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A Study of the Effect of Blood Stem Cell Transplant After Chemotherapy Alone in Patients With Fanconi Anemia

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: NCT03600909
Recruitment Status : Recruiting
First Posted : July 26, 2018
Last Update Posted : January 2, 2020
Sponsor:
Collaborator:
Pediatric Brain Tumor Consortium
Information provided by (Responsible Party):
Memorial Sloan Kettering Cancer Center

Brief Summary:
The goal of this study is to see if the study therapy can decrease the chemotherapy-related side effects while maximizing the effectiveness of disease control. The physicians will also be studying the effect of removing T-cells from the donor‟s stem cells before transplant. T-cells are a type of white blood cell that may help cause a serious side effect of transplant called Graft versus Host Disease (GVHD). The way it removes the T-cells from the donor stem cells is actually by selecting only the stem cells (called CD34 cells) by using a device called CliniMACS. This process is called CD34 selection. The CliniMACS® device is currently under the supervision of the FDA .

Condition or disease Intervention/treatment Phase
Fanconi Anemia Myelodysplastic Syndrome (MDS) Acute Myelogenous Leukemia (AML) Drug: Busulfan Drug: Fludarabine Drug: Cyclophosphamide Drug: Anti-Thymocyte Globulin (Rabbit) Device: The CliniMACS device Drug: G-CSF Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 70 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: A three-arm phase II treatment protocol designed to examine engraftment, toxicity, graft-versus-host disease, and disease-free survival following a novel cytoreductive regimen including busulfan, cyclophosphamide and fludarabine and ATG
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Trial of Hematopoietic Stem Cell Transplantation 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
Actual Study Start Date : May 15, 2018
Estimated Primary Completion Date : May 2022
Estimated Study Completion Date : May 2022


Arm Intervention/treatment
Experimental: Good Risk Patients
Patients 18 years old or younger with marrow aplasia or single lineage cytopenias (Arm A) will be conditioned for transplantation with intravenous busulfan (busulfex®) (0.6-0.8 mg/Kg/dose q 12 hours x 4 doses), cyclophosphamide (10 mg/Kg/dose x 4 doses) and fludarabine (35mg/m2/day x 4 doses).
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 Name: busulfex®

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: 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: Anti-Thymocyte Globulin (Rabbit)
Arms A, B and C - 4 doses will be given prior to transplant to promote engraftment
Other Name: hymoglobulin®

Device: The CliniMACS device
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)

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

Experimental: Intermediate risk patients
Patients 18 years old or younger with MDS or AML will be will be conditioned for transplantation with intravenous busulfan (busulfex®) (0.8-1.0mg/Kg/dose q 12 hours x 4 doses), cyclophosphamide (10 mg/Kg/dose x 4 doses) and fludarabine (35mg/m2/day x 4 doses).
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 Name: busulfex®

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: 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: Anti-Thymocyte Globulin (Rabbit)
Arms A, B and C - 4 doses will be given prior to transplant to promote engraftment
Other Name: hymoglobulin®

Device: The CliniMACS device
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)

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

Experimental: High risk patients
Patients 19 years old or older with marrow aplasia or MDS or AML will be will be conditioned for transplantation with intravenous busulfan (busulfex®) (0.4mg/Kg/dose q 12 hours x 4 doses), cyclophosphamide (10 mg/Kg/dose x 4 doses) and fludarabine (35mg/m2/day x 4 doses).
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 Name: busulfex®

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: 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: Anti-Thymocyte Globulin (Rabbit)
Arms A, B and C - 4 doses will be given prior to transplant to promote engraftment
Other Name: hymoglobulin®

Device: The CliniMACS device
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)

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




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/µl at any time in the first 28 days post-transplant. If (1) after achievement of an ANC ≥500/mm^3, the ANC declines to <500/mm^3 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.



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:   1 Month 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 (confirmed by mitomycin C or diepoxybutane [DEB] chromosomal breakage testing at a CLIA approved laboratory).

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 10^9/L or platelet transfusion dependence*
  2. ANC <1000 x 10^9/L
  3. Hgb <8 gm/dl or red cell transfusion dependence*

2. 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 > 0.5 Note that patients with chromosome 1q cytogenetic abnormalities in the absence of morphologic dysplasia will not be considered to have MDS.

    3. Acute Myelogenous Leukemia Patients with acute leukemia are included in this trial untreated, in remission or with 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.

Donor

Donor choices will be determined by the investigators according to institutional criteria. 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 no more than 2/8 loci (A, B, C or DRB1) (6/8) 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, as per institutional guidelines.

Related and unrelated donors must be medically evaluated and fulfill the criteria for collection of PBSCs as per institutional guidelines.

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) LVEF at rest must be ≥ 50% and must improve with exercise or 2) Shortening Fraction ≥ 29%
  2. Hepatic: < 5 x 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 m^2
  4. 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 per institutional guidelines.

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. Positive pregnancy test results will be reported to the parent(s) or guardian of minor participants, as required per institutional guidelines.

Exclusion Criteria:

Active CNS leukemia 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


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): NCT03600909


Contacts
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Contact: Farid Boulad, MD 212-639-6684 bouladf@mskcc.org
Contact: Maria Cancio, MD 212-639-2446

Locations
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United States, New York
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Farid Boulad, MD    212-639-6684    bouladf@mskcc.org   
United States, Ohio
Cincinnati Children's Hospital Medical Center Not yet recruiting
Cincinnati, Ohio, United States, 45229
Contact: Parinda Mehta, MD    513-636-0278      
United States, Washington
Fred Hutchinson Cancer Research Center Not yet recruiting
Seattle, Washington, United States, 98109
Contact: K. Scott Baker, MD    855-557-0555      
Sponsors and Collaborators
Memorial Sloan Kettering Cancer Center
Pediatric Brain Tumor Consortium
Investigators
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Principal Investigator: Farid Boulad, MD Memorial Sloan Kettering Cancer Center

Additional Information:
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Responsible Party: Memorial Sloan Kettering Cancer Center
ClinicalTrials.gov Identifier: NCT03600909    
Other Study ID Numbers: 17-498
First Posted: July 26, 2018    Key Record Dates
Last Update Posted: January 2, 2020
Last Verified: December 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: Yes
Keywords provided by Memorial Sloan Kettering Cancer Center:
Blood Stem Cell Transplant
busulfan
cyclophosphamide
fludarabine
17-498
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
Antilymphocyte Serum
Thymoglobulin
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs