Clinical trial NCT00352976: TBI Dose De-escalation for Fanconi Anemia
Official title: Total Body Irradiation Dose De-escalation Study in Patients With Fanconi Anemia Undergoing Alternate Donor Hematopoietic Cell Transplantation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Fanconi Anemia
Keywords: Bone Marrow transplant
stem cell transplant
cord blood transplant
total body irradiation
thymic shielding
Lead sponsor: Masonic Cancer Center, University of Minnesota
Sponsor class: OTHER
First posted: 2006-07-17
Enrollment: 83
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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).

Primary outcomes:
measure: Number of Participant With Neutrophil Recovery
timeFrame: by day 42
Secondary outcomes:
measure: Number of Participants Experiencing Grade ≥3 Regimen Related Toxicity
timeFrame: by day 100
measure: Number of Participants With Secondary Graft Failure at 100 Days
timeFrame: 100 days
measure: Number of Participants Experiencing Acute Graft-versus-host Disease (GVHD)
timeFrame: at 100 days
measure: Number of Participants Experiencing Chronic GVHD
timeFrame: at one year
measure: Number of Participants Experiencing Overall Survival
timeFrame: at one year
measure: Number of Participants Experiencing Infections by Day 100
timeFrame: by day 100
measure: Number of Participants Experiencing Infections by Day 180
timeFrame: by day 180
measure: Number of Participants Experiencing Infections by Day 365
timeFrame: by day 365
measure: Average Immunoglobulin G (IgG) Levels as a Measure of Immune Reconstitution After Transplant, by 100 Days
timeFrame: by 100 days
measure: Average IgG Levels as a Measure of Immune Reconstitution After Transplant, by 180 Days
timeFrame: by 180 days
measure: Average IgG Levels as a Measure of Immune Reconstitution After Transplant by 365 Days
timeFrame: by 365 days
measure: Average IgA Levels as a Measure of Immune Reconstitution After Transplant by 100 Days
timeFrame: by 100 days
measure: Average IgA Levels as a Measure of Immune Reconstitution After Transplant by 180 Days
timeFrame: by 180 days
measure: Average IgA Levels as a Measure of Immune Reconstitution After Transplant by 365 Days
timeFrame: by 365 days
measure: Average IgM Levels as a Measure of Immune Reconstitution After Transplant by 100 Days
timeFrame: by 100 days
measure: Average IgM Levels as a Measure of Immune Reconstitution After Transplant by 180 Days
timeFrame: by 180 days
measure: Average IgM Levels as a Measure of Immune Reconstitution After Transplant by 365 Days
timeFrame: by 365 days
Other outcomes:
Locations:
city: Minneapolis
country: United States
facility: University of Minnesota Medical Center
state: Minnesota
Study officials:
affiliation: University of Minnesota Medical Center
name: Margaret L MacMillan, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: MacMillan ML, DeFor TE, Young JA, Dusenbery KE, Blazar BR, Slungaard A, Zierhut H, Weisdorf DJ, Wagner JE. Alternative donor hematopoietic cell transplantation for Fanconi anemia. Blood. 2015 Jun 11;125(24):3798-804. doi: 10.1182/blood-2015-02-626002. Epub 2015 Mar 30.