TBI Dose De-escalation for Fanconi Anemia

• ClinicalTrials.gov Identifier: NCT00352976
• Recruitment Status: Completed
• First Posted: July 17, 2006
• Results First Posted: November 24, 2021
• Last Update Posted: November 24, 2021
• Sponsor: Masonic Cancer Center, University of Minnesota
• Information provided by (Responsible Party): Masonic Cancer Center, University of Minnesota

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Fanconi Anemia	Drug: Cyclophosphamide; Drug: Fludarabine; Procedure: Total Body Irradiation; Procedure: Bone Marrow Transplantation; Drug: Mycophenolate Mofetil; Drug: Sirolimus	Phase 2; Phase 3

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 83 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Total Body Irradiation Dose De-escalation Study in Patients With Fanconi Anemia Undergoing Alternate Donor Hematopoietic Cell Transplantation
• Actual Study Start Date: May 18, 2006
• Actual Primary Completion Date: October 9, 2020
• Actual Study Completion Date: October 9, 2020

Arms and Interventions

Arm

Intervention/treatment

Experimental: Treatment with TBI; Patients treated with total body irradiation, Fludarabine, Cyclophosphamide, Bone Marrow Transplantation, Mycophenolate Mofetil, and Sirolimus.

Drug: Cyclophosphamide; Day -5 through Day -2, subjects will receive chemotherapy of Cyclophosphamide via central line (i.e. Hickman or Broviac),10 mg/kg intravenously (IV); Other Name: cytoxan; Drug: Fludarabine; 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); Other Name: fludara; Procedure: Total 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.; Other Name: Radiation Therapy, Therapeutic radiation; Procedure: Bone 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.; Other Name: Stem Cell transplantation; Drug: Mycophenolate 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).; Other Name: MMF; Drug: Sirolimus; 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.; Other Name: Rapamycin

Outcome Measures

Primary Outcome Measures :

1. Number of Participant With Neutrophil Recovery [ Time Frame: 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 :

1. Number of Participants Experiencing Grade ≥3 Regimen Related Toxicity [ Time Frame: 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
2. Number of Participants With Secondary Graft Failure at 100 Days [ Time Frame: 100 days ]
   Secondary Graft Rejection by day 100
3. Number of Participants Experiencing Acute Graft-versus-host Disease (GVHD) [ Time Frame: at 100 days ]
   Number of participants experiencing acute GVHD (all grades) by day 100
4. Number of Participants Experiencing Chronic GVHD [ Time Frame: at one year ]
   Number of participants experiencing chronic Graft Vs Host Disease by 1 year
5. Number of Participants Experiencing Overall Survival [ Time Frame: at one year ]
   Number of participants experiencing overall survival by 1 year
6. Number of Participants Experiencing Infections by Day 100 [ Time Frame: by day 100 ]
7. Number of Participants Experiencing Infections by Day 180 [ Time Frame: by day 180 ]
8. Number of Participants Experiencing Infections by Day 365 [ Time Frame: by day 365 ]
9. Average Immunoglobulin G (IgG) Levels as a Measure of Immune Reconstitution After Transplant, by 100 Days [ Time Frame: by 100 days ]
10. Average IgG Levels as a Measure of Immune Reconstitution After Transplant, by 180 Days [ Time Frame: by 180 days ]
11. Average IgG Levels as a Measure of Immune Reconstitution After Transplant by 365 Days [ Time Frame: by 365 days ]
12. Average IgA Levels as a Measure of Immune Reconstitution After Transplant by 100 Days [ Time Frame: by 100 days ]
13. Average IgA Levels as a Measure of Immune Reconstitution After Transplant by 180 Days [ Time Frame: by 180 days ]
14. Average IgA Levels as a Measure of Immune Reconstitution After Transplant by 365 Days [ Time Frame: by 365 days ]
15. Average IgM Levels as a Measure of Immune Reconstitution After Transplant by 100 Days [ Time Frame: by 100 days ]
16. Average IgM Levels as a Measure of Immune Reconstitution After Transplant by 180 Days [ Time Frame: by 180 days ]
17. Average IgM Levels as a Measure of Immune Reconstitution After Transplant by 365 Days [ Time Frame: by 365 days ]

Eligibility Criteria

• Ages Eligible for Study: Child, Adult, Older Adult
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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).

Contacts and Locations

Locations

United States, Minnesota

University of Minnesota Medical Center

Minneapolis, Minnesota, United States, 55455

Sponsors and Collaborators

Masonic Cancer Center, University of Minnesota

Investigators

• Principal Investigator: Margaret L MacMillan, M.D.; University of Minnesota Medical Center

  Study Documents (Full-Text)

Documents provided by Masonic Cancer Center, University of Minnesota:

Study Protocol and Statistical Analysis Plan  [PDF] November 16, 2018

More Information

Additional Information:

Trial 4 listed in the article corresponds to this clinical trial. 

Publications:

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.

• Responsible Party: Masonic Cancer Center, University of Minnesota
• ClinicalTrials.gov Identifier: NCT00352976
• Other Study ID Numbers: MT2006-05; 0605M85788 ( Other Identifier: IRB, University of Minnesota )
• First Posted: July 17, 2006
• Results First Posted: November 24, 2021
• Last Update Posted: November 24, 2021
• Last Verified: October 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Masonic Cancer Center, University of Minnesota:

Bone Marrow transplant; stem cell transplant; cord blood transplant; total body irradiation; thymic shielding

Additional relevant MeSH terms:

Fanconi Syndrome; Anemia; Fanconi Anemia; Hematologic Diseases; Anemia, Hypoplastic, Congenital; Anemia, Aplastic; Congenital Bone Marrow Failure Syndromes; Bone Marrow Failure Disorders; Bone Marrow Diseases; Genetic Diseases, Inborn; DNA Repair-Deficiency Disorders; Metabolic Diseases; Renal Tubular Transport, Inborn Errors; Kidney Diseases; Urologic Diseases; Mycophenolic Acid; Sirolimus; Cyclophosphamide; Fludarabine; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Myeloablative Agonists; Antibiotics, Antineoplastic; Antibiotics, Antitubercular