Fludarabine Phosphate, Cyclophosphamide, and Total-Body Irradiation Followed by Donor Bone Marrow Transplant, Mycophenolate Mofetil, and Cyclosporine in Treating 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. Read our disclaimer for details. |
| ClinicalTrials.gov Identifier: NCT00453388 |
|
Recruitment Status
:
Active, not recruiting
First Posted
: March 28, 2007
Results First Posted
: May 24, 2017
Last Update Posted
: May 24, 2017
|
Sponsor:
Fred Hutchinson Cancer Research Center
Collaborators:
National Cancer Institute (NCI)
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Hans-Peter Kiem, Fred Hutchinson Cancer Research Center
- Study Details
- Tabular View
- Study Results
- Disclaimer
- How to Read a Study Record
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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Acute Myeloid Leukemia in Remission de Novo Myelodysplastic Syndrome Fanconi Anemia Previously Treated Myelodysplastic Syndrome | Procedure: Allogeneic Bone Marrow Transplantation Drug: Cyclophosphamide Drug: Cyclosporine Drug: Fludarabine Phosphate Other: Laboratory Biomarker Analysis Drug: Mycophenolate Mofetil Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation Radiation: Total-Body Irradiation | Phase 2 |
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.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 6 participants |
| Allocation: | Non-Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Nonmyeloablative Hematopoietic Cell Transplantation for Patients With Fanconi Anemia Using Alternative Marrow Donors: A Phase II Dose-Finding Study |
| Study Start Date : | February 2007 |
| Actual Primary Completion Date : | June 2013 |
Resource links provided by the National Library of Medicine
Genetics Home Reference related topics:
Fanconi anemia
Core binding factor acute myeloid leukemia
Cytogenetically normal acute myeloid leukemia
Familial acute myeloid leukemia with mutated CEBPA
Genetic and Rare Diseases Information Center resources:
Myeloid Leukemia
Acute Myeloid Leukemia
Acute Non Lymphoblastic Leukemia
Myelodysplastic Syndromes
Fanconi Anemia
Congenital Aplastic Anemia
Fanconi Syndrome
Nephropathic Cystinosis
Primary Fanconi Syndrome
U.S. FDA Resources
| Arm | Intervention/treatment |
|---|---|
|
Experimental: Arm I (2 vs 2.5 vs 3 Gy TBI dose-escalation)
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.
|
Procedure: Allogeneic Bone Marrow Transplantation
Undergo allogeneic bone marrow transplant
Other Names:
Drug: Cyclophosphamide
Given IV
Other Names:
Drug: Cyclosporine
Given IV or PO
Other Names:
Drug: Fludarabine Phosphate
Given IV
Other Names:
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Mycophenolate Mofetil
Given PO
Other Names:
Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic stem cell transplant
Other Names:
Radiation: Total-Body Irradiation
Undergo TBI
Other Names:
|
|
Experimental: Arm II (2 vs 2.5 vs 3 vs 1 vs 0 Gy TBI de-escalation)
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.
|
Procedure: Allogeneic Bone Marrow Transplantation
Undergo allogeneic bone marrow transplant
Other Names:
Drug: Cyclophosphamide
Given IV
Other Names:
Drug: Cyclosporine
Given IV or PO
Other Names:
Drug: Fludarabine Phosphate
Given IV
Other Names:
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Mycophenolate Mofetil
Given PO
Other Names:
Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic stem cell transplant
Other Names:
Radiation: Total-Body Irradiation
Undergo TBI
Other Names:
|
|
Experimental: Arm III (2 vs 2.5 vs 3 Gy TBI dose-escalation)
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.
|
Procedure: Allogeneic Bone Marrow Transplantation
Undergo allogeneic bone marrow transplant
Other Names:
Drug: Cyclophosphamide
Given IV
Other Names:
Drug: Cyclosporine
Given IV or PO
Other Names:
Drug: Fludarabine Phosphate
Given IV
Other Names:
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Mycophenolate Mofetil
Given PO
Other Names:
Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic stem cell transplant
Other Names:
Radiation: Total-Body Irradiation
Undergo TBI
Other Names:
|
|
Experimental: Arm IV (2 vs 2.5 vs 3 vs 1 vs 0 Gy TBI de-escalation)
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.
|
Procedure: Allogeneic Bone Marrow Transplantation
Undergo allogeneic bone marrow transplant
Other Names:
Drug: Cyclophosphamide
Given IV
Other Names:
Drug: Cyclosporine
Given IV or PO
Other Names:
Drug: Fludarabine Phosphate
Given IV
Other Names:
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Mycophenolate Mofetil
Given PO
Other Names:
Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic stem cell transplant
Other Names:
Radiation: Total-Body Irradiation
Undergo TBI
Other Names:
|
Primary Outcome Measures
:
- Number of Patients Who Engraft at Each Dose of TBI Used [ Time Frame: Up to Day 200 ]Number of subjects who engrafted. Engraftment defined as greater than 95% donor chimerism.
- Incidence of Grades III-IV Acute GVHD [ Time Frame: Up to Day 100 ]
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 [ Time Frame: Up to Day 200 ]Number of subjects who expired due to transplant-related mortality
- Incidence of Adverse Events [ Time Frame: Up to 6 years ]Number of subjects who developed reportable AEs, assessed using adapted version of the Common Toxicity Criteria
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.
| Ages Eligible for Study: | Child, Adult, Senior |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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
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): NCT00453388
Locations
| United States, California | |
| Children's Hospital and Research Center at Oakland | |
| Oakland, California, United States, 94609-1809 | |
| United States, Tennessee | |
| Vanderbilt University/Ingram Cancer Center | |
| Nashville, Tennessee, United States, 37232 | |
| United States, Washington | |
| Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium | |
| Seattle, Washington, United States, 98109 | |
| United States, Wisconsin | |
| Children's Hospital of Wisconsin | |
| Milwaukee, Wisconsin, United States, 53201 | |
| Brazil | |
| Universidade Federal do Paraná | |
| Curitiba, Paraná, Brazil, 80060-000 | |
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
National Cancer Institute (NCI)
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
| Principal Investigator: | Hans-Peter Kiem | Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium |
| Responsible Party: | Hans-Peter Kiem, Principal Investigator, Fred Hutchinson Cancer Research Center |
| ClinicalTrials.gov Identifier: | NCT00453388 History of Changes |
| Other Study ID Numbers: |
2064.00 NCI-2010-00238 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) 2064.00 ( Other Identifier: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium ) P30CA015704 ( U.S. NIH Grant/Contract ) |
| First Posted: | March 28, 2007 Key Record Dates |
| Results First Posted: | May 24, 2017 |
| Last Update Posted: | May 24, 2017 |
| Last Verified: | April 2017 |
Additional relevant MeSH terms:
|
Syndrome Leukemia, Myeloid, Acute Anemia Myelodysplastic Syndromes Preleukemia Leukemia, Myeloid Fanconi Anemia Fanconi Syndrome Disease Pathologic Processes Leukemia Neoplasms by Histologic Type Neoplasms Hematologic Diseases Bone Marrow Diseases |
Precancerous Conditions 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 Cyclophosphamide Fludarabine phosphate Cyclosporins Cyclosporine Fludarabine |