TBI Dose De-escalation for Fanconi Anemia

Study Overview
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Brief Summary
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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
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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.

Official Title
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Total Body Irradiation Dose De-escalation Study in Patients With Fanconi Anemia Undergoing Alternate Donor Hematopoietic Cell Transplantation

Conditions
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Fanconi Anemia

Intervention / Treatment
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* Drug: Cyclophosphamide
* Drug: Fludarabine
* Procedure: Total Body Irradiation
* Procedure: Bone Marrow Transplantation
* Drug: Mycophenolate Mofetil
* Drug: Sirolimus


Participation Criteria
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Eligibility Criteria
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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).
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment with TBI<br>Patients treated with total body irradiation, Fludarabine, Cyclophosphamide, Bone Marrow Transplantation, Mycophenolate Mofetil, and Sirolimus. | Drug: Cyclophosphamide<br>* Day -5 through Day -2, subjects will receive chemotherapy of Cyclophosphamide via central line (i.e. Hickman or Broviac),10 mg/kg intravenously (IV)<br>* Other names: cytoxan;Drug: Fludarabine<br>* 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)<br>* Other names: fludara;Procedure: Total Body Irradiation<br>* 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.<br>* Other names: Radiation Therapy, Therapeutic radiation;Procedure: Bone Marrow Transplantation<br>* 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.<br>* Other names: Stem Cell transplantation;Drug: Mycophenolate Mofetil<br>* 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).<br>* Other names: MMF;Drug: Sirolimus<br>* 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.<br>* Other names: Rapamycin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | by day 42 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | by day 100 | 
| Number of Participants With Secondary Graft Failure at 100 Days | Secondary Graft Rejection by day 100 | 100 days | 
| Number of Participants Experiencing Acute Graft-versus-host Disease (GVHD) | Number of participants experiencing acute GVHD (all grades) by day 100 | at 100 days | 
| Number of Participants Experiencing Chronic GVHD | Number of participants experiencing chronic Graft Vs Host Disease by 1 year | at one year | 
| Number of Participants Experiencing Overall Survival | Number of participants experiencing overall survival by 1 year | at one year | 
| Number of Participants Experiencing Infections by Day 100 |  | by day 100 | 
| Number of Participants Experiencing Infections by Day 180 |  | by day 180 | 
| 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 IgG Levels as a Measure of Immune Reconstitution After Transplant, by 180 Days |  | by 180 days | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bone Marrow transplant, stem cell transplant, cord blood transplant, total body irradiation, thymic shielding