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

NCT00453388 | Completed Phase 2 Results DMC

• 3 other identifiers: 2064.00NCI-2010-00238P30CA015704
• Study Type: interventional
• Target: 6
• Locations: 2 countries
• Sites: 5

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.

Conditions

Acute Myeloid Leukemia in Remission; de Novo Myelodysplastic Syndrome; Fanconi Anemia; Previously Treated Myelodysplastic Syndrome

Outcome Measures

Primary Outcomes (2)

• 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

• Incidence of Grades III-IV Acute GVHD

  Number of subjects who developed maximum grade acute graft-vs-host disease aGVHD Stages Skin: 1. \- a maculopapular eruption involving \< 25% BSA 2. \- a maculopapular eruption involving 25 - 50% BSA 3. \- generalized erythroderma 4. \- generalized erythroderma with bullous formation and often with desquamation Liver: 1. \- bilirubin 2.0 - 3.0 mg/100 mL 2. \- bilirubin 3 - 5.9 mg/100 mL 3. \- bilirubin 6 - 14.9 mg/100 mL 4. \- 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 Outcomes (2)

• Incidence of Transplant-related Mortality

  Up to Day 200

• Incidence of Adverse Events

  Up to Day 100

Study Arms (4)

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

EXPERIMENTAL

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; 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

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

EXPERIMENTAL

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; 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

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

EXPERIMENTAL

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; 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

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

EXPERIMENTAL

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; 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

Interventions

Allogeneic Bone Marrow Transplantation PROCEDURE

Undergo allogeneic bone marrow transplant

Also known as: Allo BMT, Allogeneic BMT

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)

Cyclophosphamide DRUG

Given IV

Also known as: (-)-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

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)

Cyclosporine DRUG

Given IV or PO

Also known as: 27-400, Ciclosporin, CsA, Cyclosporin, Cyclosporin A, Neoral, OL 27-400, Sandimmun, Sandimmune, SangCya

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)

Fludarabine Phosphate DRUG

Given IV

Also known as: 2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, Oforta, SH T 586

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)

Laboratory Biomarker Analysis OTHER

Correlative studies

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)

Mycophenolate Mofetil DRUG

Given PO

Also known as: Cellcept, MMF

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)

Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation PROCEDURE

Undergo allogeneic stem cell transplant

Also known as: Non-myeloablative allogeneic transplant, Nonmyeloablative Stem Cell Transplantation, NST

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)

Total-Body Irradiation RADIATION

Undergo TBI

Also known as: TOTAL BODY IRRADIATION, Whole-Body Irradiation

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)

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Fred Hutchinson Cancer Center: lead
• National Cancer Institute (NCI): collaborator
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (5)

Children's Hospital and Research Center at Oakland

Oakland, California, 94609-1809, United States

Location

Vanderbilt University/Ingram Cancer Center

Nashville, Tennessee, 37232, United States

Location

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Seattle, Washington, 98109, United States

Location

Children's Hospital of Wisconsin

Milwaukee, Wisconsin, 53201, United States

Location

Universidade Federal do Paraná

Curitiba, Paraná, 80060-000, Brazil

Location

MeSH Terms

Conditions

Fanconi Anemia

Interventions

Cyclophosphamide; Cyclosporine; Cyclosporins; fludarabine phosphate; Mycophenolic Acid; Whole-Body Irradiation

Condition Hierarchy (Ancestors)

Anemia, Hypoplastic, Congenital; Anemia, Aplastic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Congenital Bone Marrow Failure Syndromes; Bone Marrow Failure Disorders; Bone Marrow Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; DNA Repair-Deficiency Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Amino Acids, Peptides, and Proteins; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids; Radiotherapy; Therapeutics; Investigative Techniques

Results Point of Contact

• Title: Dr. Hans-Peter Kiem
• Organization: Fred Hutchinson Cancer Research Center

hkiem@fredhutch.org

206-667-4425

Study Officials

• Hans-Peter Kiem

  Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 27, 2007
• First Posted: March 28, 2007
• Study Start: February 1, 2007
• Primary Completion: June 1, 2013
• Study Completion: June 1, 2013
• Last Updated: January 29, 2020
• Results First Posted: May 24, 2017

Record last verified: 2019-12

Locations

US (4); BR (1)