Use of Rft5-Dga to Deplete Alloreactive Cells for Pts With Fanconi Anemia After Haploidentical SCT (RAFHAS)

This study has been terminated.
(Poor accrual)
Sponsor:
Collaborators:
UTSW-Dallas
Center for Cell and Gene Therapy, Baylor College of Medicine
Information provided by (Responsible Party):
Malcolm Brenner, Baylor College of Medicine
ClinicalTrials.gov Identifier:
NCT00586274
First received: December 21, 2007
Last updated: March 3, 2014
Last verified: March 2014
  Purpose

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%.


Condition Intervention Phase
FANCONI ANEMIA
Procedure: CD34 selected haploidentical PBSCT
Drug: Fludarabine
Biological: T cell infusion
Biological: Campath 1h
Biological: anti-CD45
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Baylor College of Medicine:

Primary Outcome Measures:
  • Determine # of donor lymphocytes that can be given to recipients of haplo-SCT with FA after depletion of recipient-reactive T lymphocytes by ex-vivo tx with a fixed dose of RFT5-dgA immunotoxin, and will result in Grade III/IV GVHD of < / = 25%. [ Time Frame: 1 yr ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • To analyze immune reconstitution in these patients. [ Time Frame: 1 yr ] [ Designated as safety issue: No ]
  • To measure their overall and disease free survival, at 100 days and at 1 year after transplant. [ Time Frame: 1 yr ] [ Designated as safety issue: No ]

Enrollment: 1
Study Start Date: March 2002
Study Completion Date: July 2009
Primary Completion Date: July 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: CD34 selected haploidentical PBSCT
CD34 selected haploidentical PBSCT
Procedure: CD34 selected haploidentical PBSCT
Infusion of CD34 selected haploidentical PBSCT
Drug: Fludarabine
day -8 through day -4 Fludarabine 30 mg/m^2
Biological: T cell infusion

At least 30 days after the stem cell infusion, patients will be dosed with T cells. 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)

Biological: Campath 1h
10 mg iv over 4 hours day-8 through day-6
Biological: anti-CD45
anti-CD45 400 ug/kg over 6 hours day -5 through day -2

Detailed Description:

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)

  Eligibility

Ages Eligible for Study:   up to 64 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • At the time of eligibility for infusion of allodepleted T -cells patients must satisfy the criteria below:
  • Patients with Fanconi anemia of all ages with severe aplasia (as evidenced by hypocellular bone marrow) who lack a suitable conventional related (i.e. 5/6 or 6/6 related) or 5/6 or 6/6 unrelated donor with at least 2 out of 3 of the following: a) ANC < 500/mm3, b) reticulocytes < 1% c) platelets < 50,000/mm3
  • Diagnosis of Fanconi anemia confirmed by studies of peripheral blood or bone marrow sensitivity to mitomycinC or DEB prior to stem cell transplant. Have received a related haploidentical CD34-selected peripheral blood stem cell transplant with evidence of a full or partial hematopoietic donor chimerism (> 50%) in the peripheral blood.

Exclusion Criteria:

  • Patients with a life expectancy (< 6 weeks) limited by diseases other than FA
  • Patients with active GVHD > / = Grade II
  • Patients with severe renal disease (i.e. creatinine greater than 3 X normal for age)
  • Patients with severe hepatic disease (direct bilirubin greater than 3ug/dl or SGPT greater than 500ug/dl)
  • Patients with a severe intercurrent infection
  • Lansky scale < 60 or Karnofsky < 60
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00586274

Locations
United States, Texas
Texas Children's Hospital
Houston, Texas, United States, 77030
The Methodist Hospital
Houston, Texas, United States, 77030
Sponsors and Collaborators
Baylor College of Medicine
UTSW-Dallas
Center for Cell and Gene Therapy, Baylor College of Medicine
Investigators
Principal Investigator: Malcolm Brenner, MB, PhD Baylor College of Medicine
  More Information

No publications provided

Responsible Party: Malcolm Brenner, Professor, Baylor College of Medicine
ClinicalTrials.gov Identifier: NCT00586274     History of Changes
Other Study ID Numbers: H-11428
Study First Received: December 21, 2007
Last Updated: March 3, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Baylor College of Medicine:
Stem Cell Transplant
Anemia
Fanconi

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
Fludarabine
Fludarabine phosphate
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on September 16, 2014