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Antibody Conditioning Regimen For Allogeneic Donor Stem Cell Transplantation Of Patients With Fanconi Anemia (Mafia)

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ClinicalTrials.gov Identifier: NCT00590460
Recruitment Status : Terminated (slow accrual)
First Posted : January 10, 2008
Results First Posted : August 9, 2012
Last Update Posted : May 24, 2018
Sponsor:
Collaborators:
The Methodist Hospital Research Institute
Center for Cell and Gene Therapy, Baylor College of Medicine
Information provided by (Responsible Party):
Malcolm Brenner, Baylor College of Medicine

Study Description
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Brief Summary:
The purpose of this study is to discover whether children and adults with Fanconi anemia (FA) can be safely and effectively transplanted with Human Leukocyte Antigen (HLA) mismatched (up to one haplotype), HLA-matched sibling, or unrelated donor stem cells, when leukocytolytic monoclonal antibodies are the sole conditioning agents (patients receiving an HLA mismatched transplant will receive Fludarabine as part of the conditioning regimen). Three monoclonal antibodies (MAb) will be used in combination. Two of them, YTH 24 and YTH 54 are rat antibodies directed against two contiguous epitopes on the CD45 (common leucocyte) antigen. They have been safely administered as part of the conditioning regimen for 12 patients receiving allografts (HLA matched and mismatched) at this center. They produce a transient depletion of >90% circulating leucocytes. The third MAb is Campath 1H, a humanized rat anti-CD52 MAb. This MAb has been widely used to treat B cell chronic lymphocytic leukemia (B-CLL) and more recently has been safely given at this and other centers as part of a sub-ablative conditioning regimen to patients with malignant disease. Because these MAb produce both profound immunosuppression and significant, though transient, myelodestruction we believe they may be useful as the sole conditioning regimen in patients with Fanconi anemia, in whom the use of conventional chemotherapeutic agents for conditioning produces a high rate of short and long term toxicity. We anticipate MAb mediated subablative conditioning will permit engraftment in a high percentage of these patients with little or no immediate or long term toxicity. Campath IH persists in vivo for several days after administration and so will be present over the transplant period to deplete donor T cells as partial graft versus host disease (GvHD) prophylaxis. Additional GvHD prophylaxis will be provided by administration of the medication FK506.

Condition or disease Intervention/treatment Phase
Fanconi Anemia Severe Aplastic Anemia Biological: CAMPATH-1H Biological: Anti-CD45 Drug: Fludarabine Procedure: Stem cell infusion Phase 1 Phase 2

Detailed Description:

If clinically feasible (no aplasia, no active malignancy), the recipients marrow will be harvested and cryopreserved as a back up for use if non-engraftment/rejection is followed by failure to undergo autologous reconstitution.

For HLA Mismatched donors, harvested peripheral blood stem cells will be enriched for CD34 cells using the Clinimacs CD34 Reagent system.

Fludarabine will be given as 5 daily intravenous infusions. Campath-1H will be given as 3 daily intravenous infusions and will be followed by Anti-CD45 which will be given as four daily intravenous infusions that will be completed two days prior to stem cell infusion. Diphenydramine will be administered intravenously every 4 hours during the period of the course of each infusion.

Day -8 Campath 1H as per CAGT SOP Fludarabine 30 mg/m2 -7 Campath 1H as per CAGT SOP Fludarabine 30 mg/m2 -6 Campath 1H as per CAGT SOP 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 -0 Stem Cell Infusion

GVHD prophylaxis will be achieved through positive selection for CD34 resulting in > 3 log T cell depletion. Previous reports have indicated that there is a low frequency of severe (Grade II/IV) GvHD after haploidentical transplants if recipients receive stem cell populations containing <5 x 10e4 CD3 positive T cells. We hope to achieve such levels with our CD34 enrichment protocol. However, pharmacologic prophylaxis will be added if the CD34 selected product contains more than 5 x 10e4 CD3+ve T cells/kg recipient weight. In addition, Campath 1H persists in the recipient circulation through the immediate transplant period and will contribute anti-GVHD activity, in vivo.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 5 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : July 2001
Actual Primary Completion Date : September 2009
Actual Study Completion Date : September 2009

Resource links provided by the National Library of Medicine

Drug Information available for: Alemtuzumab

Arms and Interventions
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Arm Intervention/treatment
Experimental: Single Arm Study: Stem Cell Transplant
CAMPATH-1H Anti-CD45 Fludarabine Stem Cell Infusion
 Biological: CAMPATH-1H
Given intravenous on days -8, -7, and -6
Other Name: Alemtuzumab

Biological: Anti-CD45

Given intravenous on days -5, -4, -3 and -2

dose is 400 micrograms/kg


Drug: Fludarabine

Given intravenous on days -8, -7, -6, -5 and -4

Dose is 30 mg/m2


Procedure: Stem cell infusion
Stem cells are infused on day 0


Outcome Measures
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Primary Outcome Measures :
  1. Number of Patients With Donor Engraftment [ Time Frame: 100 Days ]
    Number of patients with engraftment of at least 65% of donor cells 100 days after transplantation


Secondary Outcome Measures :
  1. Number of Patients With Graft Failure [ Time Frame: 100 days ]
    Graft failure is defined as engraftment of less than 65% of donor cells 100 days after transplantation.

  2. Patients With Treated Related Death [ Time Frame: 100 days ]
    Number of patients with treated related death

  3. Days to Absolute Neutrophil Count (ANC) of 500/mm3 [ Time Frame: 30 Days ]
    Number of days to Absolute neutrophil count (ANC) of 500/mm3

  4. Days to Platelet Count of 20,000/mm3 Without Transfusions [ Time Frame: 30 Days ]
    Number of days to Platelet count of 20,000 / mm3 without transfusions

  5. Patients With Grade II - IV Acute Graft Versus Host Disease (GVHD) [ Time Frame: 100 days ]
    Number of patients with grade II - IV acute Graft versus Host Disease (GVHD)

  6. Number of Patients Alive at 1 Year Post Transplant [ Time Frame: 1 year ]
    Number of patients alive at 1 year post allogeneic stem cell transplant

  7. Patients With Limited Chronic GVHD From Day 100 to 365 [ Time Frame: 365 days ]
    Number of patients with limited chronic GVHD from day 100 to 365

  8. Patients With Extensive Chronic GVHD From Day 100 to 365 [ Time Frame: 365 days ]
    Number of patients with extensive chronic GVHD from day 100 to 365.

  9. Patients With Grade III - IV Acute GVHD [ Time Frame: 100 days ]
    Number of patients with Grade III-IV acute GVHD


Eligibility Criteria
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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Diagnosis of Fanconi Anemia or other suspected DNA breakage/chromosomal instability syndromes, such as dyskeratosis congenita or Nijmegen breakage syndrome of all ages are eligible.

Diagnosis of Fanconi anemia confirmed by studies of peripheral blood or bone marrow sensitivity to mitomycin C or DEB or clinical evidence of other DNA breakage/chromosomal instability syndrome as determined by genetic testing or clinical diagnosis by a geneticist

Severe aplasia anemia as evidenced by a hypocellular bone marrow and at least 1 of the 3 criteria below: ANC < 500/mm3 Hemoglobin < 10 gm/dl with reticulocyte count < 1% Platelet count < 50,000/mm3

Availability of an HLA matched or mismatched (up to one haplotype) family member who has been documented not to have Fanconi anemia or of an unrelated HLA matched stem cell donor. Fully matched is defined at 6/6 match by high resolution DR based DNA typing.

Life expectancy greater than 6 weeks limited by diseases other than FA

Creatinine 2X normal for age or less

Karnofsky score 70% or more

Exclusion Criteria:

Patients with symptomatic cardiac disease, or evidence of significant cardiac disease by echocardiogram (i.e., shortening fraction less than 25%).

Patients with known allergy to rat serum products.

Patients with a severe infection that on evaluation by the Principal Investigator precludes ablative chemotherapy or successful transplantation.

Patients with severe personality disorder or mental illness.

Patients with documented HIV positivity.

Pregnant

NOTE: Patients who would be excluded from the protocol strictly for laboratory abnormalities can be included at the investigator's discretion after approval by the CCGT Protocol Review Committee and the FDA Reviewer.

Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00590460


Locations
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United States, Texas
Methodist Hospital
Houston, Texas, United States, 77030
Texas Children's Hospital
Houston, Texas, United States, 77030
Sponsors and Collaborators
Baylor College of Medicine
The Methodist Hospital Research Institute
Center for Cell and Gene Therapy, Baylor College of Medicine
Investigators
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Principal Investigator: Malcolm Brenner, M.B., Ph.D., Baylor College of Medicine
More Information
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Responsible Party: Malcolm Brenner, Professor, Director Center for Cell and Gene Therapy, Baylor College of Medicine
ClinicalTrials.gov Identifier: NCT00590460    
Obsolete Identifiers: NCT00058565
Other Study ID Numbers: H-9938
First Posted: January 10, 2008    Key Record Dates
Results First Posted: August 9, 2012
Last Update Posted: May 24, 2018
Last Verified: April 2018
Keywords provided by Malcolm Brenner, Baylor College of Medicine:
Allogeneic Stem Cell Transplant
Fanconi Anemia
Severe Aplastic Anemia
 fludarabine
campath
anti-CD45
Additional relevant MeSH terms:
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Fanconi Syndrome
Anemia
Anemia, Aplastic
Fanconi Anemia
Hematologic Diseases
Bone Marrow Failure Disorders
Bone Marrow Diseases
Anemia, Hypoplastic, Congenital
Congenital Bone Marrow Failure Syndromes
Genetic Diseases, Inborn
 DNA Repair-Deficiency Disorders
Metabolic Diseases
Renal Tubular Transport, Inborn Errors
Kidney Diseases
Urologic Diseases
Fludarabine
Alemtuzumab
Antineoplastic Agents
Antineoplastic Agents, Immunological