FANCONI ANEMIA Clinical Trial
Official title:
A Phase I Study Evaluating The Use Of Rft5-Dga To Deplete Alloreactive Cells For Patients With Fanconi Anemia After Haploidentical Stem Cell Transplantation
While stem cell transplantation has proven an effective means of treating a wide variety of
diseases involving hematopoietic stem cells and their progeny, a shortage of donors has
proved a major impediment to the widest application of the approach. Until recently, only
MHC identical donors could be used with safety. Such donors were originally siblings or
other closely related family members. Over the past decade, the growth of allogeneic donor
panels has allowed transplantation with stem cells obtained from a volunteer donor panel.
While it is now possible to obtain HLA identical unrelated donor stem cells for
approximately 75% of individuals of Northern European backgrounds, the situation for most
other ethnic groups is much less satisfactory. Even when a matched donor can be found, the
elapsed time between commencing the search and collecting the stem cells usually exceeds
three months, a delay that may doom many of the neediest patients. Hence there has been
considerable interest in making use of HLA haploidentical family donors. Most individuals
have a first-degree relative who would be suitable for such protocols. Fanconi anemia (FA)
is an autosomal recessive disorder characterized by the development of progressive aplastic
anemia usually evident by about age seven years and often associated with various diverse
congenital anomalies such as short stature, microcephaly, radial anomalies, horseshoe
kidney, and cafe au lait spots.
This study will determine the number of donor lymphocytes that can be given to recipients of
haploidentical stem cell transplants with Fanconi anemia after depletion of
recipient-reactive T lymphocytes by ex-vivo treatment with a fixed dose of RFT5-dgA
immunotoxin, and will result in a rate of Grade III/IV GVHD of < / = 25%.
Patients will have received a haplo-identical stem cell transplant on our on-going study
"CD45 (YTH-24 and YTH-54) and CD52 (Campath 1H) Monoclonal Antibody Conditioning Regimen for
Allogeneic Donor Stem Cell Transplantation of Patients with Fanconi Anemia" (H-9938 IND#
7233) and will become eligible to receive allodepleted T Cells following engraftment. What
follows is a summary of the treatment plan including initial transplant phase as well as
generation and infusion of allodepleted T cells.
Preparative Regimen for Patients with Fanconi Anemia:
The study will be open to patients who received a haploidentical PBSCT on the MAFIA protocol
and for patients who failed to engraft and receive a second haploidentical transplants with
alternate conditioning consisting of ATG, Fludarabine, TBI (450cGY single dose) and Cytoxan.
In Outline MAFIA conditioning (primary conditioning regimen)
Day 8 Campath 1H 10mg iv over 4hr Fludarabine 30 mg/m2 7 Campath 1H 10mg iv over 4hr
Fludarabine 30 mg/m2 6 Campath 1H 10mg iv over 4hr Fludarabine 30 mg/m2 5 YTH 24/54 400ug/kg
over 6 hr Fludarabine 30 mg/m2
- 4 YTH 24/54 400ug/kg over 6 hr Fludarabine 30 mg/m2
- 3 YTH 24/54 400ug/kg over 6 hr
- 2 YTH 24/54 400ug/kg over 6 hr
- 1 Rest
- 0 CD34-selected PBSC infusion
Stem Cell Infusion: One day after the completion of pretransplant conditioning therapy (day
0), CD34+ cells will be infused through a central venous catheter as outlined in CAGT SOPs.
This study will begin with a dose of T cells known not to cause GvHD even in haploidentical
recipients, even when the T cells administered have not first been allodepleted. Dose
escalation will follow a traditional up and down method, but as results become available
they will be used to determine subsequent dose levels by the continual reassessment method.
Initially, 2 patients will be entered beginning at dose level 1. Each and every patient will
receive up to three additional injections of T cells at the same dose, at monthly intervals,
provided there is no evidence of grade 2 or higher GVHD, until total T cell numbers are >
1000/ul.
Dose level -1 (1 x 10^3 T cells/Kg); Dose level 1 (1 x 10^4 T cells/Kg); Dose level 2 (1 x
10^5 T cells/Kg); Dose level 3 (1 x 10^6 T cells/Kg); Dose level 4 (5 x 10^6 T cells/Kg)
;
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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