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

Fanconi Anemia Clinical Trial

Official title:

Nonmyeloablative Hematopoietic Cell Transplantation for Patients With Fanconi Anemia Using Alternative Marrow Donors: A Phase II Dose-Finding Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00453388
• Other study ID #: 2064.00
• Secondary ID: NCI-2010-0023820
• Status: Completed
• Phase: Phase 2
• Start date: February 2007
• Est. completion date: June 2013

Study information

• Verified date: December 2019
• Source: Fred Hutchinson Cancer Research Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 6
• Est. completion date: June 2013
• Est. primary completion date: June 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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

Related Conditions & MeSH terms

• Acute Myeloid Leukemia in Remission
• Anemia
• de Novo Myelodysplastic Syndrome
• Fanconi Anemia
• Fanconi Syndrome
• Myelodysplastic Syndromes
• Preleukemia
• Previously Treated Myelodysplastic Syndrome
• Syndrome

Intervention

Procedure:
• Allogeneic Bone Marrow Transplantation
Undergo allogeneic bone marrow transplant

Drug:
• Cyclophosphamide
Given IV
• Cyclosporine
Given IV or PO
• Fludarabine Phosphate
Given IV

Other:
• Laboratory Biomarker Analysis
Correlative studies

Drug:
• Mycophenolate Mofetil
Given PO

Procedure:
• Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic stem cell transplant

Radiation:
• Total-Body Irradiation
Undergo TBI

Locations

Country	Name	City	State
Brazil	Universidade Federal do Paraná	Curitiba	Paraná
United States	Children's Hospital of Wisconsin	Milwaukee	Wisconsin
United States	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee
United States	Children's Hospital and Research Center at Oakland	Oakland	California
United States	Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium	Seattle	Washington

Sponsors (3)

Lead Sponsor	Collaborator
Fred Hutchinson Cancer Research Center	National Cancer Institute (NCI), National Heart, Lung, and Blood Institute (NHLBI)

Countries where clinical trial is conducted

United States,  Brazil, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Patients Who Engraft at Each Dose of TBI Used	Number of subjects who engrafted. Engraftment defined as greater than 95% donor chimerism.	Up to Day 200
Primary	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	Up to Day 100
Secondary	Incidence of Transplant-related Mortality	Number of subjects who expired due to transplant-related mortality	Up to Day 200
Secondary	Incidence of Adverse Events	Number of subjects who developed reportable AEs, assessed using adapted version of the Common Toxicity Criteria	Up to Day 100