TBI Dose De-escalation for Fanconi Anemia

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

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.

Study Overview

• Status: Completed
• Conditions: Fanconi Anemia
• Intervention / Treatment: Drug: Cyclophosphamide; Drug: Fludarabine; Procedure: Total Body Irradiation; Procedure: Bone Marrow Transplantation; Drug: Mycophenolate Mofetil; Drug: Sirolimus

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 Type: Interventional
• Enrollment (Actual): 83
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University Of Minnesota Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: Rapamycin

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Masonic Cancer Center, University of Minnesota
• Investigators: Principal Investigator: Margaret L MacMillan, M.D., University Of Minnesota Medical Center

Publications and helpful links

General 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.

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (Actual): May 18, 2006
• Primary Completion (Actual): October 9, 2020
• Study Completion (Actual): October 9, 2020

Study Registration Dates

• First Submitted: July 14, 2006
• First Submitted That Met QC Criteria: July 14, 2006
• First Posted (Estimate): July 17, 2006

Study Record Updates

• Last Update Posted (Actual): November 24, 2021
• Last Update Submitted That Met QC Criteria: October 27, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: stem cell transplant; cord blood transplant; total body irradiation; Bone Marrow transplant; thymic shielding
• Additional Relevant MeSH Terms: Metabolic Diseases; Kidney Diseases; Urologic Diseases; Bone Marrow Diseases; Hematologic Diseases; Genetic Diseases, Inborn; DNA Repair-Deficiency Disorders; Anemia, Hypoplastic, Congenital; Anemia, Aplastic; Congenital Bone Marrow Failure Syndromes; Bone Marrow Failure Disorders; Renal Tubular Transport, Inborn Errors; Anemia; Fanconi Syndrome; Fanconi Anemia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Antitubercular Agents; Antibiotics, Antitubercular; Cyclophosphamide; Fludarabine; Mycophenolic Acid; Sirolimus
• Other Study ID Numbers: MT2006-05; 0605M85788 (Other Identifier: IRB, University of Minnesota)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No