Allogeneic SCT Of Pts With SCID And Other Primary Immunodeficiency Disorders

NCT ID: NCT00579137

Last Updated: 2013-07-02

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 3 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-10-31
• Study Completion Date: 2009-10-31

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.

Conditions

Severe Combined Immunodeficiency Disease; Severe Primary Immunodeficiency Disorder; Undefined T Cell Deficiency Disorder; Wiskott-Aldrick Syndrome

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Participants With SCID or Primary Immunodeficiency Disorder

all patient will receive an allogeneic transplant with the following conditioning regimen Campath -1H, Fludarabine, Anti-CD45

Group Type: EXPERIMENTAL

Campath -1H

Intervention Type: BIOLOGICAL

Given intravenous on Days -8,-7, and -6

Campath dose is weight based: for patients less than 15 kg the dose is 3 mg; for patients >15 kg to 30 kg the dose 5 mg; for patients > 30 kg the dose is 10 mg

Fludarabine

Intervention Type: DRUG

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

Dose is 30 mg/m2

Anti-CD45

Intervention Type: BIOLOGICAL

Given intravenous over 6 hours on Days -5,-4,-3, and -2

Dose is 400 microgram/kg

Stem cell infusion

Intervention Type: PROCEDURE

stem cells are infused on day 0

Interventions

Campath -1H

Given intravenous on Days -8,-7, and -6

Campath dose is weight based: for patients less than 15 kg the dose is 3 mg; for patients >15 kg to 30 kg the dose 5 mg; for patients > 30 kg the dose is 10 mg

Intervention Type: BIOLOGICAL

Fludarabine

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

Dose is 30 mg/m2

Intervention Type: DRUG

Anti-CD45

Given intravenous over 6 hours on Days -5,-4,-3, and -2

Dose is 400 microgram/kg

Intervention Type: BIOLOGICAL

Stem cell infusion

stem cells are infused on day 0

Intervention Type: PROCEDURE

Other Intervention Names

Alemtuzumab; Fludara

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

• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Center for Cell and Gene Therapy, Baylor College of Medicine

OTHER

Sponsor Role: collaborator

Baylor College of Medicine

OTHER

Sponsor Role: lead

Responsible Party

Robert Krance

Professor Pediatrics Hematology Oncology Center for Cell and Gene Therapy

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Robert Krance, MD

Role: PRINCIPAL_INVESTIGATOR

Baylor College of Medicine

Malcolm Brenner, MD

Role: STUDY_CHAIR

Baylor College of Medicine

Locations

Texas Children's Hospital

Houston, Texas, United States

Countries

United States

Other Identifiers

21123-MASCI

Identifier Type: -

Identifier Source: org_study_id

NCT00609258

Identifier Type: -

Identifier Source: nct_alias