Fanconi Anemia
Conditions
Keywords
Bone Marrow transplant, stem cell transplant, cord blood transplant, total body irradiation, thymic shielding
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.
Interventions
DRUGCyclophosphamide
Day -5 through Day -2, subjects will receive chemotherapy of Cyclophosphamide via central line (i.e. Hickman or Broviac),10 mg/kg intravenously (IV)
DRUGFludarabine
Day -5 through Day -2 prior to transplant; subjects will receive chemotherapy of Fludarabine via central line (i.e. Hickman or Broviac),35 mg/m\^2 intravenous (IV)
PROCEDURETotal Body Irradiation
total body irradiation (300 cGy) with thymic shielding will be given six days before the stem cells are given (day -6). Thymic shielding is done by placing a piece of lead on the chest during the irradiation treatment so that the irradiation beams do not go to the thymus.
PROCEDUREBone Marrow Transplantation
A target of 5 \* 10\^6/kg and a minimum of 4 \* 10\^6 CD34+ cell/kg recipient weight will be collected by apheresis and used for transplant. In most cases this dose will be recovered in a single apheresis; however, a second or rarely third apheresis performed on the following days may be required to achieve the minimum dose.
DRUGMycophenolate Mofetil
Patients will receive MMF therapy beginning on day -3 through day +30 or for 7 days after engraftment, whichever day is later, if no acute graft-versus-host disease (GVHD). Engraftment is defined as 1st day of 3 consecutive days of absolute neutrophil count \[ANC\] \> 0.5 \* 10\^9/L. MMF will be given at a dose of 15 mg/kg/dose every 8 hours by mouth(to a maximum dose of 1 gram).
DRUGSirolimus
Sirolimus will be administered starting at day -3 with 8mg-12mg mg oral loading dose followed by single dose 4 mg/day with a target serum concentration of 3 to 12 mg/mL by high-performance liquid chromatography (HPLC). Levels are to be monitored 3 times/week in the first 2 weeks, weekly until day +60, and as clinically indicated until day +100 post-transplantation. In the absence of acute GVHD sirolimus may be tapered starting at day +100 and eliminated by day +180 post-transplantation.
Sponsors
Masonic Cancer Center, University of Minnesota
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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 With Secondary Graft Failure at 100 Days | 100 days | Secondary Graft Rejection by day 100 |
| Number of Participants Experiencing Acute Graft-versus-host Disease (GVHD) | at 100 days | Number of participants experiencing acute GVHD (all grades) by day 100 |
| 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 |
| Number of Participants Experiencing Infections by Day 100 | by day 100 | — |
| Average IgG Levels as a Measure of Immune Reconstitution After Transplant, by 180 Days | by 180 days | — |
| 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 | — |
| Average IgA Levels as a Measure of Immune Reconstitution After Transplant by 365 Days | by 365 days | — |
| Average IgM 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 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 Experiencing Infections by Day 180 | by day 180 | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment With TBI Patients treated with total body irradiation, Fludarabine, Cyclophosphamide, Bone Marrow Transplantation, Mycophenolate Mofetil, and Sirolimus. | 83 |
| Total | 83 |
Baseline characteristics
| Characteristic | Treatment With TBI |
|---|---|
| Age, Categorical <=18 years | 68 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 15 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 82 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 8 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants |
| Race (NIH/OMB) More than one race | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 66 Participants |
| Region of Enrollment Argentina | 1 participants |
| Region of Enrollment Canada | 2 participants |
| Region of Enrollment United States | 80 participants |
| Sex: Female, Male Female | 36 Participants |
| Sex: Female, Male Male | 47 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 13 / 83 |
| other Total, other adverse events | 75 / 83 |
| serious Total, serious adverse events | 4 / 83 |
Outcome results
Primary
Number of Participant With Neutrophil Recovery
Number of participant with neutrophil recovery. Neutrophil recovery is defined as absolute neutrophil count ≥500/µL for three consecutive days
Time frame: by day 42
Population: 1 patient not evaluable since deceased at day 5 post transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment With TBI | Number of Participant With Neutrophil Recovery | 78 Participants |
Secondary
Average IgA Levels as a Measure of Immune Reconstitution After Transplant by 100 Days
Time frame: by 100 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment With TBI | Average IgA Levels as a Measure of Immune Reconstitution After Transplant by 100 Days | 88.0 mg/dL | Standard Deviation 59.9 |
Secondary
Average IgA Levels as a Measure of Immune Reconstitution After Transplant by 180 Days
Time frame: by 180 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment With TBI | Average IgA Levels as a Measure of Immune Reconstitution After Transplant by 180 Days | 98.7 mg/dL | Standard Deviation 48.8 |
Secondary
Average IgA Levels as a Measure of Immune Reconstitution After Transplant by 365 Days
Time frame: by 365 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment With TBI | Average IgA Levels as a Measure of Immune Reconstitution After Transplant by 365 Days | 107.2 mg/dL | Standard Deviation 57 |
Secondary
Average IgG Levels as a Measure of Immune Reconstitution After Transplant, by 180 Days
Time frame: by 180 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment With TBI | Average IgG Levels as a Measure of Immune Reconstitution After Transplant, by 180 Days | 652.9 mg/dL | Standard Deviation 305.8 |
Secondary
Average IgG Levels as a Measure of Immune Reconstitution After Transplant by 365 Days
Time frame: by 365 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment With TBI | Average IgG Levels as a Measure of Immune Reconstitution After Transplant by 365 Days | 724.0 mg/dL | Standard Deviation 258 |
Secondary
Average IgM Levels as a Measure of Immune Reconstitution After Transplant by 100 Days
Time frame: by 100 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment With TBI | Average IgM Levels as a Measure of Immune Reconstitution After Transplant by 100 Days | 71.1 mg/dL | Standard Deviation 84.2 |
Secondary
Average IgM Levels as a Measure of Immune Reconstitution After Transplant by 180 Days
Time frame: by 180 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment With TBI | Average IgM Levels as a Measure of Immune Reconstitution After Transplant by 180 Days | 77.0 mg/dL | Standard Deviation 60.3 |
Secondary
Average IgM Levels as a Measure of Immune Reconstitution After Transplant by 365 Days
Time frame: by 365 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment With TBI | Average IgM Levels as a Measure of Immune Reconstitution After Transplant by 365 Days | 82.8 mg/dL | Standard Deviation 57.9 |
Secondary
Average Immunoglobulin G (IgG) Levels as a Measure of Immune Reconstitution After Transplant, by 100 Days
Time frame: by 100 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment With TBI | Average Immunoglobulin G (IgG) Levels as a Measure of Immune Reconstitution After Transplant, by 100 Days | 550.6 mg/dL | Standard Deviation 285.4 |
Secondary
Number of Participants Experiencing Acute Graft-versus-host Disease (GVHD)
Number of participants experiencing acute GVHD (all grades) by day 100
Time frame: at 100 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment With TBI | Number of Participants Experiencing Acute Graft-versus-host Disease (GVHD) | 15 Participants |
Secondary
Number of Participants Experiencing Chronic GVHD
Number of participants experiencing chronic Graft Vs Host Disease by 1 year
Time frame: at one year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment With TBI | Number of Participants Experiencing Chronic GVHD | 6 Participants |
Secondary
Number of Participants Experiencing Grade ≥3 Regimen Related Toxicity
Regimen related toxicities (RRT) include: significant hemorrhagic cystitis, pulmonary hemorrhage, interstitial pneumonitis, GI hemorrhage, renal failure, erythroderma, and severe hepatic veno-occlusive disease
Time frame: by day 100
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment With TBI | Number of Participants Experiencing Grade ≥3 Regimen Related Toxicity | 71 Participants |
Secondary
Number of Participants Experiencing Infections by Day 100
Time frame: by day 100
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment With TBI | Number of Participants Experiencing Infections by Day 100 | 53 Participants |
Secondary
Number of Participants Experiencing Infections by Day 180
Time frame: by day 180
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment With TBI | Number of Participants Experiencing Infections by Day 180 | 55 Participants |
Secondary
Number of Participants Experiencing Infections by Day 365
Time frame: by day 365
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment With TBI | Number of Participants Experiencing Infections by Day 365 | 56 Participants |
Secondary
Number of Participants Experiencing Overall Survival
Number of participants experiencing overall survival by 1 year
Time frame: at one year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment With TBI | Number of Participants Experiencing Overall Survival | 70 Participants |
Secondary
Number of Participants With Secondary Graft Failure at 100 Days
Secondary Graft Rejection by day 100
Time frame: 100 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment With TBI | Number of Participants With Secondary Graft Failure at 100 Days | 4 Participants |