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Fludarabine Phosphate, Cyclophosphamide, and Total-Body Irradiation Followed by Donor Bone Marrow Transplant, Mycophenolate Mofetil, and Cyclosporine in Treating Patients With Fanconi Anemia

Primary Purpose

Acute Myeloid Leukemia in Remission, de Novo Myelodysplastic Syndrome, Fanconi Anemia

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Allogeneic Bone Marrow Transplantation
Cyclophosphamide
Cyclosporine
Fludarabine Phosphate
Laboratory Biomarker Analysis
Mycophenolate Mofetil
Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation
Total-Body Irradiation
Sponsored by
Fred Hutchinson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Myeloid Leukemia in Remission

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Any patient with FA and bone marrow (BM) failure involving 2 of the following 3 lineages: granulocyte count < 0.5 x 10^9/L, platelet count < 20 x 10^9/L, or hemoglobin < 8 g/dL
  • Any patient with FA who requires red blood cell or platelet transfusions because of marrow failure
  • Any patient with FA who has a life-threatening BM failure involving a single hematopoietic lineage
  • Any patient with FA and pre-existing cytogenetic abnormality including hematopoietic malignancy (acute myeloid leukemia [AML] or myelodysplastic syndrome [MDS]) in morphological remission (defined as absence of circulating blasts and bone marrow blasts < 5% as assessed by morphology); Note that hematopoietic recovery is not required for remission status
  • Patients must have a negative cytotoxic cross match with donor
  • DONOR: Related, human leukocyte antigen (HLA)-haploidentical donors must be identical for one HLA haplotype and mismatched for any number of HLA-A, -B, -C, DRB1 or DQB1 loci of the unshared haplotype
  • DONOR: Unrelated, HLA-matched donors must be matched at HLA-A, B, C, DRB1 and DQB1 by deoxyribonucleic acid (DNA) typing at the highest resolution routinely available at the time of donor selection; a single allele mismatch at HLA-A, B, or C is allowed OR a single DQB1 mismatch is allowed
  • DONOR: Bone marrow will be the only allowed hematopoietic stem cell source
  • DONOR: Haploidentical donor selection will be based on standard institutional criteria, otherwise no specific prioritization will be made amongst the suitable available donors

Exclusion Criteria:

  • Patients having available HLA-matched related donors
  • Significant organ dysfunction that would prevent compliance with conditioning, graft-versus-host disease (GVHD) prophylaxis, or would severely limit the probability of survival, such as liver disease/failure (active hepatitis, moderate to severe portal fibrosis/cirrhosis confirmed by biopsy or uncorrectable hepatic synthetic dysfunction), lung disease, or cardiac disease (ejection fraction < 35%, or if unable to obtain ejection fraction, shortening fraction of < 26%; if shortening is < 26% a cardiology consult is required with principal investigator [PI] having final approval of eligibility)
  • Human immunodeficiency virus (HIV) seropositive patients
  • Fertile females who are unwilling to use contraceptive techniques during and for the twelve months following treatment, as well as females who are pregnant or actively breast feeding
  • Fertile males who are unwilling to use contraceptive techniques during and for the twelve months following treatment
  • AML/MDS in morphological relapse, defined as having circulating blasts or bone marrow blasts >= 5% as assessed by morphology
  • Active infectious disease concerns
  • Karnofsky performance score < 50 or Lansky performance score < 40
  • DONOR: Donors found to have Fanconi anemia based on chromosomal breakage analysis
  • 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 [IBW]) or who are unwilling to be bone marrow donors
  • DONOR: HIV-positive donors
  • DONOR: Donors who are cross-match positive with recipient
  • DONOR: Recipient homozygous at mismatched locus; if the recipient is homozygous at HLA-A, B, or C and the donor is mismatched at that locus, the donor should be avoided; exceptions must be discussed with the PI

Sites / Locations

  • Children's Hospital and Research Center at Oakland
  • Vanderbilt University/Ingram Cancer Center
  • Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
  • Children's Hospital of Wisconsin
  • Universidade Federal do Paraná

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Arm I (2 vs 2.5 vs 3 Gy TBI dose-escalation)

Arm II (2 vs 2.5 vs 3 vs 1 vs 0 Gy TBI de-escalation)

Arm III (2 vs 2.5 vs 3 Gy TBI dose-escalation)

Arm IV (2 vs 2.5 vs 3 vs 1 vs 0 Gy TBI de-escalation)

Arm Description

Patients with a history of hematologic malignancy and HLA-haploidentical donor receive fludarabine phosphate (FLU) intravenously (IV) over 1 hour on days -6 to -2, and undergo TBI on day -1 and allogeneic bone marrow transplant on day 0. Patients then receive CY IV over 1 hour on days 3 and 4, MMF orally (PO) thrice daily (TID) on days 5-35, and CSP IV or PO on days 5-84, with taper until day 180, in the absence of GVHD.

Patients with no history of hematological malignancy and HLA-haploidentical donors receive FLU IV over 1 hour on days -6 to -2, and undergo TBI on day -1 and allogeneic bone marrow transplant on day 0. Patients then receive CY IV over 1 hour on days 3 and 4, MMF PO TID on days 5-35, and CSP IV or PO on days 5-84, with taper until day 180, in the absence of GVHD.

Patients with history of hematologic malignancy and HLA-matched unrelated donors receive FLU IV over 1 hour on days -6 to -2, and undergo TBI on day -1 and allogeneic bone marrow transplant on day 0. Patients then receive CY IV over 1 hour on days 3 and 4, MMF PO TID on days 5-35, and CSP IV or PO on days 5-84, with taper until day 180, in the absence of GVHD.

Patients with no history of hematological malignancy and HLA-matched unrelated donors receive FLU IV over 1 hour on days -6 to -2, and undergo TBI on day -1 and allogeneic bone marrow transplant on day 0. Patients then receive CY IV over 1 hour on days 3 and 4, MMF PO TID on days 5-35, and CSP IV or PO on days 5-84, with taper until day 180, in the absence of GVHD.

Outcomes

Primary Outcome Measures

Number of Patients Who Engraft at Each Dose of TBI Used
Number of subjects who engrafted. Engraftment defined as greater than 95% donor chimerism.
Incidence of Grades III-IV Acute GVHD
Number of subjects who developed maximum grade acute graft-vs-host disease aGVHD Stages Skin: - a maculopapular eruption involving < 25% BSA - a maculopapular eruption involving 25 - 50% BSA - generalized erythroderma - generalized erythroderma with bullous formation and often with desquamation Liver: - bilirubin 2.0 - 3.0 mg/100 mL - bilirubin 3 - 5.9 mg/100 mL - bilirubin 6 - 14.9 mg/100 mL - bilirubin > 15 mg/100 mL Gut: Diarrhea is graded 1 - 4 in severity. Nausea and vomiting and/or anorexia caused by GVHD is assigned as 1 in severity. The severity of gut involvement is assigned to the most severe involvement noted. Patients with visible bloody diarrhea are at least stage 2 gut and grade 3 overall. aGVHD Grades Grade III: Stage 2 - 4 gastrointestinal involvement and/or +2 to +4 liver involvement, with or without a rash Grade IV: Pattern and severity of GVHD similar to grade 3 with extreme constitutional symptoms or death

Secondary Outcome Measures

Incidence of Transplant-related Mortality
Number of subjects who expired due to transplant-related mortality
Incidence of Adverse Events
Number of subjects who developed reportable AEs, assessed using adapted version of the Common Toxicity Criteria

Full Information

First Posted
March 27, 2007
Last Updated
January 17, 2020
Sponsor
Fred Hutchinson Cancer Center
Collaborators
National Cancer Institute (NCI), National Heart, Lung, and Blood Institute (NHLBI)
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1. Study Identification

Unique Protocol Identification Number
NCT00453388
Brief Title
Fludarabine Phosphate, Cyclophosphamide, and Total-Body Irradiation Followed by Donor Bone Marrow Transplant, Mycophenolate Mofetil, and Cyclosporine in Treating Patients With Fanconi Anemia
Official Title
Nonmyeloablative Hematopoietic Cell Transplantation for Patients With Fanconi Anemia Using Alternative Marrow Donors: A Phase II Dose-Finding Study
Study Type
Interventional

2. Study Status

Record Verification Date
December 2019
Overall Recruitment Status
Completed
Study Start Date
February 2007 (Actual)
Primary Completion Date
June 2013 (Actual)
Study Completion Date
June 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Fred Hutchinson Cancer Center
Collaborators
National Cancer Institute (NCI), National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This phase II trial studies how well total-body irradiation (TBI) works when given together with fludarabine phosphate and cyclophosphamide followed by donor bone marrow transplant, mycophenolate mofetil, and cyclosporine in treating patients with Fanconi anemia (FA). Giving low doses of chemotherapy, such as fludarabine phosphate and cyclophosphamide, and TBI before or after a donor bone marrow transplant helps stop the growth of abnormal cells. It may also stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving mycophenolate mofetil and cyclosporine after the transplant may stop this from happening.
Detailed Description
PRIMARY OBJECTIVES: I. Identify doses of total-body irradiation (TBI) that lead to sufficient probability of donor engraftment (> 5% donor cluster of differentiation [CD]3 chimerism) by day +200. II. Evaluate the probability of severe acute graft-versus-host disease. SECONDARY OBJECTIVES: I. Evaluate the probabilities of overall survival, regimen-related toxicity (RRT), and recurrent hematopoietic malignancy in those patients with a prior underlying history of such. II. Examine the degree to which mixed chimerism provides for amelioration of symptoms (i.e., infections due to neutropenia, hemorrhage due to thrombocytopenia) associated with bone marrow failure. III. Determine if the FA complementation group and % initial mosaicism predict engraftment and RRT outcomes. OUTLINE: Patients are assigned to 1 of 4 treatment arms. NOTE: Patients no longer receive pre-transplant cyclophosphamide as of February 2009. After completion of study treatment, patients are followed up at 6 months and then annually thereafter.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myeloid Leukemia in Remission, de Novo Myelodysplastic Syndrome, Fanconi Anemia, Previously Treated Myelodysplastic Syndrome

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
6 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm I (2 vs 2.5 vs 3 Gy TBI dose-escalation)
Arm Type
Experimental
Arm Description
Patients with a history of hematologic malignancy and HLA-haploidentical donor receive fludarabine phosphate (FLU) intravenously (IV) over 1 hour on days -6 to -2, and undergo TBI on day -1 and allogeneic bone marrow transplant on day 0. Patients then receive CY IV over 1 hour on days 3 and 4, MMF orally (PO) thrice daily (TID) on days 5-35, and CSP IV or PO on days 5-84, with taper until day 180, in the absence of GVHD.
Arm Title
Arm II (2 vs 2.5 vs 3 vs 1 vs 0 Gy TBI de-escalation)
Arm Type
Experimental
Arm Description
Patients with no history of hematological malignancy and HLA-haploidentical donors receive FLU IV over 1 hour on days -6 to -2, and undergo TBI on day -1 and allogeneic bone marrow transplant on day 0. Patients then receive CY IV over 1 hour on days 3 and 4, MMF PO TID on days 5-35, and CSP IV or PO on days 5-84, with taper until day 180, in the absence of GVHD.
Arm Title
Arm III (2 vs 2.5 vs 3 Gy TBI dose-escalation)
Arm Type
Experimental
Arm Description
Patients with history of hematologic malignancy and HLA-matched unrelated donors receive FLU IV over 1 hour on days -6 to -2, and undergo TBI on day -1 and allogeneic bone marrow transplant on day 0. Patients then receive CY IV over 1 hour on days 3 and 4, MMF PO TID on days 5-35, and CSP IV or PO on days 5-84, with taper until day 180, in the absence of GVHD.
Arm Title
Arm IV (2 vs 2.5 vs 3 vs 1 vs 0 Gy TBI de-escalation)
Arm Type
Experimental
Arm Description
Patients with no history of hematological malignancy and HLA-matched unrelated donors receive FLU IV over 1 hour on days -6 to -2, and undergo TBI on day -1 and allogeneic bone marrow transplant on day 0. Patients then receive CY IV over 1 hour on days 3 and 4, MMF PO TID on days 5-35, and CSP IV or PO on days 5-84, with taper until day 180, in the absence of GVHD.
Intervention Type
Procedure
Intervention Name(s)
Allogeneic Bone Marrow Transplantation
Other Intervention Name(s)
Allo BMT, Allogeneic BMT
Intervention Description
Undergo allogeneic bone marrow transplant
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
(-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Cyclosporine
Other Intervention Name(s)
27-400, Ciclosporin, CsA, Cyclosporin, Cyclosporin A, Neoral, OL 27-400, Sandimmun, Sandimmune, SangCya
Intervention Description
Given IV or PO
Intervention Type
Drug
Intervention Name(s)
Fludarabine Phosphate
Other Intervention Name(s)
2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, Oforta, SH T 586
Intervention Description
Given IV
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Intervention Type
Drug
Intervention Name(s)
Mycophenolate Mofetil
Other Intervention Name(s)
Cellcept, MMF
Intervention Description
Given PO
Intervention Type
Procedure
Intervention Name(s)
Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation
Other Intervention Name(s)
Non-myeloablative allogeneic transplant, Nonmyeloablative Stem Cell Transplantation, NST
Intervention Description
Undergo allogeneic stem cell transplant
Intervention Type
Radiation
Intervention Name(s)
Total-Body Irradiation
Other Intervention Name(s)
TOTAL BODY IRRADIATION, Whole-Body Irradiation
Intervention Description
Undergo TBI
Primary Outcome Measure Information:
Title
Number of Patients Who Engraft at Each Dose of TBI Used
Description
Number of subjects who engrafted. Engraftment defined as greater than 95% donor chimerism.
Time Frame
Up to Day 200
Title
Incidence of Grades III-IV Acute GVHD
Description
Number of subjects who developed maximum grade acute graft-vs-host disease aGVHD Stages Skin: - a maculopapular eruption involving < 25% BSA - a maculopapular eruption involving 25 - 50% BSA - generalized erythroderma - generalized erythroderma with bullous formation and often with desquamation Liver: - bilirubin 2.0 - 3.0 mg/100 mL - bilirubin 3 - 5.9 mg/100 mL - bilirubin 6 - 14.9 mg/100 mL - bilirubin > 15 mg/100 mL Gut: Diarrhea is graded 1 - 4 in severity. Nausea and vomiting and/or anorexia caused by GVHD is assigned as 1 in severity. The severity of gut involvement is assigned to the most severe involvement noted. Patients with visible bloody diarrhea are at least stage 2 gut and grade 3 overall. aGVHD Grades Grade III: Stage 2 - 4 gastrointestinal involvement and/or +2 to +4 liver involvement, with or without a rash Grade IV: Pattern and severity of GVHD similar to grade 3 with extreme constitutional symptoms or death
Time Frame
Up to Day 100
Secondary Outcome Measure Information:
Title
Incidence of Transplant-related Mortality
Description
Number of subjects who expired due to transplant-related mortality
Time Frame
Up to Day 200
Title
Incidence of Adverse Events
Description
Number of subjects who developed reportable AEs, assessed using adapted version of the Common Toxicity Criteria
Time Frame
Up to Day 100

10. Eligibility

Sex
All
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Any patient with FA and bone marrow (BM) failure involving 2 of the following 3 lineages: granulocyte count < 0.5 x 10^9/L, platelet count < 20 x 10^9/L, or hemoglobin < 8 g/dL Any patient with FA who requires red blood cell or platelet transfusions because of marrow failure Any patient with FA who has a life-threatening BM failure involving a single hematopoietic lineage Any patient with FA and pre-existing cytogenetic abnormality including hematopoietic malignancy (acute myeloid leukemia [AML] or myelodysplastic syndrome [MDS]) in morphological remission (defined as absence of circulating blasts and bone marrow blasts < 5% as assessed by morphology); Note that hematopoietic recovery is not required for remission status Patients must have a negative cytotoxic cross match with donor DONOR: Related, human leukocyte antigen (HLA)-haploidentical donors must be identical for one HLA haplotype and mismatched for any number of HLA-A, -B, -C, DRB1 or DQB1 loci of the unshared haplotype DONOR: Unrelated, HLA-matched donors must be matched at HLA-A, B, C, DRB1 and DQB1 by deoxyribonucleic acid (DNA) typing at the highest resolution routinely available at the time of donor selection; a single allele mismatch at HLA-A, B, or C is allowed OR a single DQB1 mismatch is allowed DONOR: Bone marrow will be the only allowed hematopoietic stem cell source DONOR: Haploidentical donor selection will be based on standard institutional criteria, otherwise no specific prioritization will be made amongst the suitable available donors Exclusion Criteria: Patients having available HLA-matched related donors Significant organ dysfunction that would prevent compliance with conditioning, graft-versus-host disease (GVHD) prophylaxis, or would severely limit the probability of survival, such as liver disease/failure (active hepatitis, moderate to severe portal fibrosis/cirrhosis confirmed by biopsy or uncorrectable hepatic synthetic dysfunction), lung disease, or cardiac disease (ejection fraction < 35%, or if unable to obtain ejection fraction, shortening fraction of < 26%; if shortening is < 26% a cardiology consult is required with principal investigator [PI] having final approval of eligibility) Human immunodeficiency virus (HIV) seropositive patients Fertile females who are unwilling to use contraceptive techniques during and for the twelve months following treatment, as well as females who are pregnant or actively breast feeding Fertile males who are unwilling to use contraceptive techniques during and for the twelve months following treatment AML/MDS in morphological relapse, defined as having circulating blasts or bone marrow blasts >= 5% as assessed by morphology Active infectious disease concerns Karnofsky performance score < 50 or Lansky performance score < 40 DONOR: Donors found to have Fanconi anemia based on chromosomal breakage analysis 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 [IBW]) or who are unwilling to be bone marrow donors DONOR: HIV-positive donors DONOR: Donors who are cross-match positive with recipient DONOR: Recipient homozygous at mismatched locus; if the recipient is homozygous at HLA-A, B, or C and the donor is mismatched at that locus, the donor should be avoided; exceptions must be discussed with the PI
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Hans-Peter Kiem
Organizational Affiliation
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Official's Role
Principal Investigator
Facility Information:
Facility Name
Children's Hospital and Research Center at Oakland
City
Oakland
State/Province
California
ZIP/Postal Code
94609-1809
Country
United States
Facility Name
Vanderbilt University/Ingram Cancer Center
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States
Facility Name
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States
Facility Name
Children's Hospital of Wisconsin
City
Milwaukee
State/Province
Wisconsin
ZIP/Postal Code
53201
Country
United States
Facility Name
Universidade Federal do Paraná
City
Curitiba
State/Province
Paraná
ZIP/Postal Code
80060-000
Country
Brazil

12. IPD Sharing Statement

Learn more about this trial

Fludarabine Phosphate, Cyclophosphamide, and Total-Body Irradiation Followed by Donor Bone Marrow Transplant, Mycophenolate Mofetil, and Cyclosporine in Treating Patients With Fanconi Anemia

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