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HSCT for Patients With Fanconi Anemia Using Risk-Adjusted Chemotherapy (RAFA)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02143830
Recruitment Status : Recruiting
First Posted : May 21, 2014
Last Update Posted : July 11, 2019
Sponsor:
Collaborators:
Memorial Sloan Kettering Cancer Center
Fred Hutchinson Cancer Research Center
Information provided by (Responsible Party):
Children's Hospital Medical Center, Cincinnati

Brief Summary:
The purpose of this study is to determine whether the use of lower doses of busulfan and the elimination of cyclosporine will further reduce transplant-related side effects for patients with Fanconi Anemia (FA). Patients will undergo a transplant utilizing mis-matched related or matched unrelated donors following a preparative regimen of busulfan, fludarabine, anti-thymocyte globulin and cyclophosphamide.

Condition or disease Intervention/treatment Phase
Fanconi Anemia Severe Marrow Failure Myelodysplastic Syndrome (MDS) Acute Myelogenous Leukemia (AML) Drug: Busulfan Drug: Cyclophosphamide Drug: Fludarabine Drug: rabbit ATG Drug: G-CSF Biological: Peripheral blood stem cell Phase 2

Detailed Description:
The trial proposed is a three arm phase II treatment protocol designed to investigate the safety and efficacy of risk-adjusted 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. Candidates for this trial will include patients with Fanconi anemia presenting with severe marrow failure (transfusion dependent) or myelodysplastic syndrome, or acute myelogenous leukemia for whom an allogeneic stem cell transplant is indicated.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 70 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Trial of HSCT for the Treatment of Patients With Fanconi Anemia Lacking a Genotypically Identical Donor, Using a Risk-Adjusted Chemotherapy Only Cytoreduction With Busulfan, Cyclophosphamide and Fludarabine
Study Start Date : April 2014
Estimated Primary Completion Date : July 2024
Estimated Study Completion Date : July 2026


Arm Intervention/treatment
Experimental: Arm A: Good Risk Patients
Patients 18 years old or younger with marrow aplasia or single lineage cytopenias will be receive intravenous busulfan (4 doses x 2 days), cyclophosphamide (4 doses x 4 days) and fludarabine (4 doses x 4 days), as used in our most current study that led to > 90% survival rates . Busulfan pharmacokinetics will not be used. All patients will receive rabbit ATG (4 doses x 4 days) prior to and granulocyte-colony stimulating factor (G-CSF) after transplant to promote engraftment. Cyclosporine will not be used for GVHD prophylaxis. The source of the stem cells for all patients will be peripheral blood stem cells mobilized by treatment of the donor with G-CSF. T-cell depletion will be performed by positive CD34 selection with the use of the Miltenyi system (CliniMACS device). Enrollment on this arm will include up to 50 patients.
Drug: Busulfan

A standard dose of busulfan, associated with excellent outcomes in our previous trial will be used for young patients with marrow aplasia (arm A).

A higher dose of busulfan will be used in younger patients with MDS and AML (arm B) to maximize disease control.

A lower dose of busulfan will be used in older patients (arm C) to minimize toxicity.

Other Names:
  • Myleran
  • Busulfex IV

Drug: Cyclophosphamide
Arms A, B and C - Cytoxan will be given as a 1-2 hour infusion for 4 days. The dose will be adjusted according to patients ideal body weight for obese patients.
Other Name: Cytoxan

Drug: Fludarabine
Arms A, B and C - Fludarabine will be given IV over 30 minutes daily for 4 days. The dose will be adjusted according to renal function according to Institutional guidelines.
Other Name: Fludara

Drug: rabbit ATG
Arms A, B and C - 4 doses will be given prior to transplant to promote engraftment.
Other Name: thymoglobulin

Drug: G-CSF
All patients will also receive G-CSF post-transplant to foster engraftment.
Other Names:
  • Granulocyte colony-stimulating factor
  • filgrastim
  • neupogen

Biological: Peripheral blood stem cell
The source of stem cells for all patients will be peripheral blood stem cells (PBSC) induced and mobilized by treatment of the donor with G-CSF for 4-6 days. T-cell depletion will be uniformly performed by positive CD34 selection with the use of the Miltenyi system (CliniMACS device).

Experimental: Arm B: Intermediate Risk Patients

Patients 18 years old or younger with MDS or AML will receive intravenous busulfan (4 doses x 2 days), cyclophosphamide (4 doses x 4 days) and fludarabine (4 doses x 4 days). Busulfan pharmacokinetics will be used in this arm, as the dose of busulfan is higher. All patients will receive rabbit ATG (thymoglobulin) (4 doses x 4 days) prior to and G-CSF post transplant to promote engraftment. Cyclosporine will not be used for prophylaxis against GVHD. The source of the stem cells for all patients will be peripheral blood stem cells induced and mobilized by treatment of the donor. T-cell will be performed by positive CD34 selection with the use of the Miltenyi system (CliniMACS device).

The maximum number of patients enrolled in this arm will be 10.

Drug: Busulfan

A standard dose of busulfan, associated with excellent outcomes in our previous trial will be used for young patients with marrow aplasia (arm A).

A higher dose of busulfan will be used in younger patients with MDS and AML (arm B) to maximize disease control.

A lower dose of busulfan will be used in older patients (arm C) to minimize toxicity.

Other Names:
  • Myleran
  • Busulfex IV

Drug: Cyclophosphamide
Arms A, B and C - Cytoxan will be given as a 1-2 hour infusion for 4 days. The dose will be adjusted according to patients ideal body weight for obese patients.
Other Name: Cytoxan

Drug: Fludarabine
Arms A, B and C - Fludarabine will be given IV over 30 minutes daily for 4 days. The dose will be adjusted according to renal function according to Institutional guidelines.
Other Name: Fludara

Drug: rabbit ATG
Arms A, B and C - 4 doses will be given prior to transplant to promote engraftment.
Other Name: thymoglobulin

Drug: G-CSF
All patients will also receive G-CSF post-transplant to foster engraftment.
Other Names:
  • Granulocyte colony-stimulating factor
  • filgrastim
  • neupogen

Biological: Peripheral blood stem cell
The source of stem cells for all patients will be peripheral blood stem cells (PBSC) induced and mobilized by treatment of the donor with G-CSF for 4-6 days. T-cell depletion will be uniformly performed by positive CD34 selection with the use of the Miltenyi system (CliniMACS device).

Experimental: Arm C: High Risk Patients
Patients 19 years old or older with marrow aplasia or MDS or AML will receive intravenous busulfan (4 doses x 2 days), cyclophosphamide (4 doses x 4 days) and fludarabine (4 doses x 4 days). In this study, we will test whether outcomes can be improved, yet engraftment maintained, with a slightly reduced dose of busulfan. Patients will receive rabbit ATG (4 doses x 4 days) prior to and G-CSF post transplant to promote engraftment. Cyclosporine will not be used for GVHD prophylaxis. The source of the stem cells will be peripheral blood stem cells collected from donors treated with G-CSF. T-cell depletion will be performed by positive CD34 selection with the use of the Miltenyi system (CliniMACS device). The maximum number of patients enrolled will be 10.
Drug: Busulfan

A standard dose of busulfan, associated with excellent outcomes in our previous trial will be used for young patients with marrow aplasia (arm A).

A higher dose of busulfan will be used in younger patients with MDS and AML (arm B) to maximize disease control.

A lower dose of busulfan will be used in older patients (arm C) to minimize toxicity.

Other Names:
  • Myleran
  • Busulfex IV

Drug: Cyclophosphamide
Arms A, B and C - Cytoxan will be given as a 1-2 hour infusion for 4 days. The dose will be adjusted according to patients ideal body weight for obese patients.
Other Name: Cytoxan

Drug: Fludarabine
Arms A, B and C - Fludarabine will be given IV over 30 minutes daily for 4 days. The dose will be adjusted according to renal function according to Institutional guidelines.
Other Name: Fludara

Drug: rabbit ATG
Arms A, B and C - 4 doses will be given prior to transplant to promote engraftment.
Other Name: thymoglobulin

Drug: G-CSF
All patients will also receive G-CSF post-transplant to foster engraftment.
Other Names:
  • Granulocyte colony-stimulating factor
  • filgrastim
  • neupogen

Biological: Peripheral blood stem cell
The source of stem cells for all patients will be peripheral blood stem cells (PBSC) induced and mobilized by treatment of the donor with G-CSF for 4-6 days. T-cell depletion will be uniformly performed by positive CD34 selection with the use of the Miltenyi system (CliniMACS device).




Primary Outcome Measures :
  1. Graft Failure or Rejection [ Time Frame: 5 years ]
    Primary non-engraftment is diagnosed when the patient fails to achieve an ANC >=500/mm3 at any time in the first 28 days post-transplant. If (1) after achievement of an absolute neutrophil count (ANC) >=500/mm3, the ANC declines to <500/mm3 for more than 3 consecutive days in the absence of relapse, or, (2) there is absence of donor cells in the marrow and/or blood as demonstrated by chimerism assay in the absence of relapse, a diagnosis of secondary graft failure is made. The patient is not evaluable for graft failure or rejection if recurrence of host MDS is detected concurrently.


Secondary Outcome Measures :
  1. Post-transplant severe morbidity and mortality [ Time Frame: 2 years post-transplant ]
    The occurrence of severe post-transplant regimen-related severe morbidity (grade IV toxicity) and/or mortality will be the second endpoint of this study. In the context of the agents or agent-combination used for cytoreduction used, particular attention will be given to toxicity involving (1) the liver, (2) the lungs, (3) the oral mucosa and gastrointestinal tract, and (4) the central nervous system.


Other Outcome Measures:
  1. Graft Versus Host Disease [ Time Frame: One year ]
    Patients will be observed for acute and/or chronic graft versus host disease (GvHD). Standard clinical criteria for the grading of acute and chronic GvHD will be done according to IBMTR guidelines.

  2. Leukemic Relapse [ Time Frame: 5 years ]
    For patients with MDS or AML, relapse will be analyzed as to type and genetic origin of the MDS/leukemic cells.

  3. Secondary malignancies [ Time Frame: 5 years ]
    Patients will be followed for 5 years through annual contact with their treatment center in order to track the risk of developing a secondary malignancy.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   3 Months and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have a diagnosis of Fanconi anemia
  • Patients must have one of the following hematologic diagnoses:

    1. Severe Aplastic Anemia (SAA), with bone marrow cellularity of <25% OR Severe Isolated Single Lineage Cytopenia and at least one of the following features:

      1. Platelet count <20 x 109/L or platelet transfusion dependence*
      2. ANC <1000 x 109/L
      3. Hgb <8 gm/dl or red cell transfusion dependence*
    2. Myelodysplastic Syndrome (MDS) (based on WHO or IPSS Classification
    3. Acute Myelogenous Leukemia (untreated, in remission or with refractory or relapsed disease)
  • Donors will be either human leukocyte antigen (HLA) compatible unrelated or HLA-genotypically matched related donors (no fully matched sibling donor).
  • Patients and donors may be of either gender or any ethnic background.
  • Patients must have a Karnofsky adult, or Lansky pediatric performance scale status > 70%.
  • Patients must have adequate physical function measured by:

    1. Cardiac: asymptomatic or if symptomatic then 1) left ventricular ejection fraction (LVEF) at rest must be > 50% and must improve with exercise or 2) Shortening Fraction > 29%
    2. Hepatic: < 5 x upper limit of normal (ULN) alanine transaminase (ALT) and < 2.0 mg/dl total serum bilirubin.
    3. Renal: serum creatinine <1.5 mg/dl or if serum creatinine is outside the normal range, then CrCl > 50 ml/min/1.73 m2
    4. Pulmonary: asymptomatic or if symptomatic, DLCO > 50% of predicted
  • Each patient must be willing to participate as a research subject and must sign an informed consent form.
  • 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 leukemia
  • Female patients who are pregnant (positive serum or urine HCG) or breast-feeding.
  • Active uncontrolled viral, bacterial or fungal infection
  • Patient seropositive for HIV-I/II; HTLV -I/II

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02143830


Contacts
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Contact: Jamie Wilhelm (513)803-1102 Jamie.Wilhelm@cchmc.org
Contact: Sara Loveless, RN (513)803-7656 Sara.Loveless@cchmc.org

Locations
Layout table for location information
United States, New York
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10174
Contact: Jessica Chaisson    646-888-5718    chaissoj@mskcc.org   
Principal Investigator: Farid Boulad, MD         
United States, Ohio
Cincinnati Children's Hospital Medical Center Recruiting
Cincinnati, Ohio, United States, 45229
Principal Investigator: Parinda Mehta, MD         
United States, Washington
Fred Hutchinson Cancer Research Center Recruiting
Seattle, Washington, United States, 98109
Contact: Sheri Ballard    206-667-4222    sballard@fredhutch.org   
Principal Investigator: K. Scott Baker, MD         
Sponsors and Collaborators
Children's Hospital Medical Center, Cincinnati
Memorial Sloan Kettering Cancer Center
Fred Hutchinson Cancer Research Center
Investigators
Layout table for investigator information
Principal Investigator: Parinda Mehta, MD CCHMC

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Responsible Party: Children's Hospital Medical Center, Cincinnati
ClinicalTrials.gov Identifier: NCT02143830    
Other Study ID Numbers: 2013-7501
First Posted: May 21, 2014    Key Record Dates
Last Update Posted: July 11, 2019
Last Verified: July 2019
Keywords provided by Children's Hospital Medical Center, Cincinnati:
marrow aplasia
cytopenia
myelodysplasia
AML
bone marrow transplant
cytoreductive regimen
T-cell reduction
Additional relevant MeSH terms:
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Leukemia, Myeloid, Acute
Fanconi Syndrome
Anemia
Myelodysplastic Syndromes
Fanconi Anemia
Hematologic Diseases
Bone Marrow Diseases
Neoplasms
Leukemia, Myeloid
Leukemia
Neoplasms by Histologic Type
Anemia, Hypoplastic, Congenital
Anemia, Aplastic
Genetic Diseases, Inborn
DNA Repair-Deficiency Disorders
Metabolic Diseases
Renal Tubular Transport, Inborn Errors
Kidney Diseases
Urologic Diseases
Metabolism, Inborn Errors
Vidarabine
Cyclophosphamide
Busulfan
Fludarabine
Fludarabine phosphate
Thymoglobulin
Lenograstim
Sargramostim
Immunosuppressive Agents
Immunologic Factors