Allogeneic SCT Of Pts With SCID And Other Primary Immunodeficiency Disorders

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Brief Title

Allogeneic SCT Of Pts With SCID And Other Primary Immunodeficiency Disorders

Official Title

CD45 and Alemtuzumab Monoclonal Antibody Conditioning Regimen For Allogeneic Donor Stem Cell Transplantation Of Patients With Severe Combined Immunodeficiency Disease (SCID) And Other Primary Immunodeficiency Disorders

Brief Summary

      This study is to discover whether children with severe combined immunodeficiency disease
      (SCID) or other primary immunodeficiency disorder (PID) for which no satisfactory treatment
      other than stem cell transplantation (SCT) exists can be safely and effectively transplanted
      from HLA mismatched (up to one haplotype) related donors or unrelated matched or mismatched
      (up to one antigen) donors, when leukocytolytic monoclonal antibodies (MAb) and Fludarabine
      are the sole conditioning agents. Three monoclonal antibodies will be used in combination.
      Two of them are rat IgG1 (immunoglobulin G1) 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. Campath 1H, Alemtuzumab, has been licensed
      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 SCID, in whom the use of conventional chemotherapeutic agents for
      conditioning may produce or aggravate unacceptable and even lethal short 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 GvHD prophylaxis. Additional Graft versus Host Disease
      (GvHD) prophylaxis may be provided by administration of FK506.
    

Detailed Description

      Donor Stem Cell Processing for Mismatched Donors: Harvested peripheral blood stem cells will
      be enriched for CD34 cells using the CliniMACS CD34 Reagent system, according to Center for
      Cell and Gene Therapy (CAGT) SOPs.

      Stem Cell Transplant Conditioning

      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 i.v. q4h during the period of the
      course of the Campath and Anti-CD45 infusions.

      Day

      8 Campath 1H as per CAGT SOP Fludarabine 10 kg or less: 1 mg/kg; > 10 kg: 30 mg/m2

      7 Campath 1H as per CAGT SOP Fludarabine 10 kg or less: 1 mg/kg; > 10 kg: 30 mg/m2

      6 Campath 1H as per CAGT SOP Fludarabine 10 kg or less: 1 mg/kg; > 10 kg: 30 mg/m2

      5 YTH 24/54 400ug/kg over 6 hr Fludarabine 10 kg or less: 1 mg/kg; > 10 kg: 30 mg/m2

      4 YTH 24/54 400ug/kg over 6 hr Fludarabine 10 kg or less: 1 mg/kg; > 10 kg: 30 mg/m2

      3 YTH 24/54 400ug/kg over 6 hr

      2 YTH 24/54 400ug/kg over 6 hr

      1 rest

      0 Stem Cell Infusion

      Campath 1H Infusion- Campath dose is weight based: for patients less than 15 killograms (kg)
      administer Campath 3 mg; for patients >15 kg to 30 kg administer Campath 5 mg; for patients >
      30 kg administer Campath 10 mg. Campath will be dosed and administered as per CAGT SOP.

      Anti-CD45- Infusion Anti-CD45 infusion will be administered according to CAGT SOPs. 3 ml of
      heparinized blood will be drawn 48 hr post Anti-CD45 to evaluate for free Anti-CD45 levels in
      the plasma. This estimation will be used to determine whether treatment with irradiated
      leukocytes is required before the bone marrow is infused.

      GVHD Prophylaxis- 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 10 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 10 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. Patients who develop acute or chronic
      GVHD will be managed according to CAGT SOPs.
    

Study Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

Number of Patients With Donor Engraftment

Secondary Outcome

 Patients Alive at 1 Year

Condition

Severe Combined Immunodeficiency Disease

Intervention

Campath -1H

Study Arms / Comparison Groups

 Participants With SCID or Primary Immunodeficiency Disorder
Description:  all patient will receive an allogeneic transplant with the following conditioning regimen Campath -1H, Fludarabine, Anti-CD45

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Biological

Estimated Enrollment

3

Start Date

October 2007

Completion Date

October 2009

Primary Completion Date

October 2009

Eligibility Criteria

        Inclusion Criteria:

        - Patients with a diagnosis of: Severe combined immunodeficiency disease

        This includes patients whose SCID is characterized by gene specific mutations as well as
        patients with clinically severe combined immunodeficiency without a defined genetic cause
        in which the diagnosis will be determined by a combination of clinical course with
        lymphocyte quantification and function assays.

        OR

        Severe primary immunodeficiency disorder, including undefined T cell deficiency disorder,
        Wiskott-Aldrich syndrome, and other severe immunodeficiencies for which satisfactory
        conventional therapy does not exist.

          -  Availability of an HLA mismatched (up to one haplotype) family member or an HLA
             matched or mismatched (up to one antigen) unrelated donor.

          -  Creatinine < 2.5 x normal for age.

          -  Life expectancy greater than 6 weeks

          -  Lansky/Karnofsky greater than or equal to 70%

        Exclusion Criteria:

          -  Patients with an HLA matched related donor

          -  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

          -  HIV positive

          -  Pregnant
      

Gender

All

Ages

N/A - N/A

Accepts Healthy Volunteers

No

Contacts

Robert Krance, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00579137

Organization ID

21123-MASCI


Responsible Party

Principal Investigator

Study Sponsor

Baylor College of Medicine

Collaborators

 Center for Cell and Gene Therapy, Baylor College of Medicine

Study Sponsor

Robert Krance, MD, Principal Investigator, Baylor College of Medicine


Verification Date

June 2013