treatment these complications of Fanconia anemia (FA) are fatal. The only treatment that can cure these complications is an allogeneic transplant of stem cells, meaning, giving the patient bone marrow cells from a healthy donor that can produce normal blood cells that will replace the bone marrow that is sick.

What has been given for the treatment of FA in the past is to use a combination of low doses of radiation to the whole body (total body irradiation) and low doses of the chemotherapy drugs (cyclophosphamide and fludarabine) before the transplant. However, the use of radiation can, later on, increase the chances of getting a second cancer of the skin, head or the neck. These chances of a second cancer are higher than normal in patients with FA.

The purpose of this study is to find out if the doctors can do the same thing with the same chemotherapy drugs used in the past. However physicians will use another chemotherapy drug called busulfan instead of the radiation. The goal of this study is to get rid of the short term and long term risks of the radiation. The first new part of this treatment will be to replace drugs for radiation with chemotherapy drugs.


Condition Intervention Phase
Aplastic Anemia
Leukemia
Myelodysplastic Syndrome
Drug: Busulfan, fludarabine, & cyclophosphamide with immunosuppression with ATG and cyclosporine.
Device: CliniMACS device
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Multicenter Phase II Trial of Hematopoietic Stem Cell Transplantation for the Treatment of Patients With Fanconi Anemia Lacking a Genotypically Identical Donor, Using a Chemotherapy Only Cytoreduction With Busulfan, Cyclophosphamide and Fludarabine

Resource links provided by NLM:


Further study details as provided by Memorial Sloan-Kettering Cancer Center:

Primary Outcome Measures:
  • The incidence and quality of engraftment and hematopoietic reconstitution [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • The incidence of early transplant related mortality [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
  • The incidence and severity of acute GvHD and chronic GVHD. [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • The incidence of overall survival and disease-free survival over time [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 45
Study Start Date: September 2009
Estimated Study Completion Date: September 2015
Estimated Primary Completion Date: September 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: chemotherapy-based cytoreductive regimen plus a CD34+ selected
This phase II trial is designed to investigate the safety and efficacy of a chemotherapy-based cytoreductive regimen plus a CD34+ selected T-cell depleted peripheral blood stem cell (PBSC) stem cell transplant for the treatment of patients with Fanconi anemia and severe hematologic disease.
Drug: Busulfan, fludarabine, & cyclophosphamide with immunosuppression with ATG and cyclosporine.
There are three parts in this transplant study. 1) There will be a pre-transplant - preparation - period to see if patient qualifies for the transplant study. This will be done as an outpatient and lasts 2-4 weeks. Once this is completed, there will be 2) the transplant period itself, during which the patient will be admitted and will be an inpatient. This period usually last for 4-6 weeks. Following that, there will be a 3) post transplant period, during which the patient will be watched carefully and monitored in clinic as an out patient. The post transplant period lasts from three months to one year.
Device: CliniMACS device
CD34+ T-cell depleted peripheral blood stem cell transplant

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Patients must have a diagnosis of Fanconi anemia (confirmed by mitomycin C or diepoxybutane [DEB] chromosomal breakage testing at an approved laboratory).
  • Hematologic Diagnosis and Status - Patients must have one of the following hematologic diagnoses:

    • Severe Aplastic Anemia (SAA) with bone marrow cellularity of <25%, or Severe Isolated Single lineage Cytopenia

AND at least one of the following features:

  • Platelet count <20 x 109/L or platelet transfusion dependence*
  • ANC <1000 x 109/L
  • Hgb <8 gm/dl or red cell transfusion dependence*
  • Myelodysplastic Syndrome (MDS) (Appendix 1: MDS Classification) - MDS at any stage, based on either one of the following classifications:

    • WHO Classification
    • Refractory anemia and transfusion dependence*
    • Any of other stages
    • IPSS Classification
    • Low risk (score 0) and transfusion dependence*
    • Any other risk groups Score > or = to 0.5
  • Acute Myelogenous Leukemia

    • Patients with acute leukemia are included in this trial in remission, refractory or relapsed disease.
    • Transfusion dependence will be defined as greater than ONE transfusion of platelets or red blood cells in the last year prior to evaluation on protocol.

      • Donors:
  • Donor choices will be determined by the investigators at each of the centers according to their own institutional criteria.
  • All patients evaluated at trial sites and eligible for this trial by virtue of disease and lack of an HLA-genotypically matched related donor will be captured in the database of this trial. Patients who will be enrolled on this protocol must have one of the following donor choices:

    • HLA-compatible Unrelated volunteer donors
    • Patients who do not have a related HLA-matched donor but have an unrelated donor who is either matched at all A, B, C and DRB1 (8/8) loci or who is mismatched at 1/8 loci (A, B, C or DRB1) (7/8) as tested by DNA analysis (high resolution), will be eligible for entry on this protocol.
    • HLA-mismatched Related donors
    • Patients who do not have a related or unrelated HLA-compatible donor must have a healthy family member who is at least HLA-haplotype identical to the recipient. First degree related donors must have a normal DEB test.
    • The donor must be healthy and willing and able to receive a 4-6 day course of G-CSF and undergo 1-3 daily leukaphereses.
    • Related and Unrelated donors must be medically evaluated and fulfill the criteria for collection of PBSCs as per institutional guidelines.

      • Patients:
  • Patients and donors may be of either gender or any ethnic background.
  • Patients must have a Karnofsky adult, or Lansky pediatric performance scale status > or = 70%.
  • At the time of referral for transplantation, patients must have no co-existing medical problems that would significantly increase the risk of the transplant procedure.
  • Patients must have adequate physical function measured by :

    • Cardiac: asymptomatic or if symptomatic then 1) LVEF at rest must be > or = to 50% and must improve with exercise or 2) Shortening Fraction > or = to 29%
    • Hepatic: < 5 x ULN SGOT and < 2.0 mg/dl total serum bilirubin.
    • Renal: serum creatinine < or = to 1.5 mg/dl or if serum creatinine is outside the normal range, then CrCl > 60-ml/min/1.73 m2
    • Pulmonary: asymptomatic or if symptomatic, DLCO > 50% of predicted (corrected for hemoglobin)
  • Each patient must be willing to participate as a research subject and must sign an informed consent form. Parent or legal guardians of patients who are minors will sign the informed consent form. Assents will be obtained as age appropriate.
  • Female patients and donors must not be pregnant or breastfeeding at the time of signing consent. Women must be willing to undergo a pregnancy test prior to transplant and avoid becoming pregnant while on study.

Exclusion Criteria:

  • Active CNS leukemic involvement
  • Female patients who are pregnant (positive serum or urine HCG) or breast-feeding. Women of childbearing age must avoid becoming pregnant while on study.
  • Active uncontrolled viral, bacterial or fungal infection
  • Patient seropositive for HIV-I/II; HTLV -I/II
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00987480

Contacts
Contact: Farid Boulad, MD 212-639-6684
Contact: Susan Prockop, MD 212-639-6715

Locations
United States, Massachusetts
Children's Hospital Boston Not yet recruiting
Boston, Massachusetts, United States, 02115
United States, New York
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Farid Boulad, MD    212-639-6684      
Principal Investigator: Farid Boulad, MD         
The Rockefeller University Not yet recruiting
New York, New York, United States, 10065
United States, Ohio
Cincinnati Children's Hospital Not yet recruiting
Cincinnati, Ohio, United States, 45229
United States, Washington
Fred Hutchinson Cancer Research Center Not yet recruiting
Seattle, Washington, United States, 98109
United States, Wisconsin
Children's Hospital of Wisconsin Not yet recruiting
Milwaukee, Wisconsin, United States
Sponsors and Collaborators
Memorial Sloan-Kettering Cancer Center
Children's Hospital Boston
Children's Hospital Medical Center, Cincinnati
Children's Hospital and Health System Foundation, Wisconsin
Rockefeller University
Fred Hutchinson Cancer Research Center
Investigators
Principal Investigator: Faird Boulad, MD Memorial Sloan-Kettering Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier: NCT00987480     History of Changes
Other Study ID Numbers: 08-031
Study First Received: September 30, 2009
Last Updated: February 20, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Memorial Sloan-Kettering Cancer Center:
Stem Cell Transplantation
Anemia
Busulfan
Cyclophosphamide
Fludarabine
08-031

Additional relevant MeSH terms:
Anemia
Anemia, Aplastic
Fanconi Anemia
Fanconi Syndrome
Leukemia
Myelodysplastic Syndromes
Preleukemia
Hematologic Diseases
Bone Marrow Diseases
Anemia, Hypoplastic, Congenital
Genetic Diseases, Inborn
DNA Repair-Deficiency Disorders
Metabolic Diseases
Kidney Diseases
Urologic Diseases
Renal Tubular Transport, Inborn Errors
Metabolism, Inborn Errors
Neoplasms by Histologic Type
Neoplasms
Precancerous Conditions
Busulfan
Cyclophosphamide
Cyclosporins
Cyclosporine
Fludarabine monophosphate
Fludarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on April 17, 2014