TBI Dose De-escalation for Fanconi Anemia

This study is currently recruiting participants.
Verified December 2013 by Masonic Cancer Center, University of Minnesota
Sponsor:
Information provided by (Responsible Party):
Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier:
NCT00352976
First received: July 14, 2006
Last updated: December 18, 2013
Last verified: December 2013
  Purpose

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 Intervention Phase
Fanconi Anemia
Drug: Cyclophosphamide
Drug: Fludarabine
Procedure: Total Body Irradiation
Procedure: Bone Marrow Transplantation
Drug: Mycophenolate Mofetil
Drug: Sirolimus
Phase 2
Phase 3

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by Masonic Cancer Center, University of Minnesota:

Primary Outcome Measures:
  • Incidence of neutrophil recovery (absolute neutrophil count ≥500/µL for three consecutive days) . [ Time Frame: by day 42 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Incidence of grade ≥3 regimen related toxicity . [ Time Frame: at day 100 ] [ Designated as safety issue: Yes ]
  • Incidence of secondary graft failure at 100 days. [ Time Frame: 100 days ] [ Designated as safety issue: No ]
  • Incidence of acute graft-versus-host disease (GVHD) [ Time Frame: at 100 days. ] [ Designated as safety issue: No ]
  • Incidence of chronic GVHD . [ Time Frame: at one year ] [ Designated as safety issue: No ]
  • Probability of survival . [ Time Frame: at one year ] [ Designated as safety issue: No ]
  • Incidence of infections . [ Time Frame: at 100 days, 6 months and one year ] [ Designated as safety issue: No ]
  • Immune reconstitution . [ Time Frame: at 100 days, 6 month and one year ] [ Designated as safety issue: No ]

Estimated Enrollment: 100
Study Start Date: May 2006
Estimated Study Completion Date: May 2016
Estimated Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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

Genders Eligible for Study:   Both
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
Please refer to this study by its ClinicalTrials.gov identifier: NCT00352976

Contacts
Contact: Margaret L MacMillan, M.D. 612-626-2778 macmi002@umn.edu

Locations
United States, Minnesota
University of Minnesota Medical Center Recruiting
Minneapolis, Minnesota, United States, 55455
Contact: Margaret L MacMillan, M.D.    612-626-2778    macmi002@umn.edu   
Sponsors and Collaborators
Masonic Cancer Center, University of Minnesota
Investigators
Principal Investigator: Margaret L MacMillan, M.D. University of Minnesota Medical Center
  More Information

No publications provided

Responsible Party: Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier: NCT00352976     History of Changes
Other Study ID Numbers: MT2006-05, 0605M85788
Study First Received: July 14, 2006
Last Updated: December 18, 2013
Health Authority: United States: Food and Drug Administration

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:
Anemia
Fanconi Anemia
Fanconi Syndrome
Hematologic Diseases
Anemia, Hypoplastic, Congenital
Anemia, Aplastic
Bone Marrow Diseases
Genetic Diseases, Inborn
DNA Repair-Deficiency Disorders
Metabolic Diseases
Kidney Diseases
Urologic Diseases
Renal Tubular Transport, Inborn Errors
Metabolism, Inborn Errors
Cyclophosphamide
Mycophenolate mofetil
Fludarabine monophosphate
Sirolimus
Everolimus
Fludarabine
Mycophenolic Acid
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on April 14, 2014