TBI Dose De-escalation for Fanconi Anemia

Phase 2

Completed

Conditions: Fanconi Anemia

Interventions: Drug: Cyclophosphamide
Drug: Fludarabine
Procedure: Total Body Irradiation
Procedure: Bone Marrow Transplantation
Drug: Mycophenolate Mofetil
Drug: Sirolimus

Registration Number: NCT00352976

Lead Sponsor: Masonic Cancer Center, University of Minnesota

Brief Summary: This is a single arm, total body irradiation (TBI) trial. All patients will be prescribed TBI 300 cGy with the goal of evaluating secondary endpoints.

Detailed Description: Study Treatment: Patients will receive voriconazole (antifungal therapy) by mouth beginning 1 month prior to conditioning therapy, if possible. 1) The subject is to receive total body irradiation (300 cGy) with thymic shielding; it will be given six days before the stem cells are given (day -6). 2) Day -5 through Day -2, subjects will receive a chemotherapy regimen of Fludarabine and Cyclophosphamide via central line (i.e. Hickman or Broviac). Starting Day -3, patients will receive sirolimus therapy with a taper commencing on day +180 and also mycophenolate mofetil (MMF) through day +30 or for 7 days after engraftment, whichever day is later, if no acute graft-versus-host disease (GVHD). 4) If the subject is receiving bone marrow or "peripheral" stem cells (cells collected from the donor's arm via a cell separator), on the day of transplantation, the stem cells taken from the donor will be put into a machine which will separate the lymphocytes (the cells that cause graft-versus-host disease \[GVHD\]) from the stem cells. If the subject is receiving an umbilical cord blood, the lymphocytes will not be removed because the risk of GVHD is not as high. Otherwise all patients will receive the same treatment. The stem cells are given as an infusion into the subject's existing catheter over 1-2 hours on day 0.5. On the day after transplant (day +1) subjects will be given G-CSF to stimulate the growth of the transplanted cells. 6. While receiving treatment and until the subject's blood counts recover he/she will have daily blood tests, and several bone marrow biopsies and aspirates. After recovery, subjects will be seen once a month for a health assessment and blood tests until at least 3 months after the cells have been infused. Additional blood tests or assessments may be done as medically indicated.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 83

Inclusion Criteria

Meeting the definition of standard risk or high risk Fanconi anemia as defined in the next two sections:

Standard risk patients must be <18 years of age with a diagnosis of Fanconi anemia with aplastic anemia (AA), myelodysplastic syndrome without excess blasts, or high risk genotype as defined below:
- Aplastic anemia is defined as having at least one of the following when not receiving growth factors or transfusions:
  - platelet count <20 * 10^9/L
  - ANC <5 * 10^8/L
  - Hemoglobin <8 g/dL
- Myelodysplastic syndrome (MDS) with multilineage dysplasia with or without chromosomal anomalies
- High risk genotype (e.g. IVS-4 or exon 14 FANCC mutations, or BRCA1 or 2 mutations)
High risk patients must have one or more of the following high risk features:
- Advanced MDS (≥ 5% blast) or acute leukemia
- Require additional HSCT for graft failure
- History at any time of systemic fungal or gram negative infection
- Severe renal disease with a creatinine clearance <40 mL/min
- Age > 18 years
Very high risk patients must have Advanced MDS (≥ 5% blast) or acute leukemia after initial hematopoietic stem cell transplant (HSCT)
Patients must have an appropriate source of stem cells. Patients and donors will be typed for HLA-A, B, C and DRB1 using high resolution molecular typing.
Adequate major organ function including:
- Cardiac: ejection fraction >45%
- Hepatic: bilirubin, AST or ALT, ALP <5 x normal
- Karnofsky performance status >70% or Lansky >50 (if < 16 years of age)
Women of child-bearing age must be using adequate birth control and have a negative pregnancy test.
Written consent.

Exclusion Criteria

Available HLA-genotypically identical related donor in standard risk patients.
Active central nervous system (CNS) leukemia at time of study enrollment.
History of squamous cell carcinoma of the head/neck/cervix within previous 2 years.
Prior radiation therapy that prevents further total body irradiation (TBI).

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment with TBI	Total Body Irradiation	Patients treated with total body irradiation, Fludarabine, Cyclophosphamide, Bone Marrow Transplantation, Mycophenolate Mofetil, and Sirolimus.
Treatment with TBI	Bone Marrow Transplantation	Patients treated with total body irradiation, Fludarabine, Cyclophosphamide, Bone Marrow Transplantation, Mycophenolate Mofetil, and Sirolimus.
Treatment with TBI	Sirolimus	Patients treated with total body irradiation, Fludarabine, Cyclophosphamide, Bone Marrow Transplantation, Mycophenolate Mofetil, and Sirolimus.
Treatment with TBI	Cyclophosphamide	Patients treated with total body irradiation, Fludarabine, Cyclophosphamide, Bone Marrow Transplantation, Mycophenolate Mofetil, and Sirolimus.
Treatment with TBI	Fludarabine	Patients treated with total body irradiation, Fludarabine, Cyclophosphamide, Bone Marrow Transplantation, Mycophenolate Mofetil, and Sirolimus.
Treatment with TBI	Mycophenolate Mofetil	Patients treated with total body irradiation, Fludarabine, Cyclophosphamide, Bone Marrow Transplantation, Mycophenolate Mofetil, and Sirolimus.

Primary Outcome Measures

Name	Time	Method
Number of Participant With Neutrophil Recovery	by day 42	Number of participant with neutrophil recovery. Neutrophil recovery is defined as absolute neutrophil count ≥500/µL for three consecutive days

Secondary Outcome Measures

Name	Time	Method
Average IgM Levels as a Measure of Immune Reconstitution After Transplant by 180 Days	by 180 days
Number of Participants Experiencing Acute Graft-versus-host Disease (GVHD)	at 100 days	Number of participants experiencing acute GVHD (all grades) by day 100
Average IgA Levels as a Measure of Immune Reconstitution After Transplant by 100 Days	by 100 days
Average IgM Levels as a Measure of Immune Reconstitution After Transplant by 100 Days	by 100 days
Number of Participants Experiencing Grade ≥3 Regimen Related Toxicity	by day 100	Regimen related toxicities (RRT) include: significant hemorrhagic cystitis, pulmonary hemorrhage, interstitial pneumonitis, GI hemorrhage, renal failure, erythroderma, and severe hepatic veno-occlusive disease
Number of Participants Experiencing Infections by Day 100	by day 100
Number of Participants Experiencing Infections by Day 365	by day 365
Average Immunoglobulin G (IgG) Levels as a Measure of Immune Reconstitution After Transplant, by 100 Days	by 100 days
Average IgA Levels as a Measure of Immune Reconstitution After Transplant by 180 Days	by 180 days
Number of Participants Experiencing Chronic GVHD	at one year	Number of participants experiencing chronic Graft Vs Host Disease by 1 year
Number of Participants Experiencing Overall Survival	at one year	Number of participants experiencing overall survival by 1 year
Average IgG Levels as a Measure of Immune Reconstitution After Transplant, by 180 Days	by 180 days
Average IgM Levels as a Measure of Immune Reconstitution After Transplant by 365 Days	by 365 days
Number of Participants With Secondary Graft Failure at 100 Days	100 days	Secondary Graft Rejection by day 100
Number of Participants Experiencing Infections by Day 180	by day 180
Average IgG Levels as a Measure of Immune Reconstitution After Transplant by 365 Days	by 365 days
Average IgA Levels as a Measure of Immune Reconstitution After Transplant by 365 Days	by 365 days