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

Sponsors

Lead Sponsor: Masonic Cancer Center, University of Minnesota

Source Masonic Cancer Center, University of Minnesota
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.

Overall Status Recruiting
Start Date May 18, 2006
Completion Date December 2022
Primary Completion Date December 2022
Phase Phase 2/Phase 3
Study Type Interventional
Primary Outcome
Measure Time Frame
Incidence of neutrophil recovery (absolute neutrophil count ≥500/µL for three consecutive days) . by day 42
Secondary Outcome
Measure Time Frame
Incidence of grade ≥3 regimen related toxicity . at day 100
Incidence of secondary graft failure at 100 days. 100 days
Incidence of acute graft-versus-host disease (GVHD) at 100 days.
Incidence of chronic GVHD . at one year
Probability of survival . at one year
Incidence of infections . at 100 days, 6 months and one year
Immune reconstitution . at 100 days, 6 month and one year
Enrollment 120
Condition
Intervention

Intervention Type: Drug

Intervention Name: Cyclophosphamide

Description: Day -5 through Day -2, subjects will receive chemotherapy of Cyclophosphamide via central line (i.e. Hickman or Broviac),10 mg/kg intravenously (IV)

Arm Group Label: Treatment with TBI

Other Name: cytoxan

Intervention Type: Drug

Intervention Name: Fludarabine

Description: 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)

Arm Group Label: Treatment with TBI

Other Name: fludara

Intervention Type: Procedure

Intervention Name: Total Body Irradiation

Description: 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.

Arm Group Label: Treatment with TBI

Other Name: Radiation Therapy, Therapeutic radiation

Intervention Type: Procedure

Intervention Name: Bone Marrow Transplantation

Description: 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.

Arm Group Label: Treatment with TBI

Other Name: Stem Cell transplantation

Intervention Type: Drug

Intervention Name: Mycophenolate Mofetil

Description: 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).

Arm Group Label: Treatment with TBI

Other Name: MMF

Intervention Type: Drug

Intervention Name: Sirolimus

Description: 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.

Arm Group Label: Treatment with TBI

Other Name: Rapamycin

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).

Gender: All

Minimum Age: N/A

Maximum Age: N/A

Healthy Volunteers: No

Overall Official
Last Name Role Affiliation
Margaret L MacMillan, M.D. Principal Investigator University of Minnesota Medical Center
Overall Contact

Last Name: Margaret L MacMillan, M.D.

Phone: 612-626-2778

Email: [email protected]

Location
Facility: Status: Contact: University of Minnesota Medical Center Margaret L MacMillan, M.D. 612-626-2778 [email protected]
Location Countries

United States

Verification Date

January 2020

Responsible Party

Type: Sponsor

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 1
Arm Group

Label: Treatment with TBI

Type: Experimental

Description: Patients treated with total body irradiation, Fludarabine, Cyclophosphamide, Bone Marrow Transplantation, Mycophenolate Mofetil, and Sirolimus.

Study Design Info

Allocation: N/A

Intervention Model: Single Group Assignment

Primary Purpose: Treatment

Masking: None (Open Label)

Source: ClinicalTrials.gov